Update in Pediatrics 2018 PDF

Shalea Piteau
Editor
Update
in Pediatrics
123
FB:Cardiologia Siglo XXI
Update in Pediatrics

Shalea Piteau
Editor
Update in Pediatrics

Editor
Shalea Piteau
Chief/Medical Director of Pediatrics at Quinte Health Care
Assistant Professor at Queen’s University
Belleville, ON
Canada
ISBN 978-3-319-58026-5 ISBN 978-3-319-58027-2 (eBook)

https://doi.org/10.1007/978-3-319-58027-2
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© Springer International Publishing AG, part of Springer Nature 2018

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Preface
Pediatrics is evolving with new advancements in knowledge, research, and

technology, making it challenging to keep up-to-date with current informa-
tion. This concise and comprehensive volume provides a review of the latest
advances and current literature in Pediatrics, so health professionals can get a
summarized overview of the different subspecialties in Pediatrics. Update in
Pediatrics includes chapters ranging from traditional disciplines such as
Infectious Disease and Cardiology, to more current disciplines such as
Adolescent Medicine and Child Maltreatment. The target audience for this
book includes any practitioner who cares for children, including pediatri-
cians, family doctors, nurses and nurse practitioners, allied health profession-
als, and health researchers. My hope is that Update in Pediatrics will serve as
a valuable resource for the busy clinician who wishes to stay up-to-date with
the latest advances in the field.
ON, Canada Shalea Piteau

Contents
1 Update in Adolescent Medicine�� 1

Raina V. Voss and Emily Ruedinger
2 Update in Pediatric Allergy�� 39
Amanda Ciccolini, Shannon French, Mark Tenn,
and Anne K. Ellis
3 Update in Pediatric Cardiology�� 61
Jane Lougheed and Jenna Ashkanase
4 Update in Child Maltreatment�� 83
Michelle G.K. Ward, Amy E. Ornstein, Tanya Deurvorst
Smith, and Karla Wentzel
5 Update in Pediatric Critical Care�� 117
Lisa A. DelSignore, Traci A. Wolbrink, and Niranjan Kissoon
6 Update in Development: Section A—Infant Development�� 133
Madhavi Moharir and Chaya Kulkarni
7 Update in Development: Section B—Autism
Spectrum Disorder�� 207
R.G. Smith and D. Samdup
8 Update in Pediatric Emergency Medicine:
Pediatric Resuscitation, Pediatric Sepsis,
Interfacility Transport of the Pediatric Patient,
Pain and sedation in the Emergency Department,
Pediatric Trauma �� 223
Tania Principi, Deborah Schonfeld, Laura Weingarten, Suzan
Schneeweiss, Daniel Rosenfield, Genevieve Ernst, Suzanne
Schuh, and Dennis Scolnik
9 Update in Pediatric Endocrinology�� 251
Seth D. Marks and Brandy A. Wicklow
10 Update in Pediatric Gastroenterology, Hepatology
and Nutrition�� 267
A. Jay Freeman, Tatyana Hofmekler, John-Paul Berauer,
and Sirish Palle
vii

viii Contents
11 Update in Pediatric Hematology�� 313

Ziad Solh, Anthony K.C. Chan, and Mihir D. Bhatt
12 Update in Pediatric Hospital Medicine�� 331
Elizabeth J.N. Davis and Ricardo Quinonez
13 Update in Pediatric Infectious Disease�� 349
Archana Chatterjee and Maya Gogoi
14 Update in Clinical Genetics and Metabolics�� 369
Christine M. Armour and Matthew A. Lines
15 Update in Pediatric Nephrology �� 391
Darcy Weidemann and Martin Bitzan
16 Update in Neonatology�� 415
Faiza Khurshid and Imtiaz Ahmad
17 Update in Pediatric Neurology�� 439
Andrea Andrade and Asuri N. Prasad
18 Update in Pediatric Oncology: Section A-New
Developments in the Treatment of Pediatric
Acute Lymphoblastic Leukemia �� 461
Shannon L. Maude and Stephen P. Hunger
19 Update in Pediatric Oncology: Section B—Solid
Tumors of Childhood �� 485
Allison F. O’Neill
20 Update in Pediatric Psychiatry �� 513
Sabina Abidi
21 Update in Pediatric Rheumatology�� 537
Roberta A. Berard and Ronald M. Laxer
Index�� 553

Contributors
Sabina Abidi, M.D., F.R.C.P.C. Department of Psychiatry at IWK, Halifax,

NS, Canada
Imtiaz Ahmad, M.B.B.S., M.Sc. Department of Biomedical and Molecular
Sciences, Queen’s University, Kingston, ON, Canada
Andrea Andrade Department of Neurology, LHSC, London, UK
Christine M. Armour, M.D., M.Sc., F.R.C.P.C. Regional Genetics Unit,
Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
Jenna Ashkanase Division of Pediatric Cardiology, Department of
Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa,
Ottawa, ON, Canada
Roberta A. Berard Division of Rheumatology, Department of Paediatrics,
Children’s Hospital, London Health Sciences Centre, Western University,
London, ON, Canada
John-Paul Berauer Division of Pediatric Gastroenterology, Emory School
of Medicine, Atlanta, GA, USA
Mihir D. Bhatt, B.H.Sc., M.D., F.R.C.P.C. Pediatric Hematology/
Oncology, McMaster Children’s Hospital, McMaster University, Hamilton,
ON, Canada
Martin Bitzan Division of Nephrology, Department of Pediatrics, McGill
University Health Center, Montreal Children’s Hospital, Montreal, QC,
Canada
Anthony K.C. Chan, M.B.B.S., F.R.C.P.C. Division of Hematology/
Oncology, Department of Pediatrics, McMaster University, Hamilton, ON,
Canada
Archana Chatterjee, M.D., Ph.D. Department of Pediatrics, University of
South Dakota Sanford School of Medicine, Vermillion, SD, USA
Amanda Ciccolini, M.D. Queen’s University, Kingston, ON, Canada
Elizabeth J.N. Davis, M.D., F.A.A.P. Division of Pediatric Hospital
Medicine, Department of Pediatrics, Baylor College of Medicine, Houston,
TX, USA
The Children’s Hospital of San Antonio, San Antonio, TX, USA
ix

x Contributors
Lisa A. DelSignore, M.D. Division of Critical Care Medicine, Department

of Anesthesia, Perioperative and Pain Management, Boston Children’s
Hospital, Harvard Medical School, Boston, MA, USA
Anne K. Ellis, M.D., M.Sc., F.R.C.P.C. Queen’s University, Kingston, ON,
Canada
Division of Allergy and Immunology, Department of Medicine,
Queen’s University, Kingston, ON, Canada
Genevieve Ernst Department of Pediatrics, Division of Pediatric Emergency
Medicine, University of Toronto, Toronto, ON, Canada
A. Jay Freeman Division of Pediatric Gastroenterology, Emory School of
Medicine, Atlanta, GA, USA
Shannon French, M.D. Queen’s University, Kingston, ON, Canada
Maya Gogoi Department of Pediatrics, University of South Dakota Sanford
School of Medicine, Vermillion, SD, USA
Tatyana Hofmekler Division of Pediatric Gastroenterology, Emory School
of Medicine, Atlanta, GA, USA
Stephen P. Hunger Division of Oncology and Center for Childhood Cancer
Research, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Department of Pediatrics, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, PA, USA
Faiza Khurshid, M.D., F.C.P.S., M.Sc. (H.Q.) Department of Pediatrics,
Niranjan Kissoon, M.D. Division of Critical Care and the Child and Family
Research Institute, Department of Pediatrics, British Columbia’s Children’s
Hospital, University of British Columbia, Vancouver, BC, Canada
Chaya Kulkarni Infant Mental Health Promotion, HSC, Toronto, ON,
Canada
Ronald M. Laxer, M.D.C.M., F.R.C.P.C. Division of Rheumatology, The
Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Matthew A. Lines, M.D., M.Sc., F.R.C.P.C. Metabolics, Clinical
Biochemical Geneticist, Children’s Hospital of Eastern Ontario, Ottawa, ON,
Canada
Jane Lougheed Division of Pediatric Cardiology, Department of Pediatrics,
Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON,
Canada
Seth D. Marks Pediatric Endocrinology and Metabolism, University of
Manitoba, Winnipeg, MB, Canada
Shannon L. Maude Division of Oncology and Center for Childhood Cancer
Research, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Department of Pediatrics, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, PA, USA

Contributors xi
Madhavi Moharir Infant Mental Health Promotion, HSC, Toronto, ON,

Canada
Allison F. O’Neill, M.D. Department of Pediatrics, Division of Pediatric
Emergency Medicine, University of Toronto, Toronto, ON, Canada
Amy E. Ornstein, M.D.C.M., M.Sc., F.R.C.P.C., F.A.A.P. Department of
Pediatrics, Dalhousie University, Halifax, NS, Canada
Sirish Palle Division of Pediatric Gastroenterology, Emory School of
Medicine, Atlanta, GA, USA
Asuri N. Prasad Department of Neurology, LHSC, London, UK
Tania Principi Department of Pediatrics, Division of Pediatric Emergency
Medicine, University of Toronto, Toronto, ON, Canada
Ricardo Quinonez, M.D. Division of Pediatric Hospital Medicine,
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Texas Children’s Hospital, Houston, TX, USA
Daniel Rosenfield Department of Pediatrics, Division of Pediatric
Emily Ruedinger, M.D. Division of Adolescent Medicine, Department of
Pediatrics, Seattle Children’s Hospital and University of Washington, Seattle,
WA, USA
D. Samdup KidsInclusive Centre for Child and Youth Development, Hotel
Dieu Hospital, Kingston, ON, Canada
Suzan Schneeweiss, M.D., M.Ed., F.R.C.P.C Department of Pediatrics,
Division of Pediatric Emergency Medicine, University of Toronto, Toronto,
ON, Canada
Suzanne Schuh, M.D., F.R.C.P.(C.), F.A.A.P. Division of Paediatric
Emergency Medicine, Research Institute, Hospital for Sick Children,
University of Toronto, Toronto, ON, Canada
Deborah Schonfeld Department of Pediatrics, Division of Pediatric
Dennis Scolnik, F.R.C.P.(C.), D.C.H., M.Sc. Department of Paediatrics,
Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Divisions of Paediatric Emergency Medicine and Clinical Pharmacology and
Toxicology, The Hospital for Sick Children, Toronto, ON, Canada
R.G. Smith KidsInclusive Centre for Child and Youth Development, Hotel
Dieu Hospital, Kingston, ON, Canada
Tanya Deurvorst Smith, M.N., N.P.-Paediatrics The Suspected Child
Abuse and Neglect (SCAN) Program, The Hospital for Sick Children,
Toronto, ON, Canada

xii Contributors
Adjunct Lecturer, Lawrence S. Bloomberg Faculty of Nursing, The University

of Toronto, Toronto, ON, Canada
Ziad Solh, M.D., M.Sc., F.R.C.P.C. Department of Pathology and Molecular
Medicine, McMaster University, Hamilton, ON, Canada
Division of Hematology/Oncology, Department of Pediatrics, McMaster
University, Hamilton, ON, Canada
Medical Services and Innovation, Canadian Blood Services, Hamilton, ON,
Canada
Mark Tenn, B.H.Sc., M.Sc. Candidate Queen’s University, Kingston, ON,
Canada
Raina V. Voss, M.D. Division of Adolescent Medicine, Department of
Pediatrics, Seattle Children’s Hospital and University of Washington, Seattle,
WA, USA
Michelle G.K. Ward, M.D., F.A.A.P., F.R.C.P.C. Department of Pediatrics,
University of Ottawa and Children’s Hospital of Eastern Ontario, Ottawa,
ON, Canada
Darcy Weidemann Section of Pediatric Nephrology, Department of
Pediatrics, University of Missouri – Kansas City School of Medicine,
Children’s Mercy Hospital and Clinics, Kansas City, MO, USA
Laura Weingarten Pediatric Emergency Physician and Assistant Clinical
Professor, Department of Pediatrics, McMaster University, Hamilton, ON,
Canada
Karla Wentzel, M.N., N.P.-Paediatrics The Suspected Child Abuse and
Neglect (SCAN) Program, The Hospital for Sick Children, Toronto, ON, Canada
Adjunct Clinical Appointment, Lawrence S. Bloomberg Faculty of Nursing,
The University of Toronto, Toronto, ON, Canada
Brandy A. Wicklow Pediatric Endocrinology and Metabolism, University
of Manitoba, Winnipeg, MB, Canada
Traci A. Wolbrink, M.D., M.P.H. Division of Critical Care Medicine,
Department of Anesthesia, Perioperative and Pain Management, Boston
Children’s Hospital, Harvard Medical School, Boston, MA, USA

Update in Adolescent Medicine
1
Raina V. Voss and Emily Ruedinger
Introduction including healthcare. Providers can help shep-

herd adolescents and their caregivers more suc-
Adolescence is a time of enormous physical, cog- cessfully through this transition by understanding
nitive, social and emotional transformation rec- the developmental nuance of adolescence, and by
ognized as a distinct developmental stage across communicating with youth and their caregivers
cultures. This period of rapid change is perhaps in a sensitive manner. In this chapter, we will
rivaled only by the changes that occur in infancy. touch upon topics for which healthcare providers
Chronologically, it can be difficult to definitively in general have developed new or more detailed
define, but roughly occurs from around the age of understanding over the past decade. Topics
onset of secondary sexual characteristics (roughly include development, interviewing, substance
age 9 or 10) through the early 20s. Adolescence use, reproductive health, sexual and gender iden-
has historically been categorized as a stormy tity, technology and media, and transitioning to
time, but in fact most adolescents transition from adult healthcare.
childhood to adulthood smoothly, maintaining
generally healthy behaviors and good relation-
ships with their caregivers (Christie and Viner
2005; Hazen et al. 2008). Adolescent Development
Because adolescence is a distinct develop-
mental stage, caregivers are also presented with Adolescence is commonly divided into three
some challenges that are unique to this popula- phases: early, middle and late. Though there are
tion. As youth transition from childhood to adult- not exact age cutoffs for each of these stages, in
hood, they take on increasingly active roles as typically developing individuals early adoles-
autonomous decision-makers in many arenas, cence is roughly ages 10–13 (the middle school
years in the United States); middle adolescence
encompasses roughly ages 14–17 (the high
school years); and late adolescence is from ages
18 through the early 20s (late high school
through the next 4 years or so). The end of ado-
R.V. Voss, M.D. (*) • E. Ruedinger, M.D.
Division of Adolescent Medicine, Department of lescence is generally marked by attainment of
Pediatrics, Seattle Children’s Hospital and University independent adult behaviors rather than a numer-
of Washington, 4540 Sand Point Way NE, Seattle, ical indicator, though there remains a good deal
WA 98105, USA of controversy over this endpoint. Conversation
e-mail: raina.voss@seattlechildrens.org;
emily.ruedinger@seattlechildrens.org in the lay community about “prolonged adoles-
© Springer International Publishing AG, part of Springer Nature 2018 1

S. Piteau (ed.), Update in Pediatrics, https://doi.org/10.1007/978-3-319-58027-2_1

2 R.V. Voss and E. Ruedinger
cence” of the current generation abounds—sim- domains can develop in a dyssynchronous man-
ply enter the term into any search engine to come ner, and development often does not occur in a
up with myriad articles and opinions. While linear fashion. Further, development along these
there is evidence to substantiate the assertion domains is context- and culture-dependent; con-
that traditional markers used to signify transition sidering context and culture is, in many regards,
into adulthood (e.g., living independently from more important than chronology when determin-
childhood family unit, finishing schooling, first ing whether or not a youth’s development is nor-
job, entering into marriage or stable partnership, mal. See Table 1.1 for a summary of important
childbearing) have shifted later in the life course, cognitive, social and emotional developmental
many experts in the field contend that this shift considerations for early, middle and late
should not necessarily be viewed in a negative adolescents.
light and may have a neutral or even positive In general, adolescents in all stages of devel-
impact (Hayford and Furstenberg 2008; opment have a reputation for taking more risks
Steinberg 2014). than adults. Imaging studies have shown that
While much of the commentary on prolonged adolescents have particularly active reward cen-
adolescence refers to cognitive, social and emo- ters; youth often perceive similar, or at times
tional development, concern about earlier physi- even greater, levels of risks as adults. However,
cal development, particularly among girls, has the potential reward, or benefit, to engaging in
also been raised. The age of onset of Tanner 2 many behaviors is perceived as greater among
breast development may have declined negligibly adolescents than among adults. Thus, adoles-
over recent years, though increased adipose tissue cents’ perception of risk-to-benefit ratios is
may be mistaken for early breast development and skewed compared to adults (Sanders 2013;
confound the issue (Walvoord 2010). The age of Ahmed et al. 2015; Chick and Reward processing
menarche, which is probably a better marker of in the adolescent brain: individual differences
true pubertal timing, has, indeed, declined in and relation to risk taking 2015). Because teens
modern times—but the importance of this is are particularly sensitive to their peers, they are
unclear, particularly when taken in a broader his- also generally more likely to participate in risky
torical context. During the industrial revolution, behaviors when surrounded by peers than if they
often used as a marker for the beginning of “mod- are alone (Ahmed et al. 2015; Chick 2015).
ern times,” menarche was delayed relative to pre- Although there does appear to be a population-
vious eras. This was likely due to remarkably level correlation between greater reward percep-
poor living and sanitation conditions. With tion and increasing risk taking behavior, the
improved living conditions over the past century, causality of this relationship has not been firmly
the current age of menarche has become relatively established and remains an area of ongoing
re-aligned with historical norms from eras prior to research; some studies show that adolescents
the industrial revolution (Papadimitriou 2016). who perceive the greatest reward are not neces-
Furthermore, the age of menarche seems to gener- sarily the same ones who take the greatest risk
ally have stabilized over the past half-century (Chick 2015).
(Walvoord 2010; Papadimitriou 2016). A com- Functional MRI studies have started to pro-
plete review of physical developmental mile- vide greater insight into how physiologic devel-
stones is beyond the scope of this chapter, but can opmental changes may correspond with
be readily found elsewhere (Rosen 2004; cognitive, psychosocial and emotional develop-
American Academy of Pediatrics Section on ment. In general, gray matter in the frontal lobes
Endocrinology 2015). peaks around early adolescence and declines
With regard to cognitive, social and emotional over middle and late adolescence, with increas-
development, there are fewer outwardly visible ing white matter over the same timeframe. This
markers to help clinicians determine a patient’s may represent synaptic proliferation early in
stage of development. These developmental adolescence followed by synaptic pruning

Table 1.1 Cognitive, psychosocial and emotional changes throughout adolescence (Christie and Viner 2005; Hazen et al. 2008; Sanders 2013; Dixon and Stein 2006)
Early (10–13 years old) Middle (14–17 years old) Late (18 years old–early/mid 20s)
Cognitive Concrete and Literal: Youth in this stage Abstract Thinking: Many teens this age have Maturing Prefrontal Cortex: The prefrontal cortex is
remain very concrete. They often have just developed the ability to introspect and have still developing during this stage, but executive
difficulty answering vague questions, such more “big concept” understanding—this allows function and future thinking is more mature. Often
1 Update in Adolescent Medicine
as, “Tell me about yourself.” More concrete middle adolescents to begin exploring concepts young people in this stage of development are able
questions, like “What did you do such as spirituality and love at a personal level, to participate in deep conversations about abstract
yesterday?” will likely be more comfortable and grasp advanced academic concepts such as topics and draw complex connections. Developing
for these kids and yield more information. allegory or calculus. Development of abstract this ability is exciting and young people in this age
Adolescents this age may be more likely to thinking may also contribute to increased group are often great activists and can be quite
perceive the interview as a test of sorts, egocentrism. Executive functioning remains passionate. “Gray” areas can still be challenging
with right or wrong answers, and provide poor, with relatively low ability to understand when it comes to morals and values—many older
the answer that they think will please the long-term consequences or impact of actions adolescents are often still concrete about what is
clinician. They often have difficulty on others; on organizing tasks; and on right and wrong from a big-picture perspective. For
organizing tasks, and usually still need self-control. However, this is often better than example, it may be hard for them to recognize why
concrete directions. They may perceive it is in an early adolescent. It can also vary by it may ever be acceptable for a politician to act in a
questions about their peers as more task or domain. This seeming ability to think way that they feel is “immoral”
conversational and less threatening than long-term in some areas but not others can be
direct, sensitive questioning (for example, frustrating to parents and clinicians. However,
asking “Are any of your friends doing the ability to think toward the future develops
XYZ…” and then asking, “What about over time. This apparent ability to apply this
you? Have you tried XYZ?”). Early sort of reasoning and executive functioning in

adolescents tend to have very little one area but not another often represents that
understanding of future consequences of they are progressing along this continuum,
their current actions rather than a deliberate choice to ‘understand’
the future in one area but not in another
(continued)
3
4
Table 1.1 (continued)
Early (10–13 years old) Middle (14–17 years old) Late (18 years old–early/mid 20s)
Psychosocial Establishing identity separate from family: Refining Self-Image: The bid for independence Time of Transition: This is a time when many teens
Early adolescents are just starting to view extends beyond appearance and into arenas transition away from their prior family and/or school
themselves as separate from their family. such as political views and philosophical roles, moving on to college, work, independent
They often “try on” different personas, opinions. Teens expressing value systems that living, and/or the military. Many young people are
often still in a very literal sense (for differ from those of their family might be preoccupied with vocation—what will come next?
example, by changing outward appearance). distressing to parents, however most (but not
They will usually start to test limits with all!) youth actually return to the values parents
parents; they still desire support, but this promoted in earlier childhood once they
can create an internal sense of conflict with emerge from this phase. Many mid-adolescents
their desire for independence. As a result, start to recognize the ‘gray’ area around
some teens act resistant. They are still morals, politics, etc., but this skill is still
usually very concrete about rules, values undeveloped as well. They might understand
and morals—things are very black and that there is a gray area (for example, that
white; something is good or bad, with little people have a variety of religious preferences,
room for middle ground, gray area, or and that there can be positive and negative
understanding nuance aspects of various religions) but tend to be
relatively rigid in their own beliefs (for
example, “I am an atheist and cannot go to
church with my grandmother because it is
against my religion,” even if it would mean a
lot to the grandparent)
Emotional Importance of Peers: Starting to separate Deeper Peer Relationships and Romance: Most Clearer Sense of Self: Dependence on peers starts to
from the family unit is emotionally mid-adolescents have fully developed lesson; many young people are now able to define
stressful, but desired. This dissonance is secondary sexual characteristics. This newly and pursue independent goals. Strong connections to
often dealt with by creating very strong developed body often leads to heightened peer school, family and/or community indicate less
connections with a peer group. Youth want and self-awareness. Because their executive likelihood of participating in risky behaviors

to be different and separate from family but functioning is not fully developed, there is
still need that comforting sense of fitting in often less understanding of consequences.
somewhere. Often this is achieved through Teens also have less impulse control. In this
peers. Adults often joke about kids this age age group there is often an increase in engaging
talking about how they want to “be in physical intimacy. Most teens start to
different,” but then looking and acting explore sexual relationships at some level.
exactly the same as their peers Twenty percent of 15-year-olds, and 48% of
17-year-olds, have had penile-vaginal
intercourse (Finer and Philbin 2013)
R.V. Voss and E. Ruedinger
1 Update in Adolescent Medicine 5
accompanied by increased myelination and Confidentiality

white matter tract organization over time.
Additionally, brain activity in certain regions is The clinician should interview the adolescent
different between adolescents and adults com- patient alone at some point during the visit.
pleting similar tasks. The cause behind this is not Private portions of the visit allow for discussion
yet clear but may relate to the neuroanatomic of topics that adolescents often prefer to keep pri-
changes described above; increasing automatic- vate from their parents. Adolescents often speak
ity/decreasing novelty of tasks over the transi- more freely without parents in the room, some-
tion toward adulthood; and/or something else times making it easier to establish a relationship
altogether. This remains an area of very active with the patient. Often, it can also be helpful to
study (Blakemore 2012). meet with the parent alone, as they may be able to
It is likely that physiologic, cognitive, psycho- provide information about their child’s mental
social and emotional changes are inter-connected health, school performance, or social stressors
in ways that are not yet fully understood. We gen- that they are not comfortable discussing in front
erally encourage providers to keep adolescent of the adolescent.
developmental concepts in mind when working Prior to interviewing an adolescent alone, it is
with teens, and recognize that behaviors that may helpful to discuss confidentiality with both ado-
not “make sense” to an adult often seem reason- lescent patients and their parents. Many provid-
able and logical to the youth because of their con- ers choose to name the topics that will be
text and developmental stage. Understanding the discussed confidentially and the specific issues
youth’s perspective is a key component of pro- that require breaking confidentiality (Table 1.3).
moting adolescent health. Starting in the early teenage years, providers
should counsel parents that adolescents often feel
more comfortable talking without their parents,
Interviewing the Adolescent and that these private visits are an important step
Patient in their process toward becoming responsible for
their own health and wellbeing.
Many issues in adolescent health center around Laws vary by jurisdiction with regard to ser-
the psychosocial world of the patient. While vices that can be provided confidentially to ado-
some of these issues fall into the category of lescents without parental consent. These services
risk behaviors, other health issues, such as men- may include contraceptive care (condoms and
tal illness and abuse, may arise due to adverse birth control methods, including long-acting
environments over which the adolescent has lit- reversible contraception), prenatal care, abortion
tle control. Regardless of the reason that an ado- services, drug and alcohol treatment services, and
lescent presents to care, the visit should be mental health treatment (including counseling
viewed as an opportunity to screen for and and medications). In the United States (U.S.), all
address common risk behaviors and psychoso- 50 states have laws allowing minors to access
cial stressors. confidential STD-related care. The age of consent
There are several different techniques that are for these services varies by state. The Guttmacher
used to perform such a screen. Best known is the Institute provides a thorough listing of state-spe-
HEEADSSS mnemonic, which serves as a history- cific minors’ consent laws for reproductive and
taking tool to cover broad domains of psychosocial sexual health: https://www.guttmacher.org/state-
assessment (Katzenellenbogen 2005; Goldenring policy/explore/overview-minors-consent-law
and Rosen 2004). This mnemonic has evolved over (Guttmacher Institute n.d.).
time to include more categories and letters. See Many jurisdictions also have laws which
Table 1.2 for examples of what can be contained in allow for the general care of adolescents with-
the HEEADSSS assessment. out parental consent in cases where the minor is

Table 1.2 The HEEADSSS assessment: a psychosocial interview tool

Home • Who do you live with?
environment • Do you feel safe at home?
• Who are you closest with?
• Is religion part of your life?
Education • What school and grade are you in?
and • Any issues with bullying?
employment
• Do you have friends at school?
• How are you doing in school? Are you failing any classes?
• What are your favorite and least favorite classes?
• Do you have any special circumstances? (504 plan, IEP, special education, tutoring, repeated
grades)
• Do you like school?
• What are your plans after high school?
• What are your plans after college?
• Do you have a job currently?
Eating • How do you feel about your body? What do you like and not like about it?
• Are you worried about your weight?
• Has your weight changed recently?
• Tell me what you might eat in a typical day
• Are you trying to lose weight?
• Do you ever starve yourself, skip meals, or make yourself throw up? Ever take diet pills,
laxatives, diuretics?
• Do you ever feel like your eating is out of control? Eat so much you feel sick?
• Do you have enough food in your home?
Activities • What do you do for fun? (With friends? With family?)
• How many hours do you spend in front of a screen (not for school/work) per day?
• Tell me about how you get exercise (explore for excessive exercise)
Drugs • Have you ever tried alcohol? Marijuana? Cigarettes? Other drugs such as ecstasy,
methamphetamines, cocaine, heroin, prescription medications (pain medicine or ADHD
medicine)?
• How do you use (pills, snorting, smoking, injecting)?
• How often and how much do you use?
• Have you been drunk? Blacked out? Vomited?
• Have you ever used alone?
• How many of your close friends use substances?
• Have you ever driven intoxicated or driven with an intoxicated driver? (This includes alcohol,
marijuana, and other drugs)
• Have drugs or alcohol ever gotten you into trouble?
• What do you think about your drug use?

Sexuality • Are you attracted to boys, girls, both, or neither?
• How do you identify? Male, female, both, neither, or neither?
• Have you dated, or had crushes?
• Are you in a relationship?
• Have you ever felt that your boyfriend/girlfriend is jealous or controlling?
• Has your boyfriend/girlfriend ever physically hurt you?
• Have you had any types of physical relationships? Holding hands, hugging, kissing, touching,
oral sex, vaginal sex, anal sex?
• Have those experiences been enjoyable?
• Have you ever had any unwanted physical/sexual activity? Have you ever felt pressured into
doing something?
• How many partners have you had all together?
• What have you (or your partner) used for protection against pregnancy? STDs?
• Have you ever been pregnant or gotten someone pregnant?
• Have you ever had an STD? Are you concerned about an STD? When were you last tested
for STDs?
• How do you talk about sex with a partner before you start doing something physical?
• Have you talked with your parents about your sexual orientation, gender, and relationships?
• Have you ever had sex in exchange for drugs, money, or other things you needed?
Suicide and • How do you think your mood is?
depression • Do you worry you might have depression or anxiety?
• Do you ever think about hurting or killing yourself?
• Have you ever hurt yourself (by cutting or other methods)?
• Have you ever tried to kill yourself?
• For more thorough depression assessment we recommend screening with the PHQ9
• For anxiety assessment, we recommend screening with the GAD7
Safety • How often do you wear a bike helmet?
• How often do you wear a seat belt?
• Do you have a driver’s license? What are the restrictions?
• Has anyone ever hurt you or touched you inappropriately?
• Is there violence in your home? School? Neighborhood? Relationship?
• Have you ever felt threatened or unsafe? (At home? At school? In your neighborhood? When
you are out of your comfort zone?)
• Have you ever felt you had to carry a weapon to be safe?
• Have you ever been in a fight?
• Are there guns or other weapons in your home, or anywhere that you could access them?
Italicized questions represent concepts that are relatively new parts of the routine HEEADSSS assessment. When
assessing safety, the provider may consider the ways that the patient’s race, gender expression, and body habitus may
impact their perception of safety

Table 1.3 Indications for breaking confidentiality

Indication for breaking confidentiality Appropriate course of action
Active suicidal ideation with plan of action Refer to ER (either by EMS or via safe transport if all parties
comfortable)
Call local crisis line
Behaviors that may cause harm to patient Discuss with parent for safety planning
(cutting, purging, risky substance use, inadequate Speak with social worker and/or therapist if available
or inappropriate prescription use)
Specific plan to harm others Report to local police
Refer patient to ER
Report of physical abuse by a caregiver, teacher, Call Child Protective Services (CPS)
or other adult responsible for the child’s • Need as much information as possible including full name
wellbeing and address of perpetrator and details of event
• If concern for child’s immediate safety, place the call while
patient still in office
Report of sexual abuse by an adult (or older Call local police
adolescent, depending on state law) • Need as much information as possible including full name
and address of perpetrator and details of event
considered “mature” or “emancipated” (Coleman stances, if used chronically, can have long-term
and Rosoff 2013). The criteria for this status as a impacts on brain development (Schepis et al.
“mature minor” varies by jurisdiction and may 2008; Squeglia et al. 2015; Yuan et al. 2015).
include living separately from parents, having a Marijuana has become the most commonly
child, being financially independent, or other cri- used illicit substance amongst U.S. teens (Miech
teria. In some states, this status may be deter- et al. 2016). Jurisdictions vary in their laws on
mined by a healthcare provider, while in some use of marijuana for medical and recreational
states this must be determined by a judge or other purposes (Office of National Drug Control Policy
qualified authority. We suggest that providers n.d.). Despite being legalized only for adults, the
familiarize themselves with the laws in their legalization of marijuana and other cultural influ-
jurisdiction, either through online resources pub- ences have made provider conversations with
lished by their local government or by consulting youth about marijuana more challenging; often,
with social workers or hospital ethics officials. parents and patients are firmly committed to the
belief that marijuana use is safe and healthy
(Miech et al. 2016). The rest of this section will
dolescent Substance Use
A focus on marijuana use in adolescents, however
and the Changing Legal many of the principles of screening and treatment
Environment of Marijuana apply to other drug use as well.
Adolescents are very likely to try illicit drugs as

they progress into adulthood. In 2015, 44% of Epidemiology
high school seniors reported that they had tried
marijuana in their lifetime, and 64% reported In 2014, 21.2% of high school seniors reported
having ever tried alcohol (Miech et al. 2016). having used marijuana in the past month via the
Most people who become addicted to drugs and Monitoring the Future study (Miech et al. 2016).
alcohol begin using in their teen years, making This rate of use has been consistent since 2011.
this an important age group to screen for sub- One study of youth who had used marijuana at
stance use (Chen et al. 2009; Grant and Dawson least five times demonstrated that 46.3% had con-
1998; Anthony and Petronis 1995). Illicit sub- tinued use after 10 years (Perkonigg et al. 2008).

Forms of Use Medical Marijuana: At the time of this publi-

cation, medical marijuana has been legalized in
The amount of THC in marijuana products has many jurisdictions, including 23 U.S. states as
been increasing over time; The mean concentra- well as the District of Columbia (Office of
tion of THC in confiscated cannabis products has National Drug Control Policy n.d.). There is no
increased from 3.4% in 1993 to 8.8% in 2008 chemical difference between medical and recre-
(Mehmedic et al. 2010). ational marijuana. Typical state laws intend med-
Inhaled use: Marijuana may be consumed in ical marijuana use for adults over age 21. In most
the form of cigarettes (joint), cigars (blunt), using states where medical marijuana is legal, minors
a small pipe (bowl), or a large water pipe (bong). may obtain medical marijuana with parental per-
Marijuana may also be vaporized using vape mission. Some research suggests that marijuana
pens or vape guns. Dabbing is the practice of may be effective in treating cancer-related pain
using THC-rich resins extracted from the mari- and nausea, however data is limited to adults and
juana plant. The extract can be obtained in the quality research on this topic is generally lacking
form of oil, wax, or shatter, an amber-colored (Wilkie et al. 2016; Harrison et al. 2015).
solid (National Institute on Drug Abuse n.d.-a). Pharmaceutical cannabinoids: There are two
This form of use is extremely potent and carries forms of synthetic cannabinoids available in the
high risk for negative experiences. The extracts United States. Neither have been studied in chil-
are prepared for smoking using butane, which dren. Both dronabinol (trade name Marinol, man-
has led to several house fires, explosions, and ufactured by Abbvie) and nabilone (trade name
burns (National Institute on Drug Abuse n.d.-a). Cesamet, manufactured by Meda Pharmaceuticals)
Edible marijuana is available in the form of are FDA approved for chemotherapy- induced
brownies, cookies, candies, and tea. Because the nausea and vomiting.
ingested marijuana has to be digested and
absorbed into circulation, the effect takes over an
hour and users will often ingest more marijuana Adverse Effects
while waiting to get the desired effect. Because
of this risk of overuse, this form of use often Addiction: An estimated 9% of marijuana users
results in overdose experiences (National Institute will become addicted to the substance. Among
on Drug Abuse n.d.-a). In Washington, where people who begin using as teens, the rate of addic-
marijuana is legal for adults ages 21 and above, tion is 17%. The mechanism for addiction to mari-
edible marijuana products are being sold in pack- juana is similar to that of other substances, which is
aging that is increasingly similar in appearance to via up-regulation of endogenous neurotransmitter
non-drug products, which may increase the like- receptors due to overstimulation by the exogenous
lihood of accidental ingestion by children. drug (Hasin et al. 2015; Winters and Lee 2008).
Synthetic Marijuana is commonly known as Lung disease: Marijuana use is associated with
K2 or Spice. These substances are chemically increase risk of pneumonia, bronchitis and chronic
related to THC but do not come from the mari- cough, and increased sick days due to respiratory
juana plant (National Institute on Drug Abuse illness (Hashibe et al. 2006; Polen et al. 1993).
n.d.-a). These drugs can be smoked or obtained in Studies linking marijuana with lung cancer are as
liquid form and vaporized through e-cigarettes or yet inconclusive (Hashibe et al. 2006).
other vaping devices. They are typically much Testicular cancer: Two studies have shown an
more potent than smoked marijuana. Adverse increased risk of testicular germ cell tumors in
effects noted from use of Spice and K2 include marijuana users (Lacson et al. 2012; Daling et al.
anxiety and agitation, nausea and vomiting, high 2009). Marijuana users who began use before age
blood pressure, shaking and seizures, hallucina- 18 had a 2.8 times higher risk of testicular germ
tions and paranoia, and violent behavior. These cell tumor.
substances may not show up on drug tests Driving: Marijuana use has a dose-dependent
(National Institute on Drug Abuse n.d.-a). effect on driving speed, accuracy, and reaction

times. This risk appears to be compounded when quently, sexually transmitted infections. The
marijuana is used in association with alcohol relationship between substance use and sexual
(Lenné et al. 2010; Ramaekers et al. 2004). A assault is thought to be bi-directional, in that
review of epidemiologic data showed a twofold prior assault increases risk for substance abuse,
increase in risk of a motor vehicle accident after and substance abuse increases risk for assault
cannabis use (Hartman and Huestis 2013). (Resnick et al. 2013). One study found that, of
Mental Health: While it is difficult to establish women reporting to an emergency room for rape-
causality, marijuana use has been associated with related medical exam, 54% reported alcohol use
a more than fivefold increase in reporting of and 12% reported marijuana use at the time of
depression and anxiety in young adults (Patton assault (Resnick et al. 2012).
et al. 2002). Studies have found links between
marijuana use and psychosis as well, though cau-
sality is difficult to determine (Caspi et al. 2005; Policy and Legal Considerations
Barkus 2016). Some patients likely use mari-
juana (and other substances) in attempts to self- Marijuana has been legalized for medical use in 23
medicate mental illness. Because mental illnesses U.S. states as well as the District of Columbia and
are so frequently present in patients who use Canada. Four U.S. states (Colorado, Oregon,
drugs, it is important to establish their presence Washington, and Alaska) have legalized both medi-
in order to refer the patient for concurrent treat- cal and recreational marijuana use (Office of
ment of both mental illness and substance use. National Drug Control Policy n.d.). At the time of
Cognitive development: Research suggests this publication, the use of recreational marijuana is
that marijuana has deleterious effects on cogni- illegal in Canada (Government of Canada 2016).
tive development. Several studies in animals have The American Academy of Pediatrics (AAP)
demonstrated long-term effects on memory and updated their policy statement on marijuana use
learning which are amplified when marijuana is in youth in 2015 (Committee on Substance Abuse
used in the adolescent period (Gleason et al. and Committee on Adolescence 2015). The AAP
2012; Lisdahl Medina et al. 2007; Meier et al. opposes marijuana use in children and adoles-
2012; Schweinsburg et al. 2008). A New Zealand cents under age 21 and opposes use of medical
study found an average decrease in IQ of 8 points marijuana “outside the regulatory process of the
in adults who were heavy marijuana users during U.S. Food and Drug Administration.” The AAP
adolescence. This effect was not seen among calls for further research into pharmaceutical
marijuana users who began using during adult- cannabinoids. They also propose decriminaliza-
hood (Meier et al. 2012). Research has also have tion of marijuana use, focusing instead on a treat-
shown that marijuana users have lower likelihood ment approach for marijuana use in young
of graduating high school (Macleod et al. 2004). people. Lastly, they discourage marijuana use by
Marijuana use has been associated with lower adults in the presence of young people.
income, lower life satisfaction, unemployment,
and welfare dependence (Brook et al. 2013;
Fergusson and Boden 2008). Screening and History
Sexual Health Providers should screen children and teenagers

Little research has suggested a relationship regularly for substance use during clinic visits.
between marijuana use and sexually transmitted This should be done at well child checks as
infection, although one study did demonstrate a well as intermittently in subspecialty clinic
correlation between the two in a survey of Black visits. Providers should ask explicitly about
college students (Keen et al. 2016). It is generally use of a variety of substances including alco-
felt that substance use may impair judgment, hol, cigarettes, marijuana, methamphetamines,
leading to riskier sex behaviors and, subse- cocaine, heroin, mushrooms, ecstasy, Molly,

LSD/acid, non-prescribed medications (such as severity of substance use. Brief Intervention is

Benadryl), and misuse of prescribed medica- an opportunity to express concern, increase the
tions (such as stimulants or benzodiazepines). youth’s insight into their use and provide moti-
Providers may choose to utilize the CRAFFT vation toward behavioral change. Referral to
screen (Fig. 1.1) from Boston Children’s treatment is an opportunity to provide resources
Hospital, which can identify problematic sub- for care to patients who warrant treatment. Teens
stance use and indicate the need for further dis- should be referred for professional assessment
cussion (The Center for Adolescent Substance and treatment for any of the following: (1) use
Abuse Research n.d.). that has impaired functioning, such as decreased
grades or school attendance or withdrawal from
activities, (2) use associated with problematic
creening, Brief Intervention
S outcomes or unsafe situations such as intoxi-
and Referral to Treatment (SBIRT) cated driving, legal or family problems, (3)
youth interested in quitting, (4) youth demon-
SBIRT is a method of identifying and addressing strating signs of dependence such as using alone,
substance use that is intended for primary care having cravings, or having unsuccessful attempts
providers, and was also developed at Boston at quitting. Importantly, the SBIRT model rec-
Children’s (Committee on Substance Abuse ommends providing praise and discussing pre-
et al. 2011). Screening (using CRAFFT or CAR vention for youth who are not actively using
questions) is intended to assess the presence and substances.
The CRAFFT Screening Interview

Begin: “I’m going to ask you a few questions that I ask all my patients. Please
be honest. I will keep your answer confidential.”
Part A
During the PAST 12 MONTHS, did you: No Yes
1. Drink any alcohol (more than a few sips)?
(Do not count sips of alcohol taken during family or religious events.)
2. Smoke any marijuana or hashish?
3. Use anything else to get high?
(“anything else” includes illegal drugs, over the counter and
prescription drugs, and things that you sniff or “huff”)
For clinic use only: Did the patient answer “yes” to any questions in Part A?
No Yes
Ask CAR question only, then stop Ask all 6 CRAFFT questions
Fig. 1.1 The CRAFFT Part B No Yes

screening interview. © 1. Have you ever ridden in a CAR driven by someone (including
John R. Knight, MD, yourself) who was “high” or had been using alcohol or drugs?
Boston Children’s 2. Do you ever use alcohol or drugs to RELAX, feel better about
Hospital, 2016. All yourself, or fit in?
rights reserved.
Reproduced with 3. Do you use alcohol or drugs while you are by yourself, or ALONE?
permission 4. Do you ever FORGET things you did while using alcohol or drugs?

onfidentiality and the Role
C Table 1.4 Drug treatment approaches (National Institute
on Drug Abuse n.d.-b)
of the Family
Behavioral Group therapy—employs CBT
Disclosure of substance use by a minor does not approaches techniques
Individual CBT
legally require providers to make a report to authori-
Adolescent Community
ties or parents, unless the patient is at immediate risk
Reinforcement Approach (A-CRA)
of serious harm. In some states, minors have the Contingency management
right to access substance use treatment services Motivational enhancement therapy
without consent from parents. In these cases, the Twelve-step facilitation therapy
provider may choose to assist the minor in accessing Family based Brief Strategic Family Therapy
services confidentially. However, most therapy approaches (BSFT)
approaches for adolescent substance use rely heavily Family behavior therapy
on family support; for this reason, providers should Functional family therapy
strongly encourage teen patients to discuss their use Multidimensional family therapy
with their parents (National Institute on Drug Abuse Medications Available for opioid, alcohol and
n.d.-b). Providers can often help to facilitate this dis- nicotine addiction
cussion in the clinic. Families can also be key play-
ers in motivating the teen patient to engage in
treatment. In some states, parents may initiate drug anxiety, and cravings. No medical intervention is
treatment despite the teen’s unwillingness to typically needed for this process.
participate.
Behavioral Treatment
Treatment
No medications are available for treating marijuana
Much of the approach to treatment for marijuana addiction at this time. The mainstay of treatment is
abuse is similar to treatment for abuse of other behavioral therapy. This typically is provided by a
substances. Many youth who use marijuana have chemical dependency professional (CDP). See
co-morbid use of other substances; treatment can Table 1.4 for a list of drug treatment approaches.
target the use of multiple substances simultane- Patients with problematic use should undergo
ously. The National Institute of Drug Abuse rec- a drug and alcohol assessment to determine the
ommends treatment of substance use even in appropriate level of treatment (Table 1.5). Level
adolescents with low levels of use due to the high of treatment is determined by (1) the presence of
likelihood of substance use impacting adulthood other behavioral or emotional conditions, (2)
(National Institute on Drug Abuse n.d.-b). motivation to change, (3) risk of relapse or con-
For assistance in finding available drug treat- tinued drug use, (4) recovery environment (e.g.
ment resources, we recommend utilizing the family, peer, school, community), (5) level of
Substance Abuse and Mental Health Services intoxication and potential for withdrawal, (6)
Administration Treatment Locator at www.find- presence of other medical conditions.
treatment.samhsa.gov or by calling 1-800-662-
HELP (Substance Abuse and Mental Health
Services Administration n.d.). Support Groups
While not recognized as evidence-based treat-

Detox/Withdrawal ment options, Narcotics Anonymous, Marijuana
Anonymous, and other support groups offer
Users often report symptoms upon quitting such social support and accountability to people who
as sleeplessness, irritability, decreased appetite, are undergoing (or have completed) treatment for

Table 1.5 Substance abuse treatment settings (National Institute on Drug Abuse n.d.-b)
Treatment setting Description Indication
Drug/alcohol One-time session or limited series, Relatively isolated incident of drug-related
education often court ordered infraction (legal, school-related, etc.)
Limited outpatient 1–2 sessions per week, usually Less severe addiction, few additional mental health
treatment individual, may involve family issues, supportive living environment
Intensive outpatient 3+ sessions per week for several As above, possibly after failure of limited treatment
treatment hours a day, often involving family
Partial Also known as “day treatment.” Severe substance use disorders, safe to reside in
hospitalization 4–6 hours a day, 5 days a week home environment
Residential/ 24-hour structured environment Severe addiction and/or comorbid mental or physical
inpatient treatment health conditions that require 24 h supervision
chemical dependency. Youth-specific groups are Starting the Conversation

rare and youth often feel uncomfortable attend-
ing general meetings, however they are typically Providers can start by initiating a conversation
welcome to attend. with every teen. It is best to start the conversation
by taking a general sexual history, as described in
the “Sexuality” section of Table 1.2 in this
Resources for Patients chapter. If a teen is not sexually active, the pro-
vider can initiate a conversation about healthy
Providers may refer older adolescent patients or relationships, providing positive reinforcement
parents to the National Institutes of Drug Abuse that abstinence is a safe and healthy sexual
(NIDA) website, www.drugabuse.gov, for more choice. Also remind the teen that if and when
information on marijuana and other substances they choose to become sexually active, if they are
(National Institute on Drug Abuse n.d.-a). For not seeking a pregnancy it is best to initiate con-
younger adolescents, http://kidshealth.org/en/ traception prior to their first episode of inter-
teens/drug-alcohol/ is a site directed toward teen- course. Providers can invite teens to come back
agers that answers drug and alcohol questions and discuss this further at another visit.
(TeensHealth n.d.). If a teen is sexually active, the provider should
ask if they are currently trying to get pregnant
(for females with any male partner(s)) or cur-
Contraception rently seeking to become a father (for males with
any female partner(s)). If no, the provider should
Seventy-one percent of youth have experienced probe further to find out what the patient and
coitarche by the age of 19 (Guttmacher Institute their partner(s) are doing to prevent a pregnancy.
2014). Although teen pregnancy rates have been Assess the teen’s level of knowledge around vari-
declining steadily over the past 20 years, nearly ous contraceptive methods, as well as any contra-
250,000 infants are born to adolescent mothers ceptive methods they have used and their
each year and over three-quarters of all adoles- satisfaction with these methods.
cent pregnancies are described as unintended or
occurring “too soon” (Office of Adolescent
Health 2016). These rates are significantly higher nderstanding Eligibility for Various
U
in the U.S. then most other developed countries. Methods
Health care providers working with youth must
ensure access to high-quality, reliable contracep- Next, assess what options are medically viable
tive counseling. Ideally, teens will access contra- for the patient. The Centers for Disease Control
ception prior to becoming sexually active. publish U.S. Medical Eligibility Criteria for

Contraceptive Use (USMEC), which can easily tions, lifestyle factors and family history. Some
be accessed free-of-charge online, or down- of the most commonly encountered conditions
loaded as an app onto a smartphone (Centers among adolescents that have an impact on con-
for Disease Control and Prevention 2010). The traceptive decision- making are listed in
USMEC provides evidence-informed guidance Table 1.6; this is not an exhaustive list so please
around the use of various contraceptive meth- refer to the full USMEC guidelines for individ-
ods in patients with a variety of medical condi- ual patients.
Table 1.6 Commonly encountered conditions among adolescents that have an impact on contraceptive decision-
making
Condition Special considerations
Obesity Most contraceptive options have not been studied specifically in obese and/or morbidly
obese women. It is generally accepted that even if there is a decrease in efficacy for some
methods, use of one of these methods will still provide contraceptive benefit. Women with
obesity should receive full options counseling (Robinson and Burke 2013; McNicholas
et al. 2013)
IUD (copper and levonorgestrel) effectiveness does not vary with BMI category. This may
be a particularly good option and is Category 1 per the USMEC (Centers for Disease
Control and Prevention 2010; Robinson and Burke 2013; Reifsnider et al. 2013)
Etonorgestrel levels decline with increasing body weight in individuals with the
etonorgestrel implant. The implant may need to be replaced sooner than the standard 3 year
interval. However, one study found no significant differences in failure rates by body mass
(Xu et al. 2012)
Serum medroxyprogesterone levels decline with increasing body mass index in patients
using depot medroxyprogesterone acetate (DMPA) (Robinson and Burke 2013). DMPA
has been associated with weight gain among obese adolescents (Centers for Disease
Control and Prevention 2010)
It remains unclear if there is a difference in efficacy for the combined hormonal patch, ring
or pill. The risk of venous thromboembolism (VTE) is increased in women with obesity,
but combined methods remain category 2 per the USMEC (Centers for Disease Control and
Prevention 2010; Robinson and Burke 2013; Reifsnider et al. 2013)
Patients at risk for DMPA use can lead to a loss of bone mineral density (BMD). BMD can be regained after
low bone mineral discontinuation, but the full implications of use (especially long term use) are unknown.
density (e.g., This is not an absolute contraindication to use of DMPA among adolescents with or at risk
anorexia nervosa, for low BMD (Centers for Disease Control and Prevention 2010; American College of
wheelchair bound) Obstetricians and Gynecologists 2006)
Smoking The risk of VTE is increased in smokers using combined hormonal contraceptives. In the
adolescent age group, this remains category 2 (Centers for Disease Control and Prevention
2010). Advise smokers to quit; advise non-smokers not to start
Hyperlipidemia Initiation of combined hormonal contraceptives is category 3 (Centers for Disease Control
and Prevention 2010)
Hypertension Varies by level of blood pressure control; however, combined hormonal contraceptives are
generally considered category 3 or 4, as estrogen may exacerbate hypertension (Centers for
Disease Control and Prevention 2010)
Known Combined hormonal contraceptives are category 4 (Centers for Disease Control and
thrombogenic Prevention 2010)
mutation
Depressive disorders All methods are category 1 (Centers for Disease Control and Prevention 2010)
Diabetes mellitus All methods are category 1 in patients without vascular disease (Centers for Disease
Control and Prevention 2010). When vascular disease is present, consult the USMEC
directly

Condition Special considerations
Anemia A single, small study showed a potential decrease in bone pain among patients with sickle
cell disease using DMPA (Manchikanti Gomez et al. 2007)
The copper IUD may cause heavy menses and worsen anemia. This is category 2 (Centers
for Disease Control and Prevention 2010)
Combined hormonal contraceptives are category 2 for patients with sickle cell disease
(Centers for Disease Control and Prevention 2010). Some providers and patients avoid
these due to the increased risk of VTE
Migraine headaches With aura: Combined hormonal contraceptives are category 4 due to increased risk of
stroke (Centers for Disease Control and Prevention 2010)
Without aura: Combined hormonal contraceptives are category 2 for initiation; category 3
to continue if migraines develop or worsen on the method (Centers for Disease Control and
Prevention 2010)
Use of Phenytoin, carbamazepine, barbiturates, primidone, topiramate, and oxcarbazepine
anticonvulsants decrease efficacy of combined oral contraceptives and progestin only oral contraceptives.
Use of these methods is category 3 (Centers for Disease Control and Prevention 2010). If
used, contraceptive efficacy may be diminished and a minimum 30 mcg of ethinyl estradiol
should be chosen
Lamotrigine levels decrease while on combined oral contraceptives, and can then
significantly increase during placebo week. Use of this method is category 3 (Centers for
Disease Control and Prevention 2010). If used, consult with the patient’s neurologist and
consider using continuously to avoid alterations in lamotrigine levels during the placebo
week once a steady state is achieved
HIV/AIDS Recommendations vary based on stage of illness and medications. Consult the USMEC
Category 1 = no restrictions; 2 = benefits generally outweighs risks; 3 = risks generally outweighs benefits;
4 = contraindicated
escribing Contraceptive Options

D Obstetricians and Gynecologists 2012). LARC
to Teens methods include IUDs (copper or levonorg-
estrel (LNG)-containing) and the implantable
Once you have determined what options the levonorgestrel rod. LARC methods are the
patient is eligible for, describe the patient’s con- most effective forms of contraception (other
traceptive options to her in order of most effec- than abstinence) currently available. Return to
tive to least effective (Table 1.7). Uptake tends to conception is possible immediately upon
be higher for the options presented earliest in the device removal.
conversation. Always recommend that the patient Despite recommendations to use LARCs as
use barrier protection for STI prevention, in addi- first-line methods among teens, many pediatric
tion to any other form of contraceptive the patient and adolescent health providers are less familiar
chooses. with these methods. A recent review article high-
lighted a number of barriers that led to limited
ong-Acting Reversible Contraception
L uptake of these reliable, first-line contraceptive
(LARC) devices, including: provider attitudes, miscon-
LARC should be the first option that is ceptions and lack of training; cost; concerns
discussed with most adolescent patients. This around consent and confidentiality; and patient
recommendation is now supported by the misconceptions and lack of awareness (Kumar
AAP and the American Congress of and Brown 2016).
Obstetricians and Gynecologists (ACOG) Systems are in place to address barriers around
(American Academy of Pediatrics Committee cost, consent and confidentiality. Per the
on Adolescence 2014; American College of Affordable Care Act mandate in the US, contra-

Table 1.7 Effectiveness of contraceptive options placed. Many jurisdictions provide funding to
Most Effective certain clinics where youth may be able to
Abstinence access contraceptive services without using
Long-Acting Reversible Contraception (LARC): their insurance.
Intrauterine Devices (IUDs), implantable rods
If you are unable to place LARC devices in
Depot-medroxyprogesterone acetate (DepoProvera®,
“the shot”, “depo”) your office, consider accessing the website www.
Etonorgestrel-ethinyl estradiol vaginal ring bedsider.org for a list of providers who place
(NuvaRing®, “the ring”); (contains estrogen and a LARCs. First and foremost, it is important that
progestin)
providers understand LARC options and provide
OrthoEvra®patch (contains estrogen and a progestin)
Combined hormonal oral contraceptives (contains accurate, positive messaging around LARC for
estrogen and a progestin) the teens with whom they are working.
Progestin-only oral contraceptives A review of the various LARC options is
Barrier protection (most commonly, male condoms)
available in Table 1.8.
Other (e.g., you can consider discussing natural family
planning, withdrawal, etc. depending on patient—
these are all better than nothing!) Non-LARC Options
Nothing The other contraceptive methods mentioned
Least Effective above have been on the market for several
Note: permanent sterilization is generally not offered as decades with relatively high uptake among teens
an option to adolescent patients and providers. These methods will not be covered
in detail in this update book. If providers or ado-
ception (including LARC) is now generally cov- lescents desire more information on any of the
ered by insurance with no out-of-pocket cost methods available, there are now a number of
unless the patient’s insurance company has an high-quality, internet based resources that can
exempt status. With regard to confidentiality and easily be accessed. www.youngwomenshealth.
consent, we gently encourage teens to involve org is factually accurate and suitable for teens of
their caregivers in all health-related decision- all ages. www.bedsider.org is another excellent
making, including reproductive health, when it is source of reliable information, presented in a
feasible and safe for them to do so. Some adoles- teen-friendly format that includes “hooks” such
cents will do this on their own, while others will as jokes, videos, infographics, and testimonials.
request that their provider help guide the discus- It is a sex-positive site and potentially not devel-
sion. However, many youth do not wish to dis- opmentally suitable for young adolescents. This
cuss their reproductive health with their site can also be used to get free text reminders
caregiver(s). Most jurisdictions allow adoles- sent to patients’ phones for birth control pills,
cents to consent to their own reproductive health- appointments and refills. A portion of the site is
care. Providers should familiarize themselves geared toward providers.
with the minors’ consent laws in their own juris-
diction of practice. These are summarized by the
Guttmacher Institute (www.guttmacher.org) and Emergency Contraception
through the Center for Adolescent Health and the
Law (http://www.cahl.org). There are currently four methods of Emergency
Providers should also be aware that some Contraception (EC) available in the United
insurance providers send itemized bills, which States: the copper IUD, ulipristal acetate (UPA),
may be addressed to the parent, to the home. levonorgestrel EC (LNG-EC) and the Yuzpe
This can lead to an accidental breach of confi- method.
dentiality. If this is a concern to your patient, The copper IUD can be placed within 5 days
you may need to investigate the policies of their of unprotected intercourse. This is the most effec-
insurance provider and/or understand the billing tive EC (Cheng et al. 2012). The copper IUD has
policies of the clinic where the device will be the added benefit of providing ongoing contra-

Table 1.8 Long-acting reversible contraceptive options

Duration of
contraceptive
Procedure notes Mechanism of action effectiveness Other
Copper IUD Placement typically is Copper ions kill sperm; may 10 years Hormone free
(ParaGuard®) done as an office disrupt implantation though Menses continue with
procedure (though in this is debated same regularity; may be
special circumstances, heavier
such as girls with Can be used as emergency
developmental delays, it contraception if placed
can be done under within 5 days of
anesthesia). Placement unprotected intercourse
is typically well Can be placed immediately
tolerated, though most postpartum
Levonorgestrel patients experience Thickened cervical mucus Liletta® 5 years Very low systemic
(LNG) IUD some cramping at the diminishes number of sperm (19 μg hormone levels.
(Mirena®, time of the procedure. passing through cervix per day) Also highly effective
Liletta®, While it can vary by LNG causes thinning of Mirena® (more than pill) at treating
Kyleena®, and provider and patient, the endometrium and (20 μg dysmenorrhea and at
Skyla®) actual procedure usually environment not amenable per day) treating heavy menstrual
only takes a few minutes to sperm survival, bleeding/abnormal uterine
There is an increased fertilization or implantation bleeding
risk of infection during Periods typically become
the first approximately lighter and less frequent
20 days after placement, over time (approximately
likely related to 90% of patients).
introduction of microbes Approximately 40% of
during the procedure. patients will develop
Ongoing increased risk amenorrhea
of infection was a 3 years Even lower systemic
Skyla®
concern with a type of (14 μg hormone levels than
IUD that is no longer on per day) Mirena/Liletta. Most
the market due to the patients continue to have
filaments that were used regular periods
in the string of the IUD.
Current IUDs have
monofilament strings
and do not promote
infection. IUD’s are
considered safe even in
patients with history of
prior infection or
multiple partners.
Patients should be
screened for gonorrhea
and chlamydia at the
time of placement, and
treated if infection is
present
Etonorgestrel Inserted into arm, Thickened cervical mucus 3 years Radio-opaque

(ENG) implant procedure is very simple diminishes number of sperm
(Nexplanon®) with minimal discomfort passing through cervix
and is typically done in ENG effects within uterus
the office. Training is leads to thinning of
easy to obtain; needs to endometrium and
be done through the environment not amenable
pharmaceutical company to sperm survival,
fertilization or implantation
Inhibition of ovulation

ceptive benefit for up to 10 years. Use of this among medication options, UPA is preferred
method requires access to a provider trained to (Glasier et al. 2011). For all young women,
place the copper IUD within 5 days of unpro- regardless of fertility timing or weight status, the
tected intercourse, and willingness/desire of the use of LNG-EC is preferred over nothing.
young woman to undergo the procedure. Obtaining a copper IUD or UPA is often more dif-
Ulipristal acetate (UPA) 30 mg is the most ficult and costly than obtaining LNG-EC, and this
effective oral form of EC (Glasier et al. 2010). must be taken into consideration.
UA is a selective progesterone receptor modula- EC is not intended for use as regular contra-
tor and can prevent or delay ovulation even after ception. Adolescents seeking EC should be coun-
lutenizing hormone (LH) starts to peak (Gemzell- seled on their options for reliable contraception
Danielsson 2010). UPA is therefore the superior moving forward, as well as on the benefits of
option for use right around the time of ovulation. consistent condom use.
UPA requires a prescription from a provider in
some jurisdictions and can be dispensed directly
by the pharmacist in other jurisdictions. UPA is Heavy Menstrual Bleeding
not stocked by all pharmacies. It can be obtained
online and shipped overnight through PRJKT The AAP and ACOG have jointly endorsed a
RUBY (www.prjktruby.com). statement describing the importance of consider-
Levonorgestrel (LNG-EC) 1.5 mg is available ing menstruation to be a “vital sign” among ado-
without a prescription to males and females, and lescent girls, as a means by which to assess
is the most widely used form of EC in the United development and to identify pregnancy and a
States. It is less expensive than UPA. LNG-EC is number of potentially serious pathologies includ-
most effective when used within 72 h of unpro- ing nutritional problems, endocrinopathies, and
tected intercourse, but maintains some efficacy bleeding disorders (American College of
out to 5 days (120 h); LNG-EC is not effective Obstetricians and Gynecologists 2015). The
once LH starts to peak (Gemzell-Danielsson median age of menarche for girls in the United
2010). LNG-EC is superior to the Yuzpe method, States is 12.43; 90% of all US girls have achieved
which involves taking multiple combined hor- menarche by age 13.75 (Chumlea et al. 2003).
monal contraceptive pills 12 h apart. Dosing regi- Adolescent bleeding patterns may vary some-
mens by type of OCP can be found at www. what from adult patterns (Table 1.9). Anovulatory
bedsider.org, but are not included here because cycles are common in the first 1–5 years following
this method is generally no longer utilized due to menarche, with prevalence decreasing over time.
the wide availability of other, more effective Up to 85% of cycles may be anovulatory during
options. the first year after menarche, and up to 44% by
The risk of pregnancy is highest around the 4 years after menarche (Holland-Hall 2013).
time of ovulation; sperm can live for up to 5 days Anovulatory cycles can lead to irregular bleeding;
in the reproductive tract. Ovulation occurs 14 days being familiar with the range of adolescent men-
prior to the menstrual period. Predicting the date strual patterns can help the clinician distinguish
of the next menstrual period, and therefore deter- between normal and pathological bleeding.
mining the expected fertile window, can be more Heavy menstrual bleeding (HMB) is a com-
difficult in teens who are not yet regular and are mon presenting gynecologic complaint among
still having anovulatory cycles. However, if the adolescents. HMB can significantly impact a
patient is felt to be within her fertile window, we teen’s quality of life, including school attendance
recommend more strongly considering the IUD or and sports participation, and can lead to severe
UPA even if somewhat more difficult to obtain. anemia. Heavy menstrual bleeding has been
The effectiveness of medical EC is also dimin- defined as prolonged bleeding (more than 7 days)
ished in women with a BMI >25 kg/m2; the cop- or blood loss greater than 80 mL per cycle among
per IUD remains the most effective option, but adult women, but these may not be appropriate

Table 1.9 Normal menstrual cycles in adolescent girls first day of bleeding for their last few cycles, if
(American College of Obstetricians and Gynecologists
possible. Many free smart phone apps are avail-
2015)
able for girls to track their periods.
Menarche (median 12.43 years Clinicians should inquire if the patient per-
age)
ceives their flow to be normal, heavy or light, and
Mean cycle interval 32.2 days in first gynecologic
year further define this by asking how often pads or
Menstrual cycle Typically 21–45 days tampons are changed; absorbency level of pads
interval or tampons that are used (e.g., super plus, super,
Menstrual flow length 7 days or less regular, light, overnight, etc.); level of soiling of
Menstrual product 3–6 pads or tampons per day the product when changed (this may be aided by
use use of the PBAC, which is readily available
online using any search engine); history of soak-
Table 1.10 Warner Criteria-Factors correlated with ing through pad or tampon in 1 hour or less; need
blood loss >80 mL per cycle for simultaneous use of a pad and a tampon to
1. Rate of changing sanitary products (>every 1–2 h) prevent soaking through onto clothing or bed-
2. Clot size >30 mm ding; passing clots greater than the size of a quar-
3. High total number of products used ter or large grape; or flooding or gushing
4. Subnormal ferritin level (Holland-Hall 2013). It is also helpful to define if
5. Need to change sanitary protection during the night the patient’s bleeding pattern has changed dra-
matically over time.
If the patient does have a bleeding pattern that
cutoffs for adolescents and are of questionable is clinically abnormal, the clinician should pro-
clinical significance even among adults (Warner ceed with a comprehensive evaluation. The dif-
et al. 2004a). Regardless, quantifying blood loss ferential diagnosis for heavy menstrual bleeding
can be difficult among both adolescents and is extensive and a thorough history and examina-
adults. The Warner criteria (Table 1.10) list clini- tion can help guide further testing. In 2011, the
cal features that are associated with blood loss of International Federation of Gynecology and
>80 mL per cycle (Warner et al. 2004b). The Obstetrics proposed use of the PALM-COEIN
Pictorial Bleeding Assessment Chart (PBAC) is a mnemonic (polyp, adenomyosis, leiomyoma,
scoring tool that is widely used for adult women malignancy and hyperplasia, coagulopathy, ovu-
to identify those with clinically significant bleed- latory dysfunction, endometrial, iatrogenic and
ing (Higham et al. 1990). Both of these assess- not yet classified) to classify potential causes of
ment tools were developed in adult women and abnormal uterine bleeding and create consistent
might not be as accurate in teens. nomenclature among providers (American
College of Obstetricians and Gynecologists
2013). The etiologies included in the “PALM”
Evaluation part of the mnemonic are rare in adolescents, but
this may serve as a familiar framework for some
In the absence of any validated screening tool for clinicians and reminds pediatric and adolescent
adolescents, clinicians are called upon to take a clinicians to attend to anatomic causes. A more
careful and detailed history from adolescent detailed list of causes of abnormal uterine bleed-
patients presenting with a complaint of heavy ing in adolescent girls is included below
menstrual bleeding. History should include all of (Table 1.11).
the factors described above in Tables 1.9 and
1.10. Cycle interval is standardly defined as the History
interval from first day of one menstrual period to A careful review of systems can substantially help
the first day of the next menstrual period. It can the clinician narrow down their differential diag-
be helpful to have patients give the date of the nosis. Questions should include screening for

possible complications of heavy bleeding, namely toms; joint hypermobility; and cardiac symptoms
anemia and intravascular depletion. The clinician can also provide clues toward a potential etiology.
should also inquire about any other history of Dyspareunia, vaginal pain or pelvic discomfort
heavy bleeding: frequent or prolonged epistaxis may point to anatomic or infectious etiologies.
(especially if nosebleeds have required medical A complete past medical history should be
intervention such as cautery or packing); gum performed. Ask about any chronic illnesses, his-
bleeding; prolonged bleeding after cuts; rectal tory of chemotherapy or radiation, and history of
bleeding; ecchymoses, purpura and/or petichiae; hepatic or renal disease. The medical history
and deep tissue bleeding. A comprehensive review should also include a pregnancy history and any
of systems that includes inquiry about weight gain history of genital trauma. Patients should be spe-
or loss; fatigue; constipation or diarrhea; dry skin/ cifically asked about any surgical history, includ-
hair/nails; development of acne and/or hirsutism; ing if they experienced abnormal bleeding with
changes in vocal tone; visual field abnormalities; surgery. In particular, brisk post-operative bleed-
palpitations; level of stress; lymphadenopathy; ing following a tonsillectomy, adenoidectomy, or
abdominal masses; abdominal or pelvic pain; oral surgery may be a clue to an underlying
vaginal discharge; dyspareunia; urinary symp- bleeding disorder, particularly if the patient
Table 1.11 Differential diagnosis for abnormal uterine bleeding in adolescents (American College of Obstetricians
and Gynecologists 2015; Emans and Laufer 2012)
Anatomic (eg, carcinoma, endometrial hyperplasia, hemangioma, polyp, sarcoma)
Anovulatory cycles
Immature hypothalamic-pituitary-ovarian axis
Hyperandrogenic anovulation (eg, polycystic ovary syndrome, congenital adrenal hyperplasia, androgen-
producing tumors)
Bleeding disorder (eg, hemophilia, hepatic failure, platelet function disorder, thrombocytopenia, von Willebrand
disease)
Foreign body or trauma
Hypothalamic dysfunction
Eating disorder
Significant, rapid weight loss
Stress-related
Idiopathic
Iatrogenic
Intrauterine device
Medication (eg, androgens, anticoagulants, antipsychotics, chemotherapy, hormonal contraceptives, selective
serotonin reuptake inhibitors)
Radiation
Other endocrine disorders
Hyperprolactinemia
Thyroid disease
Cushing syndrome
Primary ovarian insufficiency
Pregnancy or pregnancy-related complications
Sexually transmitted infections
Systemic disease
Celiac disease
Chronic kidney disease
Diabetes mellitus
Systemic lupus erythematosus

required a return to the operating room or trans- blood from the vaginal vault in order to allow
fusion. A complete medication list should be visualization of internal structures. If tolerated, a
obtained, including prescription, over the coun- bimanual examination should also be performed
ter, and herbal preparations. Among adolescents, to assess for pelvic masses.
two commonly encountered classes of medica-
tions that can impact bleeding include non- Testing
steroidal anti-inflammatory drugs (NSAIDs) and Findings from the history and physical examina-
selective serotonin reuptake inhibitors (SSRIs). tion should be used to guide laboratory testing
NSAIDs tend to diminish menstrual bleeding, (see Table 1.12). In patients complaining of heavy
though may worsen menstrual bleeding in indi- bleeding, but for whom a normal bleeding pattern
viduals with bleeding disorders. is described, reassurance without any additional
Social history should include a complete sex- testing may be appropriate. Otherwise, at a mini-
ual history, including screening for abuse or mum, a urine pregnancy test and complete blood
trauma. Family history should include questions count should be obtained in nearly every patient
about bleeding disorders and blood clots or clot- with the complaint of heavy bleeding. If there is
ting disorders, as well as the menstrual and preg- concern for significant anemia and/or cardiovas-
nancy histories of female relatives. Providers cular compromise, a type and screen or type and
should ask if any males have had bleeding with crossmatch should also be obtained. It is better to
circumcision, and if any relatives have had heavy obtain additional testing prior to transfusion, but
bleeding with surgeries, in particular tonsillec- treatment of an acutely unstable patient should
tomy and adenoidectomy or dental extractions. never be delayed solely to perform additional test-
ing. Clinicians can consider obtaining a ferritin
Physical Exam for patients in whom the history suggests clini-
Similar to the review of systems, the physical cally significant bleeding and the clinician is sus-
exam should be comprehensive. The clinician picious for a possible bleeding disorder.
should carefully attend to any signs of cardiovas-
cular compromise related to the heavy bleeding.
Decision of whether or not to pursue a pelvic Management
exam should be guided by history. An external
genitourinary exam should be performed in most The first role of the clinician is to triage the patient
cases, assessing for general anatomy, including to an appropriate level of care. The vast majority of
clitoromegaly; lacerations or lesions; and evi- patients with heavy menstrual bleeding can be
dence of urethral or rectal source of bleeding. An managed in the outpatient setting, but some will
internal exam can provide helpful information, require emergency intervention and/or hospitaliza-
particularly if you are suspicious for an anatomic tion. Patients with ongoing, severe bleeding and
or infectious cause, but is neither necessary nor moderate anemia are usually stabilized in the hos-
tolerable for all patients. A vaginal exam should pital. Exact cutoffs vary somewhat by institution
not be performed on a patient who does not will- and situation, but we recommend consideration of
ingly assent to the procedure. Some virginal hospitalization for patients with a Hgb <8–10,
patients will tolerate a single-digit vaginal exam especially if bleeding is not slowing down; or if the
to assess for foreign body or any palpable masses. patient has an unstable home situation, lack of clear
Most sexually active patients and some virginal follow up or inability to comply with medication
patients (especially those who use tampons) will regimen. For patients with a Hgb of 8–10, provid-
tolerate a speculum examination. If a patient is ers can consider close follow up and discharge
actively bleeding, it is helpful to have multiple home if bleeding is slowing, patient has transporta-
long, cotton-tip applicators on hand to remove tion to return for follow up, and is easily accessible

Table 1.12 Laboratory and imaging studies for initial evaluation of patients with heavy menstrual bleeding
All patients CBC with differential—obtain in all patients, to assess hematocrit,
platelet count, and rule out multi-cell line suppression that would
suggest a hematologic malignancy
Urine pregnancy test
Patients with no clear etiology identified on TSH with or without free T4
history or exam, OR with symptoms of
thyroid disease
Personal or family history suspicious for von Willebrand Screen (von Willebrand Factor antigen (vWF Ag),
bleeding disorder Factor VIII, vonWillebrand factor ristocetin cofactor activity)—It is
preferable to order these tests before starting treatment, as estrogen
can lead to elevation of vWF Ag and Factor VIII. An abnormal test
result in the setting of estrogen use is likely a true positive, but a
normal result may be a false negative. Test is most sensitive in first
3 days of menses, when estrogen and progesterone levels are at their
nadir. In an acutely bleeding patient, treatment should not be
significantly delayed to obtain the blood test
PT, aPTT, fibrinogen
Ferritin- increases sensitivity of screening for “true” heavy bleeding,
even in the face of a normal hematocrit and hemoglobin
TSH
Sexually active patients Gonorrhea and chlamydia PCR (urine or vaginal)
Patients with evidence of hyperandrogenism 17-OH-Progesterone
(acne, hirsutism, clitoromegaly) or family DHEA-S
history of PCOS
Free and total testosterone
Patients with significant anemia and/or Screen for bleeding disorder, as above
signs of cardiovascular compromise Type and Screen or Type and Cross
Other considerations Ultrasound—most providers do not get this first line unless history
suggestive of an anatomic abnormality; would consider second line
if patient not responding to therapy as expected
LH, FSH—can be supportive of a PCOS diagnosis if ratio > 3:1;
elevated FSH can suggest primary ovarian insufficiency and should
be considered for first-line screening in patients with a history of
malignancy, particularly if they had pelvic/abdominal radiation
Liver Function Tests- generally second line if coagulation studies
abnormal, along with bilirubin to assess synthetic function of the
liver; or first line if history suggestive of hepatic disease
Prolactin- particularly if periods irregular; more likely to cause
hypomenorrhea than heavy menstrual bleeding
with reliable phone number. Patients who are expe- edical Options for Menstrual
M
riencing severe anemia, Hgb <7, pancytopenia, Suppression
cardiovascular compromise (significant tachycar- Patients who report heavy bleeding, but are with-
dia, hypotension, persistently symptomatic ortho- out significant anemia and/or are not actively
stasis), or ongoing heavy bleeding should also be bleeding, are candidates for a number of menstrual
hospitalized. suppressive options. The 52 mg levonorgestrel-
Patients for whom the history reflects a bleeding containing IUD is an excellent long-term option
pattern that actually seems normal can be provided for menstrual suppression, leading to lightening of
with reassurance. However, if a teen’s bleeding periods in about 90% of users, and amenorrhea for
pattern is bothersome and impacting her quality about 40% of users (Hidalgo et al. 2002). It should
of life—even if within the realm of normal—it is be noted that the IUD does not provide immediate
quite reasonable to offer menstrual suppression. changes to bleeding patterns, and many women

experience ongoing bleeding and spotting for the acid with OCPs. This allows for less frequent and/
first few months after placement. Most women or lower dosing of estrogen, reducing unpleasant
have experienced a reduction in bleeding by about estrogen-related side effects such as nausea. At
6 months. It is an effective option for adults, with present, combined use of estrogen and fibrinolysis
studies showing that it is more effective than oral inhibitors has not been well studied and patients
medication options (Matteson et al. 2013; Gupta should be counseled about the theoretical
et al. 2013). Although most studies on the use of increased risk of clots. It is not known how this
this method for heavy menstrual bleeding have risk directly compares to the risk of clot with very
been done in adults, one small study in adolescents high-dose estrogen.
shows this to be a viable option for this age group Intravenous equine estrogen remains an option
as well (Adeyemi-Fowode et al. 2017) and we feel for patients who cannot tolerate oral estrogen or
that this practice is acceptable and safe in have ongoing bleeding even with frequent dosing
adolescents. of oral contraceptive pills. Many institutions are
Medication management is generally required moving away from this in favor of combining
to stop acute bleeding, and may be preferred by fibrinolysis inhibitors with combined oral contra-
some patients even if they do not require acute ceptives, but this is still an effective, reasonable
intervention. Combined estrogen-progesterone option that remains part of the standard treatment
contraceptive pills have been a mainstay of treat- pathway in many institutions. Patients who can-
ment for HMB for quite some time. For patients not take estrogen can use progesterone-only
without significant, active bleeding, once daily methods such as medroxyprogesterone acetate or
pills usually suffice. Providers can talk with the depot medroxyprogesterone acetate. As with
patient about continuous cycling if the patient combined oral contraceptive pills, dosing regi-
wishes to suppress menstruation completely. The mens are readily available (American College of
pill can be dosed two- to three-times daily in Obstetricians and Gynecologists 2013; Emans
patients who have acute bleeding but are being and Laufer 2012).
managed in the outpatient setting. For patients Non-steroidal anti-inflammatory medications
who are hospitalized with heavy bleeding, the (NSAIDs) such as naproxen or ibuprofen can
combined pills can be given more frequently; slow menstrual bleeding due to their anti-
however, many patients taking the pill at this fre- prostaglandin effects, and may suffice as mono-
quency require an anti-emetic. OCPs can be therapy for patients with mild complaints about
given rectally if the patient cannot take the pill their bleeding, or in combination with the IUD or
orally. We do not recommend intra-vaginal dos- a hormonal method. However, NSAIDs may
ing, as the pill is generally expelled in patients increase bleeding in women with a bleeding dis-
who have heavy flow. order so should be avoided in women with
Tranexamic acid (oral) or aminocaproic acid known/suspected coagulopathy.
(parenteral) are fibrinolysis inhibitors that are In rare instances, a procedural intervention
being used more frequently in lieu of, or in com- such as balloon tamponade is required. Surgical
bination with, oral contraceptive pills. Studies intervention such as dilatation and curettage,
show a reduction in bleeding by 30–55% with endometrial ablation or hysterectomy are gener-
these medications (American College of ally reserved only as a last-resort and are rarely
Obstetricians and Gynecologists 2013). indicated or necessary in the adolescent popula-
Tranexamic acid (trade name Lysteda) is a good tion. A gynecologist and a hematologist should
option for patients who wish to avoid the use of be involved in cases where bleeding is refractory
hormonal medications and do not want an IUD, or to medical treatment.
for those who do not want daily medication dos-
ing. It is taken only during menses, and does not Additional Treatment Considerations
provide menstrual suppression. For acute bleed- All patients with low hemoglobin and/or low fer-
ing, many providers will combine tranexamic ritin should be started on iron. Compliance with

prescribed iron regimens is variable; patients Caring for LGBTQ Teens

should be warned about potential side effects
(constipation and GI upset) and offered gentle Providers who work with adolescents are likely
stool softeners such as docusate, or bulking to encounter patients who identify as gay, les-
agents such as polyethylene glycol, if they are bian, bisexual, or transgender. Development of
prescribed high dose iron supplementation. We sexual orientation is often a long process that
recommend menstrual suppression (e.g., continu- spans childhood, adolescence and early adult-
ous cycling of OCP’s) until hemoglobin levels hood. Gender identity begins to develop in early
and iron stores are repleted, which may take sev- childhood (Weinraub et al. 1984). As part of the
eral months. Some patients may not tolerate con- HEADSS assessment, discussing gender identity
tinuous cycling due to breakthrough bleeding; if be as simple as asking “do you think of yourself
this occurs, patients may stop pills for 3–5 days as male, female, both, or neither?”
and then resume.
Patients who are diagnosed with an underly-
ing bleeding disorder may benefit from alterna- Terminology
tive therapies, such as DDAVP. Many academic
pediatric institutions now offer combined When talking with patients about gender and sex-
hematology- gynecology clinics to streamline uality, it is important to keep in mind the distinc-
management for adolescents with heavy mention between biological sex, sexual orientation,
strual bleeding and a known or suspected bleed- gender identity, and gender expression (Fig. 1.2)
ing disorder. If no such clinic is available, (Trans Student Educational Resources n.d.).
providers managing the patient’s gynecologic Sex assigned at birth sex is the assignment of
care are encouraged to partner with a local hema- people as male, female, intersex, or another sex,
tologist to determine the optimal management typically based on chromosome testing or the
strategy. appearance of external genitalia. People who are
born with ambiguous genitalia may be termed as
having differences of sexual development (DSD),
a topic not discussed in this chapter. People with
Fig. 1.2 The gender

unicorn. Reproduced
with permission from
Trans Student
Educational Resources
(TSER) http://www.
transstudent.org/
graphics

DSD are often assigned a sex based on best judg- by a discrepancy between a person’s gender iden-
ment of their families and providers (McCann- tity and that person’s sex assigned at birth”
Crosby and Sutton 2015) (American Psychiatric Association 2013). An
Gender identity is the internal feeling of being important distinction should be made between gen-
male, female, neither, both, or another gender. der nonconformity and gender dysphoria; not all
Aside from identifying as male or female, terms people who identify as gender non-conforming
that people may use to describe their gender have discomfort or stress associated with their gen-
include agender (neither male nor female), gender identity. The diagnosis of Gender Identity
derqueer, or non-binary, among others. A person Disorder, listed in the DSM-IV, is no longer
whose gender identity is the same as their bio- utilized.
logical sex may be referred to as cis-gender or Research is lacking on the rates that gender
gender conforming, while a person whose gender dysphoria persists into adulthood. One study
identity does not align with biological sex may found that intensity of gender dysphoria in child-
refer to themselves as transgender or gender hood correlated with persistence of gender dys-
non-conforming. A person who was assigned phoria into adolescence (Steensma et al. 2013).
female sex at birth and identifies as male is Nearly all people who have gender dysphoria in
referred to as a transgender male, while a person adolescence have persistence of gender dyspho-
who was assigned male sex at birth and identifies ria into adulthood (de Vries et al. 2011).
as female is a transgender female.
Gender expression refers to the external pre-
sentation of gender using things such as dress, Referral and Treatment
actions and demeanor. Gender expression does
not always align with gender identity. For exam- Each person with gender dysphoria should be
ple, a person may wear masculine clothing but treated with an individualized approach. Pediatric
identify as a female. patients with gender dysphoria should be treated
Sexual attraction or sexual orientation are by trained providers, typically in the fields of
terms that describe which type of person some- pediatric endocrinology and/or adolescent medi-
one is attracted to; this may be men, women, cine. In patients who present with gender dys-
both, or neither. Adolescents may use the term phoria, referral at a young age is preferable.
asexual to describe having no physical attraction These patients can be followed closely, and when
or pansexual to describe being attracted to people they begin having early signs of puberty, they
of all genders. Rather than trying to define a may choose to pursue use of puberty-blocking
patient’s gender and sexuality in the most accu- medications (Kreukels and Cohen-Kettenis
rate terms possible, we recommend having open 2011). These medications are analogs of gonado-
discussions with patients to determine the words tropin releasing hormone (GnRH) and work by
they use to identify themselves. blocking hypothalamic release of
With adolescent patients, it is critical to assess GnRH. Medications used include intramuscular
which parts of the patients’ gender and sexuality leuprolide injections, subcutaneous triptorelin
they have shared with family and friends. injections, and subcutaneous histrelin implants.
Patients may prefer to use different names and These medications block progression of puberty
pronouns with providers than they do with fam- in order to eventually allow an active decision
ily members. about development of either masculine or femi-
nine secondary sex characteristics.
Based on published guidelines, many provid-
Gender Dysphoria ers wait until adolescents reach 16 years of age to
begin cross-gender hormones, however some
The 5th Revision of the Diagnostic and Statistical providers are beginning to provide hormone ther-
Manual of Mental Disorders (DSM-V) defines apy at a younger age in order to allow patients to
Gender Dysphoria as “discomfort or stress caused progress through puberty along with their peers

(World Professional Organization for Transgender aging the stress of gender transition, and mak-
Health 2012). In people assigned female sex at ing the decision to pursue medical treatments
birth with gender dysphoria, suppression of men- such as cross-gender hormones and surgical
struation with hormonal contraception may pro- interventions (both of which have some level of
vide some relief of dysphoria. Surgical interventions irreversible effects). It is important that patients
are usually performed after patients reach adult- understand that the goal of psychotherapy is to
hood, and patients should be referred specifically to manage the stress, stigma and discomfort asso-
surgical specialists with experience working with ciated with gender nonconformity, not to
transgender patients. change or influence the patient’s gender
Many people who have significant gender identity.
dysphoria can benefit from psychotherapy. Not all patients will require all of the manage-
Therapists can provide support to patients in ment options available, and the order in which
navigating relationships with loved ones, man- these options are pursued may vary (Table 1.13).
Table 1.13 Management of gender dysphoria (World Professional Organization for Transgender Health 2012)
Psychotherapy Assistance with social transitions including gender expression and legal
name/gender changes
Support in family relationships
Hair removal Waxing
Electrolysis
Voice and communication therapy
Pubertal blockers (GnRH analogs) Leuprolide (Lupron-Depot®) intramuscular injection
Histrelin (Supprelin LA®) implant
Triptorelin (Trelstar®) subcutaneous injection
Menstrual suppression Oral contraceptive pills
Oral medroxyprogesterone
Intrauterine device placement
Vaginal ring (NuvaRing®)
Depot Medroxyprogesterone Injection
Masculinizing hormones Implantable, transdermal or parenteral testosterone
Feminizing hormones Androgen-blocking medications (i.e. spironolactone)
Oral, transdermal, or parenteral estradiol
Feminizing surgeries Facial feminization surgery
Thyroid cartilage reduction
Voice surgery
Breast augmentation
Penectomy
Orchiectomy
Vaginoplasty
Clitoroplasty
Vulvoplasty
Masculinizing surgeries Voice surgery
Mastectomy
Vaginectomy
Hysterectomy
Salpingo-oophorectomy
Phalloplasty
Scrotoplasty

Sensitive Care offered PrEP, a medication which can be taken

daily to prevent HIV. This is especially important
There are a number of measures that providers in those who have unprotected anal intercourse,
can take to ensure a safe and comfortable envi- which confers a high risk of HIV.
ronment for LGBTQ patients (Gridley et al. Transgender males should have regular STD
2016). Clinics may choose to include open-ended screening, and providers should continue to con-
questions on intake forms to allow patients to sider gynecologic etiologies if pelvic symptoms
describe their own gender, rather than offering arise. Transgender males should receive ongoing
only a few options to be selected. Clinic staff can birth control counseling and management, and
ask patients which pronouns they prefer—she/ should have routine pap smears starting at age 21.
her, he/him, they/them, or another option. LGBTQ youth are at high risk for family con-
Providers can make efforts to assess the patient’s flict and homelessness (Rice et al. 2013). We rec-
gender identity and sexual orientation privately, ommend assessing patients’ living situation to
knowing that a physician may be the first person ensure they have stable housing and safe relation-
with whom a youth feels comfortable discussing ships with family members. We also recommend
their sexuality or gender identity. Other measures assessing whether LGBTQ youth are being sexu-
that providers can take to maintain a welcoming ally exploited. After asking whether the patient is
environment for LGBTQ youth and families sexually active, providers may ask “have you ever
include providing gender-neutral bathrooms and had sex in exchange for drugs, money, or other
wearing or posting images that indicate that the things you needed?”
clinic is an LGBTQ-friendly space. LGBTQ youth are also at high risk for sub-
stance abuse, depression, and suicidality, espe-
cially if their sexuality or gender identity are not
ther Health Considerations in
O supported by friends or family (Puckett et al.
LGBTQ Patients 2016; Aitken et al. 2016). While these issues are
typically assessed in the HEADS assessment,
Regardless of whether an LGBTQ patient is providers should remain attuned to the fact that
referred for specialty care, primary care provid- LGBTQ youth are at higher risk for complica-
ers should continue to manage these patients for tions or escalation of what might be considered
their general healthcare needs. mild mental health issues or substance abuse. In
One issue of importance is sexual and repro- transgender patients, psychological well-being is
ductive healthcare. Girls who identify as lesbians often improved by treating gender dysphoria
should be offered routine STD screening, and birth (through methods listed in Table 1.13), however
control options should be reviewed and encour- it is important to diagnose and treat co-morbid
aged. Teens identifying as lesbian may sometimes mental illness as well (de Vries et al. 2014).
have physical relationships with men and have Resources for transgender patients and their fam-
been shown to have higher risk of pregnancy than ilies include:
teen girls identifying as heterosexual (Lindley and
Walsemann 2015). Risk of STDs with oral sex • Refuge Restrooms: Smartphone app and web-
should be reviewed and barrier methods such as site to search for gender-neutral bathrooms
dental dams should be provided and encouraged. • www.trevorspace.org: Social networking site
Men who have sex with men (MSM) are at for LGBTQ youth ages 13–24
high risk for STDs and should be screened fre- • www.thetrevorproject.org: or 866-488-7386:
quently using the CDC guidelines for STD pre- 24 hour crisis line for LGBTQ youth
vention (Centers for Disease Control and • www.pflag.org: A national organization with
Prevention 2015). This should include anal gon- local chapters to support LGBTQ people and
orrhea and chlamydia screening. MSM and trans- their families. Many chapters have support
gender people who have sex with men should be groups.

Media and Adolescents An increasing body of international literature

identifies problematic media use as an emerging
Technology is pervasive—an unavoidable part of area of concern in regard to social development
our modern environment. Today’s youth have and mental health, as well. Colloquially, this may
grown up in a world where personal devices, be termed media “addiction.” The DSM-V
instant information, and virtual connection are included Internet Gaming Disorder as an area for
the norm. Parents and providers alike may find it further study, but does not include internet or
difficult to keep up with the nuances of new tech- media addiction as official diagnoses. However,
nologies, particularly in this era of very rapid this remains an active area of ongoing research
change. Technological advances over the past and is a recognized diagnosis in some parts of the
few decades have come with new challenges and world. Regardless, problematic or excessive use
risks to adolescent health, in addition to creating has been associated with increased depressive
novel avenues for adolescents’ education, social symptoms, higher level of school burnout, and
connection, health promotion and civic lower measures of well-being (Mei et al. 2016;
engagement. Chang and Hung 2012; Kawabe et al. 2016;
In earlier childhood, parents are encouraged to Salmela-Aro et al. 2017).
closely monitor their child’s media usage. As Cyberbullying is a well-documented phenom-
young people progress through adolescence, enon, and is associated with increased risk of
however, this becomes more complicated. Teens depression, self harm and suicidality (Jacobson
often begin to use media more as contributors, et al. 2016; Moreno and Kolb 2012). Cyberbullying
rather than just consumers, and to build an indi- can present unique challenges due to the ability
vidual online presence. As they move toward for this form of bullying to occur anytime, any-
independence, adolescents make more autono- where; remain anonymous; and rapidly reach
mous media usage decisions. Parents are called large numbers of individuals.
upon to support their teen’s transition to self- Social media can create an illusion of what is
governing media usage, and providers may be normative, and lead teens to change their own
asked to give advice on age-appropriate limits behavior (Moreno and Kolb 2012). For example,
around media usage. Understanding the risks and exposure to pictures of friends engaging in sub-
benefits of media usage among teens can help stance use through social media is associated
providers and parents support the development of with higher levels of smoking and alcohol use,
healthy media behaviors. particularly among adolescents who do not have
high numbers of drinking friends (Huang et al.
2014). Social media is also rife with negative
Risks messaging regarding weight and body image,
which can promote disordered eating behaviors
Excessive media use has been associated with (Simpson and Mazzeo 2016; Holland and
numerous negative physical consequences, Tiggemann 2016; Sidani et al. 2016; Lydecker
namely obesity and obesity-related metabolic et al. 2016).
complications, although prospective, longitudi- Current technologies have also created numer-
nal studies are an ongoing research need as most ous new landmines in regard to sexual health and
studies to date have been cross-sectional (van development of adolescents. The worlds of por-
Ekris et al. 2016). There are negative correlations nography, solicitation and sex trafficking of
between screen time and sleep (Jacobson et al. minors are rapidly evolving in response to new
2016; Sayin and Buyukinan 2016), and texting technologies. Predators have increased access
while driving presents a significant threat to and anonymity to take advantages of youth, who
physical health related to increased risk of acci- may not fully understand the implications of their
dents (Jacobson et al. 2016). online actions. Similarly, youth may be more

prone to engage in risky, inappropriate or even Technology offers many positive ways to inter-
illegal sexual behaviors with and toward other act with teens around their health. As this technol-
teens, including solicitation, sexting, or photo- ogy grows, providers must remain mindful of
graphing/video recording sexual acts. maintaining patient confidentiality. For example,
more and more health systems are moving toward
granting patients online access to all or part of
Benefits their health record. Additionally, some clinics are
moving toward the use of text for things such as
Of course, there are also benefits to the increase appointment reminders, to follow-up on lab
in technology. New technologies generate oppor- results, or to reinforce behavior change goals set
tunities for social connection, civic engagement, during a visit. While the possibilities for
and novel educational applications (Moreno and technology- enhanced patient engagement are
Kolb 2012). Given the prevalence of smartphones exciting, they are not always straightforward in
and personal devices, technology can also be this age group. At present, many questions remain
used to help teens become more engaged in their unanswered in regard to managing parental and
health management. Websites (such as bedsider. teen access to medical documentation, which may
org) and free phone apps can be used to provide contain confidential information.
reminders to take birth control or other medica-
tions. Numerous studies have employed technol-
ogy to improve self management among teens Providers’ Use of Social Media
with type-1 diabetes (Vaala et al. 2015). Health-
related smartphone applications can be used to Patients have a window into their providers’
engage teens in health-related activities such as worlds unlike ever before through the use of
tracking their menstrual cycle, quantifying their social media. Patient-provider relationships can
exercise, adhering to a nutritional plan, or even be fractured if the patient or caregiver finds that
working toward recovery from an eating disorder. the provider has created, endorsed or is identi-
A number of high-quality, health-related web- fied in posts the patient finds inappropriate or
pages, blogs and twitter feeds are geared toward offensive. Nonetheless, numerous studies have
improving access for adolescents, a population documented that providers are often using social
with notoriously low health care utilization. media in ways that can negatively impact their
Some examples include: reputation with patients, often without realizing
that what they are posting is either public or
• www.youngwomenshealth.org: General infor- potentially inappropriate/offensive (Jain et al.
mation on health for adolescent and young 2014; Langenfeld et al. 2015; Osman et al. 2012;
adult females MacDonald et al. 2010). When interacting with
• www.youngmenshealthsite.org: General teens, we recommend working under the
information on health for adolescent and assumption that a patient or their caregiver could
young adult males potentially discover anything the provider posts.
• http://teenology101.seattlechildrens.org: Because adolescent health is so intimately
Adolescent health focused blog for parents of related to risk behavior reduction, the safest pol-
teens icy is not to post or endorse anything that you
• https://twitter.com/TeenHealthGov: Twitter would not feel confident having a patient or their
feed managed by the Office of Adolescent caregiver view. While the decision on how any
Health individual provider cultivates their online pres-
• http://www.crisistextline.org/textline: Web ence is up to the provider’s discretion, online
page including information on multiple crisis postings should never contain patient-related
phone and text contacts information, even if identifying information has

been removed. Many health care systems have guidelines around media usage, as well as discuss
developed their own policies for providers around anticipated consequences of failing to follow the
social media use. set guidelines. Whenever possible, adolescents
and their caregivers should engage in these discus-
sions before expanding an adolescents level of
asic Guidance for Parents
B autonomy over their own usage, such as prior to
and Patients giving a child his or her own smartphone.
However, it is never too late. We advise families to
Providers should have conversations around have these conversations when everyone is calm—
media usage early and often. At a minimum, the not, for example, immediately after there has been
AAP recommends asking the following two ques- a fight or major negative consequence related to
tions at every well visit with children and teens media usage. Some families may prefer to formal-
(American Academy of Pediatrics Council on ize their written conversation with a written con-
Communications and Media 2013): tract for certain items (such as a smartphone or a
new video game console). Every family situation
1. How much recreational screen time does your is different. We suggest giving families some start-
child or teenager consume daily? ing questions to consider (Table 1.14).
2. Is there a TV set or an Internet-connected Expectations will need to change as the teen
electronic device (computer, iPad, cell phone) matures, and because new issues will undoubtedly
in the child’s or teenager’s bedroom? come up along the way as technology continues to
evolve. Families may benefit from setting pre-
By opening the door to talking about media, determined times to check in on how things are
providers can help both parents and teens undergoing and make any necessary adjustments. Some
stand the risks and benefits of media usage. parents may seek guidance from their provider
Families should be encouraged to continue the around what the answers to these questions should
conversation around media usage with each other be, related to their child’s developmental stage.
at home. The AAP “SafetyNet” website (http://safetynet.
We recommend encouraging caregivers to set aap.org/) contains links to a number of high-qual-
aside devoted time to sit down with their adoles- ity websites for both parents and providers. The
cent to talk about media. Teens and their caregiv- AAP’s www.healthychildren.org website also has
ers should create a set of mutually agreed upon a section on media with useful tips for parents.
Table 1.14 Potential questions to guide discussion with families about media use
Where will the teen be allowed to use media devices? Only in public areas of the home? In their bedroom?
Elsewhere?
When is media usage allowed? Where will the device be kept during times the adolescent is not supposed to be
using it?
Are certain sites, apps, channels, games off-limits?
Are there restrictions on what or where the adolescent may post?
With whom may the adolescent engage virtually? Friends, family, friends-of-friends, others? What are family
expectations around communication with individuals who are only known virtually?
How should the adolescent respond if they encounter something or someone that is inappropriate or threatening? If
they experience or witness bullying, solicitation or someone else threatening to harm themself or others?
What aspects of the teen’s media usage will the parent have access to?
Who will pay any bills or fees associated with the media usage?
Are there other non-media related behaviors that could result in the device being taken away or usage restricted?

Transitioning to Adult Healthcare of drug use and sexual activity. Meeting with
teens alone beginning in early adolescence gives
Healthcare providers play a critical role in preparing them an opportunity to express their own health
children for adulthood. Just as young children ben- priorities and concerns. In private meetings, pro-
efit from support and practice to develop motor, ver- viders can use motivational interviewing
bal and social skills, older children can benefit from techniques to help direct adolescents to health
support and practice in managing health-related and topics of importance, including substance use,
non-health-related responsibilities. This process sexual health, and long term effects of any
must be started early in adolescence and evaluated chronic diseases they may have. A gradual shift
often (American Academy of Pediatrics et al. 2011). from parent-driven health concerns to teen-driven
Development of adult skills in the healthcare health concerns can help the teen patient to
setting is referred to by terms such as transition, slowly understand that they have control over
transfer of care and self-management. The neces- many aspects of their health. For adolescents
sary set of skills and behaviors may be very dif- with chronic illness, there is conflicting evidence
ferent for adolescents with and without special regarding the prevalence of health risk behaviors
healthcare needs. (e.g. substance use, disordered eating, and sexual
While there are various methods to assess risk-taking) as compared to healthy adolescents
transition readiness and assist in transfer of care, (Suris and Parera 2005; Surís 2002; Valencia and
there is currently no agreed-upon “best” tool or Cromer 2000). Adolescents with chronic dis-
program (Chu et al. 2015; Davis et al. 2014). eases may be particularly vulnerable to the effects
of health risk behaviors, and require consistent
health surveillance, which requires the coordina-
Developing a Policy for Transition tion of efforts between primary care physicians
and subspecialists (Lyons et al. 2014).
We recommend developing a clinic-wide prac-
tice for addressing transition and transfer of ealth-Related Skills and Knowledge
H
care (American Academy of Pediatrics et al. Providers and parents/families should work
2011). Www.gottransition.org has an array of together to assist teens with skill development.
resources available to assist with understanding Some skills and knowledge, listed in Table 1.16,
and managing the transition process (Table 1.15) are important for general participation in the
(The National Alliance to Advance Adolescent healthcare system (Moynihan et al. 2015).
Health n.d.). Patients with chronic diseases will have addi-
tional disease-related skills and knowledge to
master during adolescence.
Guiding Transition in Clinical Practice
Clinicians can be involved in several aspects of ransitioning Patients with Chronic

T
the transition process for adolescents, including Health Conditions
development of health values and health-related
skills, finding an adult provider, and planning for About 500,000 youth with special healthcare
future health needs. needs turn 18 each year (Data Resource Center
for Child and Adolescent Health n.d.; http://
Health Values www.childhealthdata.org/learn/NS-CSHCN).
Beginning in early adolescence, young people For patients with chronic diseases, subspecialty
begin to develop personal values about their providers often play a key role in assisting teens
health. These may include things like physical in developing self-management skills. Often,
appearance, physical abilities, nutritional priori- however, primary care providers are available to
ties, mood, and attitudes about the health impacts meet with patients and families more frequently

Table 1.15 The Six Core Elements of Transition (The National Alliance to Advance Adolescent Health n.d.)
Transition Develop a transition policy describing the practice’s approach to transition with input from youth
policy and families
Educate staff about the practice’s policy and the roles of the youth, family, and pediatric and adult
health care teams in the transition process
Post policy and share/discuss with youth and families beginning at age 12–14, and review
regularly
Transition Establish criteria and process for identifying transitioning youth/young adults and enter their data
tracking and into a registry
monitoring Utilize individual flow sheet or registry to track youth’s transition progress with the Six Core
Elements
Incorporate the Six Core Elements into clinical care process, using EHR if possible
Transition Conduct regular transition readiness assessments, beginning at age 14, to identify and discuss with
readiness families their needs and goals in self-care
Jointly develop goals and prioritized actions with youth and parent/caregiver, and document
regularly in a plan of care
Identify and list providers interested in caring for adults
For adult providers: establish a process to welcome and orient new young adults into the practice,
including online or written information about the practice and a “get-acquainted appointment”
Transition Develop and update a plan of care (readiness assessment findings, goals, medical summary,
planning emergency plan)
Prepare youth and parent for adult approach to care (legal changes, privacy and consent, access to
information)
Determine level of need for decision-making supports for youth with intellectual challenges
Plan with youth/parent for optimal timing of transfer
Assist youth in identifying an adult provider and communicate with selected provider
Link patient/parent to resources for insurance, self-care management, community support
Transfer of Complete transfer package, including final transition readiness assessment, plan of care with
care transition goals, medical summary, emergency care plan
Confirm date of first adult provider appointment
For adult providers:
Clarify adult approach to care (shared decision making, privacy, adherence)
Conduct self-care assessment and discuss needed self-care skills
Review young adult’s health priorities
Transfer Contact young adult and parent 3–5 months after last visit to confirm transfer to adult practice
completion Communicate with adult practice to confirm completion of transfer
Elicit feedback from young adult to assess experience with transition process
Build ongoing and collaborative partnerships with adult primary and specialty care providers
Adapted with permission from GotTransition.org
or consistently and can provide ongoing support chronic health condition, while others are spe-
as teens take gradual ownership over their chronic cific to common diseases.
illnesses. Fewer than half of children with special
There are several tools available to track an healthcare needs receive services within a medi-
adolescent’s progress as they develop the ability cal home. However, children who do receive care
to manage their chronic disease (Schwartz et al. within a medical home are nearly twice as likely
2014; The National Alliance to Advance to receive transition services (Data Resource
Adolescent Health n.d.). Some are “disease- Center for Child and Adolescent Health n.d.;
generic” and could apply to any patient with a Lotstein et al. 2005).

Table 1.16 Key health-related skills and knowledge (Moynihan et al. 2015)
Skills Carry health insurance information
Call healthcare provider with questions or concerns
Pick up prescriptions from pharmacy and call for refills
Transport oneself to appointments
Access urgent care resources
Schedule appointments
Attend routine health maintenance visits
Meet with providers alone
Prepare questions/concerns for appointments
Knowledge Know insurance carrier, general coverage plan, and find a covered provider
Understand effects of health risk behaviors (sexual activity, substance use, nutrition)
Understand how to prevent pregnancy and STDs
Understand how to assess risks and benefits of medical treatments
Medication Adherence Finding an Adult Healthcare Provider

In adolescents with chronic diseases, medication
adherence often becomes an issue of contention The process of identifying a new health care provider
between patients and their parents or providers. should begin long before the expected transition of
Several considerations may help the teen to care. This may be an opportunity for adolescents to
improve adherence. Firstly, providers must be begin taking over management of their healthcare;
confident that a teen fully understands their con- however, many teens will require the assistance of
dition, implications of non-adherence, and what their parents in this process. Clinic social workers
expectations providers have for achieving ade- may also be helpful, if available. Families will need to
quate disease control. It may also be helpful for work with their insurance companies to identify
teens to understand which areas of disease man- options for new providers, and should feel free to
agement are negotiable, such as not taking a vita- question their new adult provider(s) about their com-
min every day, and which lapses in self-care may fort in working with young adults.
be dangerous, such as not taking insulin (in the
case of a type 1 diabetic) or an immunosuppres-
sant medication (in the case of a patient with an
organ transplant). Secondly, providers should be
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Update in Pediatric Allergy
2
Amanda Ciccolini, Shannon French, Mark Tenn,
and Anne K. Ellis
Food Allergy Prevalence
Introduction The prevalence of food allergy is a challenging

entity to accurately determine because it is calcu-
Food allergy is a reproducible, abnormal immune lated based on variable factors, including allergy
response to a food. It is broadly categorized into definitions, methodologies, study populations
immunoglobulin E (IgE) and non-IgE mediated and more (Sicherer 2011). Many studies gather
reactions (Johansson et al. 2004). There are hun- data based on self-reported food allergy, which is
dreds of food proteins which have been reported as less accurate than confirming an allergy with an
allergens, however, the most common food aller- oral food challenge in a clinical setting (McGowan
gens in the North American population include and Keet 2013). Recent literature reviews con-
milk, peanuts, tree nuts, egg, shellfish, fish, wheat, clude that food allergy affects more than 1–2%
and soy which account for 90% of all food aller- but less than 10% of the population, however an
gies (“The Food Allergy and Anaphylaxis Network increased prevalence in food allergy has not yet
2016”). Food allergy remains one of the main been confirmed (Chafen et al. 2010).
causes of anaphylaxis presenting to the emergency In Canada the prevalence of food allergy is
department (Sampson 2004). This section will estimated to be approximately 7%, based on self-
give an overview of food allergy, with a focus on reported data (Soller et al. 2012). Recent data
the new literature that has emerged on the topic. suggests that food allergy is becoming more
prevalent. The US Centers for Disease Control
and Prevention completed a data brief in 2013
A. Ciccolini, M.D. • S. French, M.D. • M. Tenn, which demonstrated that among children age
B.H.Sc., M.Sc. Candidate 0–17 years, there was an increase in the preva-
lence of food allergies from 3.4% in 1997–1999
e-mail: 13ac51@queensu.ca; 14sbf@queensu.ca;
0mwt2@queensu.ca to 5.1% in 2009–2011 (Jackson et al. 2013). On a
global scale, studies from the UK (Kotz et al.
A.K. Ellis, M.D., M.Sc., F.R.C.P.C. (*)
Queen’s University, Kingston, ON, Canada 2011), China (Hu et al. 2010), the US, and
Australia (Osborne et al. 2011) have also demon-
Division of Allergy and Immunology, Department of
Medicine, Queen’s University, Kingston, ON, Canada strated an increase in the prevalence of food
e-mail: ellisa@kgh.kari.net allergy (Sicherer 2011).


40 A. Ciccolini et al.
Pathophysiology Risk Factors
Significant advancements have been made in the Family history, genetics, ethnicity, sex, geography
past few years to better our understanding of the and lifestyle are all thought to play a role in deter-
pathophysiology of food allergy, however there is mining the likelihood of developing food allergy.
still much to be discovered. Food allergy reactions Children are at a higher risk for developing food
are generally categorized into immunoglobulin E allergy if there is a first-degree relative who has an
(IgE)-mediated or non-IgE-mediated processes, allergic condition such as food allergy, atopic der-
although mixed processes also occur (Burks et al. matitis, allergic rhinitis or asthma (Muraro et al.
2012). IgE mediated food allergic reactions are 2004). A study done by Hourihane et al. showed
more common and occur quickly, with the onset that there is a sevenfold increase in the risk of
usually occurring minutes to two hours after inges- developing peanut allergy for a child with a sib-
tion. Following the initial consumption of the aller- ling or parent with peanut allergy (Hourihane
genic food, the allergic individual becomes et al. 1996). It has also been shown that in mono-
‘sensitized.’ The allergenic food protein stimulates zygotic twins there is a 64% likelihood of one
IgE antibody production which is specific to the twin developing a peanut allergy if their twin has
food. These antibodies then bind to basophil and a peanut allergy (Sicherer et al. 2000). In a
mast cells. When the allergenic food is later con- National Health and Nutrition Examination
sumed, it binds to its specific IgE antibody to acti- Survey study conducted from 2005 to 2006, Liu
vate an immune response involving histamine, et al. demonstrated an increased risk of develop-
leukotriene, and prostaglandin release. This ing food allergy in non-Hispanic black study sub-
response vasodilation, mucus secretion, and jects (Liu et al. 2010). Gupta et al. also completed
smooth muscle contraction, which causes the clini- a study in 2012 which also demonstrated increased
cal signs and symptoms of an IgE mediated aller- risk of food allergy in black and Asian subjects
gic reaction, such as urticaria (Sicherer and (Gupta et al. 2011).
Sampson 2010). The activated mast cells also The Western lifestyle has been associated with
release various cytokines which results in further an increased risk of food allergies, and this has
inflammatory cell recruitment. This can also be been demonstrated in North America, Europe,
responsible for late-phase allergic responses (Perry Australia and Asia (Graham-Rowe 2011). Children
and Pesek 2013). living in urban areas are more likely to develop
Non-IgE mediated food allergy is caused by a food allergy than those living in rural areas
T cell response to the allergenic food protein, (Majkowska-Wojciechowska et al. 2007). Specific
rather than an IgE response. This then results in a food allergies are more likely in certain areas of
cell mediated inflammatory response invoked by the world. For example, mustard seed allergy has
the activated T Cells. This reaction type usually been reported to be more common in France
results in gastrointestinal and dermatological (Rancé et al. 2000), and royal jelly allergy has
symptoms of allergy. Examples of non-IgE medi- been found to be more prevalent in Hong Kong
ated food allergies include food protein-induced (Leung et al. 1997). Interestingly, peanut allergy
proctocolitis, food protein-induced enterocolitis, has been found to be ten times more prevalent in
and dermatitis herpetiformis. Mixed IgE and Jewish children living in the UK than in Jewish
non-IgE mediated food allergy can also occur, children living in Israel (Du Toit et al. 2008).
and an example of this type of entity includes Several studies have demonstrated a relation-
eosinophilic esophagitis (Sicherer and Sampson ship between sex and likelihood of developing
2006; Sicherer and Sampson 2010). food allergy. Research done by Lie et al. looked

2 Update in Pediatric Allergy 41
at food specific IgE levels from 8203 participants gastrointestinal and cutaneous symptoms. An
in the National Health and Nutrition Examination example is food protein-induced enterocolitis
Survey and found that males had an increased syndrome (FPIES), which can present with gas-
risk of developing food allergy (Liu et al. 2010). trointestinal symptoms; typically profuse vomit-
Studies have also shown that risk stratification ing and diarrhea after ingestion of the allergenic
based on sex varies depending on age. As an food. FPIES usually presents in infancy and is
example, Sicherer et al. found in their study that often secondary to a reaction to infant formula or
male children were nearly five times more likely maternal breast milk (Sicherer 2005).
to develop peanut allergy than female children, A summary of IgE mediated and non-IgE
however male adults were not more likely than mediated reaction symptoms is listed by body
female adults to develop a peanut allergy system in the table below.
(Sicherer et al. 2003). Similar patterns have been
found for tree nut allergies (Emmett et al. 1999). Non-IgE-
mediated
IgE-mediated (delayed/
(immediate chronic
Clinical Presentation reactions) reactions)
Skin:
Food allergy has a broad and variable clinical pre- Urticaria √
sentation. Presentations can range from mild reac- Angioedema √
tions to life threatening depending on the severity. Erythema √ √
As mentioned above, food allergy can be IgE medi- Pruritus √ √
ated, non-IgE mediated, or a mix of the two. IgE Eczematous rash/ √ √
lesions
mediated reactions tend to occur quickly, while
Respiratory:
non-IgE mediated reactions tend to be delayed or
Laryngeal edema √
more chronic (Waserman and Watson 2011).
Rhinorrhea √
The mildest IgE mediated reaction is called
Bronchospasm √
the ‘oral allergy syndrome (a.k.a. pollen food
Nasal congestion √
syndrome)’. Individuals with this syndrome are
Cough √
usually pollen allergic and develop itchiness and
Chest tightness √
tingling of the oropharynx after consumption of Wheezing √
things like fresh vegetables and fruits. Oral Dyspnea √
allergy syndrome is caused by IgE antibodies Gastrointestinal:
cross reacting to certain pollens with proteins Angioedema of the √
found in fresh vegetables and fruit. The proteins lips, tongue, palate
are sensitive to heat, which is why some of these Oral pruritus √
individuals may tolerated these foods if they are Tongue swelling √
cooked, which denatures the protein. Skin testing Vomiting √ √
is typically negative for these foods in these indi- Diarrhea √ √
viduals (Conners and Waserman 2010). Pain √ √
IgE mediated allergic reactions can present Cardiovascular:
with cutaneous, respiratory, gastrointestinal, and Presyncope/syncope √
cardiovascular symptoms, with cutaneous reac- Hypotension √
tions being the most common (Boyce et al. 2010). Tachycardia √
Non-IgE mediated reactions tend to present with Waserman and Watson (2011), Perry and Pesek (2013)

Diagnosis Management
It is important to complete a relevant history and The main treatment for food allergy is strict
clinical examination to aid your diagnosis prior avoidance of the allergenic food (Boyce et al.
to completing investigations. 2010). All patients diagnosed with a food allergy
The history should include:

• Details of suspected foods causing allergy • Family history of allergic and atopic
diseases
• Manner of food preparation (i.e. cooked vs. raw, added • Description of all symptoms and severity
spices, oils, or other ingredients)
• Reproducibility of symptoms with food exposure • Duration of reaction
• Factors potentiating allergic reactions (i.e. NSAIDs use or • Occurrence of bimodal or delayed reaction
exercise) (Sicherer and Sampson 2010)
• Route of exposure (i.e. ingestion, inhalation, skin contact) • Response to treatment
• Timing of the onset of reaction • Episodes requiring hospital presentation or
admission
Physical examination:
Physical examination during an allergic reaction can yield many of the signs and symptoms of allergy that were
previously described above. However, assessments are not always done while allergic reactions are occurring. The
physical examination in these cases is useful in assessing for evidence of atopic and allergic disease, such as atopic
dermatitis. It is also important to rule out other conditions which can mimic food allergy. All pediatric physical
examinations should also include assessment for overall health, growth and nutrition status
Diagnostic tests
1. Skin prick testing:
sterile needle
positive test:
area becomes red and swollen
suspected allergen
a number of suspected allergens are

tested on the arm at the same time
• Rapid, safe and sensitive screening method for suspected IgE-mediated food allergy
• Positive SPT appears as a wheal and flare when the food extract is applied to the skin and pricked
• The larger the wheal size the more likely that a clinical allergy exists
• Takes less than 20 min to complete
• Can be done on infants in first few months of life
• Positive SPT has a sensitivity of roughly 90%, although specificity is only approximately 50%
• SPT should only be completed for foods that are relevant to the patient history
• SPT has a negative predictive value of >95% (Sampson 2004; Scurlock et al. 2005; “Allergy Skin Test 2016”)

2. Serum-specific IgE testing:

• Specific IgE antibodies to foods can be quantified by in vitro laboratory methods
• Less sensitive and more expensive than SPT
• Predictive value of serum-specific IgE testing may be affected by patient ethnicity, age, and time since last
ingestion of food allergen (Celik-Bilgili et al. 2005)
• May be useful where SPT is not possible (i.e. dermatographism or generalized dermatitis) or if SPT is
negative and there is a high degree of clinical suspicion of food allergy (Boyce et al. 2010)
3. Oral food challenge
• Considered the gold standard for diagnosis of food allergy
• Time consuming
• May be appropriate if diagnosis is uncertain based on results of SPT and/or serum-specific IgE levels
• Involves ingesting gradually increasing portions of the suspected food
• Must be done under careful physician supervision with frequent assessments for symptoms of allergy
• Should only be done in locations where anaphylaxis can be appropriately treated (i.e. hospitals, clinics)
• Challenge is stopped if symptoms develop and treatment is given if required (Nowak-Wegrzyn et al. 2009)
4. Elimination diet
• Requires strict avoidance of suspected food for a time period (usually 1–2 weeks)
• Patient is then monitored for a decreased in their symptoms
• Limitations include bias, patient compliance and this being a time consuming endeavor (Sicherer and
Sampson 2010)
5. Patch testing
• Involve exposing skin to a food allergen for 24 h under occlusion, then assessing skin for signs of allergic
reaction (i.e. erythema) in the subsequent 24–72 h
• Routine use for food allergy is not recommended due to lack of evidence and standardization (Bernstein et al.
2008)
• Shown to have value in assessing potential food triggers in pediatric eosinophilic esophagitis (Spergel et al.
2012)
6. Basophil activation test
• Relatively new assessment of basophil response to food allergen
• Limited to research currently and not recommended for clinical setting (Leysen et al. 2011)
should be prescribed an epinephrine autoinjector, wear medic alert bracelets (Conners and
which should be dosed according to weight in the Waserman 2010).
pediatric population and kept with the child at all Patients with suspected food allergy should
times (Sicherer and Simons 2007). Parents, chil- be referred to an allergist to confirm the diag-
dren, care givers and schools should be trained in nosis and investigate for other potential aller-
epinephrine administration (Sicherer and gies. The natural history of food allergy is
Sampson 2010). If patients have received emer- quite variable depending on the allergen and
gency epinephrine they must be brought to the the patient. Some food allergies are commonly
hospital for observation and assessment. outgrown, such as egg (Savage et al. 2007),
Epinephrine autoinjectors should be stored at the while others are generally lifelong. Long term
appropriate temperature and checked regularly management should involve regular assess-
for their expiration date. Patients and caregivers ment and testing for evidence of tolerance to
must also receive education on food avoidance foods that the individual previously developed
and label reading, identification and treatment of reactions to, and also for the development of
allergic reactions, and how to obtain medical new food allergies (Fleischer et al. 2003;
assistance. Food allergic individuals should also Sicherer 2011).

Prevention and New Research A follow up trial to the LEAP study was done
to determine if the rate of peanut allergy remained
The American Academy of Pediatrics in the year low after a 12-month period of peanut avoidance
2000 recommended delaying the introduction of in the study group who had an early introduction
potential high risk foods for infants at an elevated to peanuts. This was compared with the group
risk of developing allergy (e.g., cow’s milk pro- who avoided peanuts until age 60 months. This
tein until 1 year of age, peanut until 3 years of follow up trial, called the LEAP-ON study, fol-
age) (Fleischer et al. 2005). This was solely based lowed 556 of the original 640 children who par-
on expert opinion because, at the time, there was ticipated in LEAP (both consumer and avoiders)
no convincing data to support this. Fortunately, for 12 months of complete peanut avoidance. In
this has now changed. Since 2000, there has been the LEAP-ON study there were 274 previous
a large amount of new evidence to suggest that peanut consumers and 282 previous peanut
delayed introduction of high risk foods has no avoiders. All of these individuals were followed
effect on preventing allergy, and rather it may for 1 year of peanut avoidance, and at completion
actually increase the likelihood of developing an it was found that only 4.8% of the original peanut
allergy to these foods (Nwaru et al. 2013). In consumers were found to be allergic, compared
2008 the American Academy of Pediatrics issued to 18.6% of the original peanut avoiders. This
a new guideline which confirmed that there was demonstrates that a 12-month period of peanut
no convincing evidence to show that delaying avoidance was not associated with an increase in
solid food introduction, including peanuts, fish, the prevalence of peanut allergy in children who
and egg, past 4–6 months of age has a significant have been introduced to peanuts in the first year
effect towards preventing allergy (Greer et al. of life and continued until age 5. For the most
2008). part, the immune system has been shown to sus-
Nearly a decade ago the Learning Early About tain its tolerance in these individuals, despite a
Peanut (LEAP) study was started in the United break in regular exposure to peanuts (Du Toit
Kingdom. This study was a prospective trial et al. 2016).
which aimed to investigate whether early intro- While the LEAP trial showed success with
duction of peanuts to the diet may be protective peanuts and high-risk infants, it did not look at
from the development of peanut allergy. The whether this method could prevent allergies in
LEAP trial randomly assigned over 600 high-risk children in the general population, and if it could
infants age 4–11 months to either an early intro- be applied to other common dietary allergens.
duction of peanut protein (at 4–10 months of age) The Enquiring about Tolerance (EAT) study
or delayed introduction (at 5 years of age). Infants investigated whether early introduction of com-
assigned to the early introduction were fed a min- mon dietary allergens from 3 months of age in
imum of 6 g of peanut protein per week, distrib- exclusively breast-fed infants in the general pop-
uted in at least three meals per week, until the age ulation would prevent food allergies, compared
of 60 months. Infants in the late introduction with infants who only receive breast milk for
group were instructed to avoid peanut until the approximately 6 months. A total of 1303 exclu-
age of 60 months. All participants were assessed sively breast fed 3 month old infants were
at baseline, 12, 30 and 60 months of age. Of the recruited from the general population, and ran-
children in the avoidance group, 17% developed domly assigned to the exclusive breast feeding
a peanut allergy by the age of 60 months. group until approximately 6 months, or the early
However, in the early introduction group, only introduction of six allergenic foods group. These
3% developed a peanut allergy by age 60 months. six foods were cooked egg, peanut, cow’s milk,
It was concluded that the early introduction of sesame, whitefish, and wheat. They were regu-
peanuts in high-risk infants decreased the fre- larly assessed for food allergy to one or more of
quency of peanut allergy (Du Toit et al. 2015). these six foods between 1 and 3 years of age.

Results of this study were variable. There was both. It was also recommended that parents of
a significant 67% lower relative risk of food high risk infants check with their health care pro-
allergy overall in the early-introduction group, viders prior to introducing peanuts. Health care
but only in those that adhered strictly to the study providers may consider doing specific IgE blood
protocol by consuming the recommended testing, skin prick testing and/or an oral food
amounts of the allergenic foods. As well, in those challenge before introducing peanut-containing
who adhered strictly to the diet the prevalence of foods for high risk infants.
any food allergy was significantly lower in the The second guideline addendum proposes that
early introduction group than in the group who peanut-containing foods be introduced to infants
was exclusively breast-fed until approximately who have mild to moderate eczema around
6 months of age (2.4% vs. 7.3%, P = 0.01) The 6 months of age in order to reduce their risk of
prevalence of peanut allergy (0% vs. 2.5%, developing a peanut allergy. The expert panel
P = 0.003) and egg allergy (1.4% vs. 5.5%, suggests that infants in this category may have
P = 0.009) was also lower in this group. However, peanut-containing foods introduced in their
significant effects were not observed with milk, home, however recognizing that some health care
fish, wheat or sesame. Interestingly, higher levels professionals may prefer to supervise this in their
of peanut and egg-white ingestion were associ- office. The third addendum suggests that infants
ated with lower prevalence of allergies to peanut who do not have any food allergies or eczema
and egg, compared with lower ingestion levels. may have peanut-containing foods freely intro-
This raises the question as to whether preventing duced. It is recommended in all cases, however,
food allergies through early introduction of aller- that other solid foods be introduced prior to
genic foods was dose-dependent. It was found peanut-containing foods to ensure that the infant
that the early introduction of all six foods was is developmentally ready for solid food
safe, however challenging to eat the recom- introduction.
mended amounts. Despite the promising findings NIH-sponsored expert panel issues clinical
listed above, overall this trial did not show the guidelines to prevent peanut allergy [Internet].
efficacy of early introduction of allergenic foods National Institutes of Health (NIH). 2017 [cited 6
in an intention-to-treat analysis. This study was April 2017]. Available from: https://www.nih.
published in The New England Journal of gov/news-events/news-releases/nih-sponsored-
Medicine in May 2016. More research is cur- expert-panel-issues-clinical-guidelines-prevent-
rently being done in this area of allergy and peanut-allergy
immunology.
In response to the new evidence found in some
of the aforementioned studies, in January 2017 Atopic Dermatitis
the National Institute of Health issued a new
three-part addendum to the current clinical guide- Updates in Atopic Dermatitis
lines on the early introduction of peanuts-
containing foods to infants. The guidelines are Atopic dermatitis (AD) is the most common
aimed at a variety of health care professionals, chronic inflammatory skin disorder in children,
and are meant to help clarify peanut introduction affecting up to 30% of infants, and is characterized
for infants at different levels of risk of developing by pruritus (itchy skin), enhanced transepidermal
a peanut allergy. Part one of the addendums rec- water loss (TEWL; outward loss of water), reduced
ommends that infants at high risk of developing skin barrier function, and increased permeability to
peanut allergy should have peanut-containing environmental allergens (Bieber 2008; Hon et al.
foods introduced to their diets as early as 2013). Moreover, 50% of children with AD often
4–6 months. Infants were deemed to be high risk demonstrate symptoms within the first 6 months of
if they already had severe eczema, egg allergy or life, highlighting the need for i nterventions

targeting the skin barrier in infants early in life to (emollient used as needed by parents) group
reduce the risk of AD (Bieber 2008, 2010). (P = .012, log-rank test) (Horimukai et al. 2014).
Currently, the main treatments for AD include topi- In the same cohort of Japanese high-risk neo-
cal corticosteroids (TCSs), topical calcineurin nates, a retrospective post-hoc analysis was recently
inhibitors (TCIs), and topical emollients. The goals performed to evaluate the efficacy of different mea-
of these treatments are to reduce both skin inflam- surements of neonatal skin barrier function in pre-
mation and pruritus, and maintain skin barrier dicting AD development. The investigators
hydration. TCSs are commonly used to treat severe observed a significantly higher incidence of AD in
and chronic cases of AD. However, long-term use neonates with high TEWL (defined as ≥6.5 gwater/
of TCSs is often associated with both local (includ- m2/h) than in neonates with low TEWL (defined as
ing skin atrophy or “skin thinning”) and systemic <6.5 gwater/m2/h), reporting a hazard ratio (HR) of
adverse events (including hypertension and hyper- 2.00 (95% CI, 1.05–3.80; P < .05). Similar findings
glycemia), restricting their use on thin- skinned were observed in the control group (HR, 2.65; 95%
areas such as the eyelids (Silverberg et al. 2016). CI, 1.16–6.06; P < .05), but not for the intervention
TCIs have also been available for AD treatment for group (HR, 1.60; 95% CI, 0.57–4.49, P = .368). All
over a decade. They relieve inflammation by inhib- TEWL measurements were made within the first
iting the production of pro-inflammatory cytokines 7 days of life and were made on the forehead
from T cells (Kalavala and Dohil 2011). However, (Horimukai et al. 2016). Moreover, these findings
physicians may be reluctant to prescribe TCIs to were confirmed in a recent prospective birth cohort
their patients due to the FDA Black Box warning study following infants up until 12 months of age.
highlighting the theoretical lymphoma risk associ- With mean forearm TEWL measured at 2 days and
ated with TCI usage (Siegfried et al. 2013). Topical 2 months after birth, infants with day 2 TEWL
emollients are mixtures of fats and oils that form an readings ≥9.0 gwater/m2/h exhibited an increased
occlusive layer on the skin, preventing water evap- odds of developing AD at 12 months compared to
oration and maintaining skin hydration (Hon et al. infants with day 2 TEWL readings <9.0 gwater/m2/h
2013). Emollients may appeal to children of all (odds ratio [OR], 7.1; 95% CI, 1.8–12.9; P = .001).
ages due to the low amount of associated side Similar results were also seen in infants with
effects and has been a focus of AD prevention in 2 month TEWL readings ≥12.3 gwater/m2/h com-
recent studies. pared to infants with 2 month TEWL readings
The efficacy of emollients in reducing the <12.3 gwater/m2/h (OR, 7.9; 95% CI, 1.7–25.0;
incidence of AD in high-risk neonates (defined as P = .01) (Kelleher et al. 2015).
having a parent or sibling with AD, asthma, or Overall, these studies support the use of emol-
allergic rhinitis) was recently investigated in a lient therapy as a simple and low-cost interven-
randomized controlled trial. The investigators tion that could be used from birth to potentially
observed a significant association between daily reduce the risk of AD. The latter two studies also
full-body emollient therapy and reduced AD highlight the use of TEWL measurements taken
incidence at 6 months of age. Forty-three percent as early as 2 days after birth as an effective tool in
of untreated infants developed AD at 6 months of identifying neonates at high risk of AD. TEWL
age compared with the 22% observed in the measurements are non-invasive, quick to per-
emollient-treated infants, reporting a relative risk form, and can identify high risk infants in time to
reduction of 50% (relative risk, 0.50; 95% confi- start preventative interventions.
dence interval [CI], 0.28–0.90; P = .017)
(Simpson et al. 2014). This protective effect was
replicated in a separate cohort of high-risk ilaggrin Mutations and Skin Barrier
F
Japanese neonates. Approximately 32% fewer Function
neonates in the intervention (daily emollient
application) group developed AD/eczema by Filaggrin (FLG) is a critical structural protein
week 32 compared to neonates in the control involved in the maintenance of proper skin barrier

function and is primarily expressed in keratino- ood Allergy Risk with Atopic
F
cytes located in the stratum granulosum. Initially Dermatitis
made as profilaggrin polymers, these polymers
are dephosphorylated and cleaved to form FLG Skin barrier impairment is often shown to pre-
monomers, which aid in the maintenance of natu- cede allergic disease development. This is known
ral moisturizing factors (NMFs; a group of as the atopic march, the tendency for infants to
metabolites that help maintain skin hydration and progress from AD to other allergic diseases
pH) and the transformation of keratinocytes into (including food allergy and asthma) in later life
corneocytes in the skin (Proksch et al. 2008; (Bantz et al. 2014). An impaired skin barrier
Sandilands et al. 2009; Thyssen and Kezic 2014). brought upon by AD or FLG null mutations is
Null mutations in the gene encoding FLG pro- thought to enhance the percutaneous penetration
duce truncated profilaggrin polymers, leading to of food protein, augmenting the risk of both food
abnormal keratinocyte morphology, skin barrier sensitization (FS) and food allergy (FA) in
impairment, and increased permeability to envi- children.
ronmental allergens (Brown and McLean 2012). The association between AD and both FS and
While the prevalence of FLG null mutations is FA in children has been evaluated in a very recent
estimated to be 10% in the normal population, systematic review. In the identified population-
this proportion can largely vary depending on based studies, approximately 15% of children
race with prevalence being as low as <1% in the with AD developed FA symptoms after a food
African population (Thyssen and Kezic 2014; challenge while up to 60% of children with AD
Asai et al. 2013). These mutations also represent were also reported to be food sensitized. The
the strongest genetic risk factor for AD develop- investigators also observed a significant associa-
ment (McGrath 2012). Initially observed in an tion between AD and overall FS in 3 month old
Irish cohort of children with dermatologist-diag- children (OR, 6.18; 95% CI, 2.94–12.98;
nosed AD, the strong association between FLG P < .001). Although the adjusted OR for sensiti-
null mutations and AD has been confirmed in zation to different foods (including peanut, milk,
several meta-analyses, reporting an overall OR of and egg) varied, the reported values remained
3.12–4.78 (Palmer et al. 2006; van den Oord and statistically significant (Tsakok et al. 2016). The
Sheikh 2009; Rodríguez et al. 2009). relationship between early-life skin barrier
Recent studies have also reported an associa- impairment and the development of FS and FA at
tion between FLG null mutations and disease 2 years of age was also examined in a recent pro-
severity in pediatric AD. A prospective birth spective birth cohort study. Infants were followed
cohort study followed children from 1 month up until 2 years of age with mean TEWL measured
until 7 years of age and observed that children at 2 days after birth (neonatal), 2 months, and
with FLG null mutations had an early age of AD 6 months of age. The investigators observed a
onset (246 vs. 473 days; P < .0001) and more significant association between FA development
widespread dermatitis (10% vs. 6% of body area; at 2 years of age and having top-quartile neonatal
P < .001) compared to children without mutations TEWL (defined as >9 gwater/m2/h) compared to
(Carson et al. 2012). Moreover, a separate pro- infants with bottom-quartile neonatal TEWL
spective cohort study demonstrated that children (defined as ≤5 gwater/m2/h), reporting an OR of
with FLG null mutations had more persistent AD, 18.7 (95% CI, 7.13–49.3; P < .0001). Even in
and were 50% less likely to have symptom-free infants without AD, those with top-quartile neo-
skin over a 6-month period compared to children natal TEWL were more likely to develop FA at
without mutations (OR, 0.54; 95% CI, 0.41–0.71; 2 years compared to infants with bottom-quartile
P < .0001) (Margolis et al. 2012). Altogether, neonatal TEWL (OR, 3.5; 95% CI, 1.3–11.1;
these findings highlight the strong association P = .04) (Kelleher et al. 2016). Overall, these
between FLG null mutations and both the devel- findings support the strong relationship between
opment and severity of AD in children. AD and FS/FA development in children, and

highlight for the first time the association between AD in both pediatric and adult patients. TCIs avoid
changes in skin barrier function at birth and FA the risk of skin atrophy and percutaneous/systemic
development at 2 years of age. absorption through the skin (both commonly asso-
Although FLG null mutations can impair the ciated with TCS usage) and is the only approved
skin barrier, the association with food allergy drug for the management of chronic pediatric AD
development has only been recently investigated. (Siegfried et al. 2013). There are currently two
In a cross-sectional study involving a mixed approved TCIs available for use: pimecrolimus
cohort of English, Dutch, and Irish children, FLG (available as a 1% cream) and tacrolimus (available
null mutations were significantly associated with as a 0.03 and 0.1% ointment). Both inhibit the
peanut allergy, yielding an overall OR of 5.3 actions of calcineurin, a calcium-binding messen-
(95% CI, 2.8–10.2; P = 3.0 × 10−6). Even after ger protein, thereby preventing the production and
controlling for coexisting AD, the association release of pro-inflammatory cytokines and media-
remained significant (Brown et al. 2011). Another tors from T cells and mast cells (Kalavala and Dohil
prospective birth cohort study followed children 2011). Common side effects associated with TCI
from birth up until 11 years of age and found a usage include site-specific burning and pruritus
significant association between FLG null muta- (itching of the skin). Although several clinical trials
tions and early-life environmental peanut expo- have demonstrated the efficacy of both pimecroli-
sure (EPE). Children with FLG null mutations mus and tacrolimus over TCS in the management
demonstrated a sixfold and threefold increase in of AD in children (Kalavala and Dohil 2011), a US
the odds of peanut sensitization and peanut FDA Black Box warning was implemented in
allergy to increasing house dust peanut protein January 2006 highlighting the theoretical associa-
levels respectively compared to children without tion between TCI usage and lymphoma/skin mela-
mutations (Brough et al. 2014). Similarly, chil- noma development, the lack of long-term safety
dren with either AD (OR, 1.97; 95% CI, 1.26– data for both pimecrolimus and tacrolimus, and
3.09, P < .01) or severe AD (OR, 2.41; 95% CI, emphasized its use only in adults and children
1.30–4.47, P < .01) also had an increased risk of ≥2 years of age. (Segal et al. 2013; Siegfried et al.
peanut sensitization associated with EPE (Brough 2013). Since the warning was issued, several physi-
et al. 2015). Regarding different types of foods, cian groups (including the Canadian Society of
the odds of being reactive to at least one food Allergy and Clinical Immunology and the American
(including different types of tree nuts, eggs, soy, Academy of Dermatology) have raised concerns
and milk) was also increased in children with regarding the validity and need of the warning due
FLG null mutations compared to children with- to the apparent lack of evidence from human stud-
out mutations, reporting an OR of 4.9 (95% CI, ies (Segal et al. 2013; Berger et al. 2006).
1.6–14.7; P = .005) (van Ginkel et al. 2015). To date, several studies have been conducted
In summary, these studies emphasize the to evaluate lymphoma risk associated with both
importance of the skin barrier in the development pimecrolimus and tacrolimus in the management
of both FS and FA in children. With several stud- of pediatric AD. In a longitudinal cohort study of
ies consistently observing an increased FS and the Pediatric Eczema Elective Registry cohort, no
FA risk in children with AD or FLG null association was found between increased lym-
mutations, early introductions of interventions
phoma risk and topical pimecrolimus use in
aimed at repairing the skin barrier may be benefi- patients 2–17 years old, yielding standardized
cial in reducing the risk of FA development. incidence ratios of 1.2 (95% CI, 0.5–2.8), 2.0
(95% CI, 0.5–8.2), and 2.9 (95% CI, 0.7–11.7)
for all reported malignancies, leukemia, and lym-
afety of Calcineurin Inhibitors
S phoma cases respectively. None of these findings
in Atopic Dermatitis reached statistical significance (Margolis et al.
2015). Similar results were also observed in a
Since their introduction in 2001, TCIs have been recent retrospective cohort study of patients with
used as alternatives to TCSs for the treatment of atopic and endogenous eczema, reporting

adjusted HRs for overall malignancy of 1.30 Despite the FDA Black Box warning, these
(95% CI, 0.59–2.45, P = .460) and 0.82 (95% CI, studies suggest that there is no significant asso-
0.44–1.39, P = .508) for pimecrolimus-exposed ciation between TCIs and increased lymphoma
and tacrolimus-exposed respectively when com- risk. Long-term safety profiles have been demon-
pared to the unexposed group (Cai et al. 2016). strated for both pimecrolimus and tacrolimus in
Furthermore, two recent meta-analyses observed children, and pimecrolimus has been established
no significant association between lymphoma as a potential non-TCS alternative for young
and malignancy risk and use of TCIs in the man- infants (≤2 years of age) with mild-to-moderate
agement of AD (Legendre et al. 2015; Broeders AD, associated with TCS-sparing effects and
et al. 2016). These findings together suggest that excellent treatment success.
in both children and adults with AD, pimecroli-
mus and tacrolimus are not significantly associ-
ated with increased lymphoma risk. Allergic Rhinitis
Two recent clinical studies have evaluated the
long-term safety associated with tacrolimus and Allergic rhinitis is estimated to affect 20–25% of
pimecrolimus use for AD management in a 4 and the Canadian population and has a significant
5 year follow-up study respectively (Reitamo impact on quality of life, with many patients report-
et al. 2008; Sigurgeirsson et al. 2015). Although ing inadequate control of their symptoms (Keith
both studies reported adverse events, these events et al. 2012). Mainstays of treatment for allergic rhi-
were minor and included skin infection, skin nitis include avoidance, intranasal steroids, oral
burning, and pruritus. Of note, nine malignancy antihistamines and leukotriene receptor antagonists
and carcinoma cases (out of 690 patients aged (Small and Kim 2011). Specific immunotherapy
2 years and older) were reported in the 4 year offers the advantage of disease- modifying treat-
study. However, an independent monitoring ment for those uncontrolled by, intolerant or adverse
board did not find an association between the to pharmacotherapy (Moote and Kim 2011).
cases and tacrolimus use (Reitamo et al. 2008). Currently two types of allergen immunother-
Both follow-up studies demonstrated that tacroli- apy are used clinically: subcutaneous immuno-
mus and pimecrolimus have excellent long-term therapy (SCIT) and sublingual immunotherapy
safety profiles when used to treat AD. Moreover, (SLIT). SLIT was first accepted as an alternative
not only was pimecrolimus well-tolerated after to SCIT by the WHO in 1998, and then incorpo-
5 years of follow up, the study population was rated into the ARIA guidelines (Canonica et al.
comprised of infants aged 3–12 months, suggest- 2009; Bousquet et al. 2008). While SLIT has
ing that pimecrolimus can be used to treat infants been available in Europe for decades, Canada
≤2 years of age with mild-to-moderate first approved a sublingual grass immunotherapy
AD. Within the 5 year open-label study, >85% of tablet in 2012. At present there are three sublin-
infants achieved overall treatment success with gual tablet immunotherapy products on the mar-
minimal side-effects on the immune system ket in Canada (Table 2.1), two of which are
(Sigurgeirsson et al. 2015). approved for use in the pediatric population
Table 2.1 Health Canada approved sublingual immunotherapy tablets

Timing of
initiation before
Extract composition Age indication Dose initiation pollen season Daily dose
Oralair® 5 grass pollen 5–50 years 3 day escalation 8–16 weeks 300IR
Grastek® Timothy grass 5–65 years Full dose At least 8 weeks 2800 BAU
pollen
Ragwitek® Short ragweed 18–65 years Full dose At least 12 Amb a
pollen 12 weeks 1-U
Merck Canada Inc. (2013), Merck Canada Inc. (2014), Paladin Labs Inc. (2012)

(Oralair® and Grastek®). The sublingual route of 1% of the placebo group (Radulovic et al. 2011).
immunotherapy offers several potential benefits In an extensive 2013 systematic review the
over the subcutaneous route including: the com- authors comment on the lack of a standardized
fort of avoiding injections, convenience of home grading system for adverse events among studies,
administration and a favourable side effect pro- and the inconsistent reporting of adverse events
file (Hankin and Cox 2014; Dranitsaris and Ellis as a whole. They deem the evidence insufficient
2014). to comment on safety, but do note that while local
reactions were common, severe systemic reac-
tions were rare with no reported cases of anaphy-
How Effective Is SLIT? laxis (Lin et al. 2013).
Clinical trials of Grastek® estimated the rate of
Strength of evidence is seen to support use of severe adverse events at 2.9% versus 1% of the
SLIT in children in a 2013 systematic review by placebo population. The most common local
Lin et al. (2013). This evidence was based on reactions were oral pruritus (26.7%), throat irrita-
nine studies with 471 participants, and was tion (22.6%) and ear pruritus (12.5%) (Hankin
deemed moderately strong to support SLIT use and Cox 2014). In two randomized, double-blind,
for treatment of rhinoconjunctivitis in this placebo controlled studies of grass tablet immu-
population. notherapy published in 2011 including 439 and
SLIT has been shown to have a sustained ben- 345 patients, each reported one use of epineph-
efit once treatment has been discontinued, sup- rine for treatment-related adverse reactions. The
porting its disease modifying properties. One former study reported one non-treatment related
2013 study demonstrated sustained efficacy in the use in the placebo group, while the latter reported
year post-treatment after 3 years of pre and co- one non-treatment related use in both the placebo
seasonal treatment with a 5 grass pollen sublin- and treatment arms (Nelson et al. 2011; Blaiss
gual tablet (Didier et al. 2013). Durham et al. et al. 2011). To date there have been no reported
(2012) also demonstrated sustained efficacy deaths attributed to sublingual immunotherapy.
2 years after completion of 3 years of pre-seasonal Insufficient evidence is available to make recom-
Grastek® treatment. Most studies of SLIT have mendations regarding the safety of SLIT in preg-
looked at treatment for a single allergen. Very lit- nancy, severe autoimmune disease and immune
tle data is available regarding multiallergen SLIT deficiency.
in polysensitized individuals (Calderon et al.
2012). While there are few studies directly com-
paring the efficacy of SLIT and SCIT, a 2013 When Should SLIT Be Prescribed?
meta-analysis indirectly compared systematic
reviews. As expected from prior studies, both had Sublingual immunotherapy is indicated for those
significant benefits over placebo, however one with rhinitis or rhinoconjunctivitis in the context
modality could not conclusively be deemed supe- of allergen exposure, who have not responded to
rior to the other (Dretzke et al. 2013). or tolerated, or are adverse to use of conventional
pharmacotherapy. Failure of treatment with tradi-
tional pharmacotherapy is not an absolute
How Safe Is SLIT? requirement for use of SLIT. Patients require evi-
dence of sensitization to the relevant pollen via
To date, all studies have shown a common occur- skin prick or in vitro testing. While SLIT has
rence of local side effects with SLIT, with no been shown to be safe and effective in children as
reports of severe systemic reactions, anaphylaxis young as 5, currently only the grass extract prod-
or epinephrine use. While only 15 studies ucts have been approved for use in children
reported drop-out due to adverse reactions, this (Merck Canada Inc. 2013, 2014; Paladin Labs
was seen in 5% of the SLIT group compared to Inc. 2012; Lin et al. 2013).

Sublingual immunotherapy is contraindicated by an immunologic mechanism involving immu-

in patients with severe, unstable or uncontrolled noglobulin E (IgE), which leads to the release of
asthma, and it should not be used patients on chemical mediators from mast cells and baso-
beta-blocker therapy or in those with active oral phils. Signs and symptoms can be quite variable
inflammation or sores (Merck Canada Inc. 2013, involving multiple organ systems and occur
2014; Paladin Labs Inc. 2012; Canonica et al. within minutes, or up to a few hours, after expo-
2014). sure to a known or likely trigger. Diagnosis is
Treatment should be initiated 8–16 weeks based primarily on clinical signs and symptoms,
prior to and through to the end of the pollen sea- as well as a detailed description of the acute epi-
son (Table 2.1). For all available SLIT products sode including preceding events and exposures.
the first dose should be observed in the prescrib- Prompt administration of intramuscular epineph-
ing physician’s office with subsequent doses self- rine remains the first-line therapy. Other second-
administered at home. The patient should be line therapies including H1 and H2 antihistamines,
monitored for 30 min after the first dose with no bronchodilators and glucocorticoids, are often
food or drink for 5 min after. The current avail- used as adjunctive agents but should never be
able SLIT products in Canada are initiated at full used as the initial or sole treatment. A period of
dose or with a short 3-day escalation depending observation following acute treatment is recom-
on the product (Merck Canada Inc. 2013, 2014; mended because of the risk of biphasic reactions.
Paladin Labs Inc. 2012). Long-term management for children who have
Continuation of therapy relies on patient com- experienced an anaphylactic episode includes the
pliance to the home regimen. Currently all avail- prescription of an epinephrine auto-injector, edu-
able product monographs advise returning to the cation around allergen avoidance (if known),
prescribing physician for re-initiation should development of an emergency action plan and
more than 7 days of therapy be missed. Clear referral to an allergist for further evaluation.
instructions should be given to the patient not to
take extra doses if a dose is missed (Merck
Canada Inc. 2013, 2014; Paladin Labs Inc. 2012). Definition
While some physicians may chose to equip those
at increased risk for reaction with an epinephrine Anaphylaxis is defined as a serious allergic reac-
auto-injector, this is not an absolute requirement tion that is rapid in onset and may cause death
for SLIT administration, but should be left to the (Sampson et al. 2006). Most cases of anaphylaxis
discretion of the individual allergist. are mediated through an immunologic mecha-
In summary, SLIT is an effective modality of nism involving IgE. This classic form involves
treatment for allergic rhinitis and rhinoconjuncti- the cross-linking of cell-bound allergen-specific
vitis. Similar to SCIT in efficacy, it can provide IgE upon exposure to a sensitizing allergen with
long-term benefit with a potentially more favour- subsequent activation of mast cells and basophils.
able side effect profile and increase patient accep- Upon activation, these cells rapidly release
tance in the pediatric population. inflammatory mediators such as histamine, trypt-
ase, leukotrienes, and prostaglandins, which pro-
duce the clinical effects seen in anaphylaxis
Anaphylaxis (Simons 2010). Other mechanisms of anaphy-
laxis include immunologic IgE-independent
Introduction reactions (immune complex complement-
mediated and IgG-dependent), nonimmunologic
Anaphylaxis is a severe and potentially life- reactions (direct activation of mast cells and
threatening systemic allergic reaction. It remains basophils in the absence of immunologlobulins)
a substantial health problem and its incidence and idiopathic reactions (Simons 2010). Despite
appears to be rising. In most cases it is mediated having different underlying mechanisms, these

reactions are clinically indistinguishable and cases were triggered by food, with peanut and
have the same acute management (Lieberman tree nut being the most predominant. Even though
et al. 2005). these results were limited to one pediatric centre,
In the pediatric population, food continues to they are consistent with previous literature out-
be the most common trigger of anaphylaxis lining an overall increase in anaphylaxis rates
(Simons et al. 2011). Any food can potentially (Hockstadter et al. 2016). Furthermore, a report
trigger anaphylaxis, but the predominant foods by the Canadian Institute for Health Information
include peanuts, tree nuts, cow’s milk, egg, fish, (CIHI) released in 2015 found similar increases
shellfish and soy (Lieberman et al. 2010). Other in anaphylaxis rates based on Canadian ED vis-
triggers include venom from stinging insects its. The data revealed that while the number of
(such as bees, wasps, yellow jacket, hornets), visits to Canadian EDs for all allergic reactions
medications (most commonly penicillins, other remained stable over a 7-year period, the number
antibiotics and nonsteroidal anti-inflammatory of visits per 100,000 population specifically for
drugs) and natural rubber latex. Less common anaphylaxis significantly increased by 95%.
causes include physical factors (exercise, cold, Specifically, the rate of anaphylaxis visits in
heat, sunlight/UV radiation), food additives (such Ontario and Alberta (for which complete data
as spices and monosodium glutamate) and hor- was available) nearly doubled over the study
monal changes (menstrual factors) (Simons period for children less than 18 years of age.
2016). In certain cases, the trigger is unknown; Adolescents (ages 13–17) experienced the high-
this is referred to as idiopathic anaphylaxis est increase. The study also reported that there
(Simons et al. 2011). The aforementioned trig- was a 64% increase in the rate of individuals pre-
gering agents can induce anaphylaxis through scribed an epinephrine auto-injector (CIHI 2015).
immunologic or nonimmunologic mechanisms. The exact reasons for the increasing rates are not
Foods, medications and insect stings, the most clear but increasing awareness is thought to be
common triggers of anaphylaxis in children, are one of the contributing factors.
mediated through an IgE-dependent immunolog-
ical mechanism (Simons 2016).
Clinical Presentation
Epidemiology Anaphylaxis can present with a wide variety of

signs and symptoms depending on the body sys-
The prevalence of anaphylaxis from all triggers is tems affected. Typically, at least two or more tar-
estimated to be 0.05–2% (Lieberman et al. 2006); get organs are involved, which can include the
however, the rate of occurrence appears to be cutaneous, respiratory, gastrointestinal, cardio-
increasing (Wood et al. 2014). This observation vascular and central nervous systems. Skin
is supported by various studies, including a involvement (urticaria, angioedema, itching,
recently published Canadian study by Hockstadter flushing) is the most common clinical manifesta-
et al. (2016). The data for the study was collected tion and is reported in up to 80–90% of patients
from the Cross-Canada Anaphylaxis Registry (Simons et al. 2011). In the absence of skin
(C-CARE), which is an initiative that aims to involvement, the diagnosis of anaphylaxis may
assess the rate, triggers, management and tempo- be difficult to make but cannot be excluded
ral trends of anaphylaxis. The findings show that (Lieberman et al. 2010). Respiratory tract and
the percentage of pediatric emergency depart- cardiovascular involvement are of the more con-
ment (ED) visits due to anaphylaxis doubled over cerning signs and symptoms, which present in
a 4-year period (2011 to 2015), from 0.20 to 60–70% and up to 45% of individuals, respec-
0.41%, with the largest increase seen in the final tively (Simons 2010).
2 years of the study period. The authors also Signs and symptoms of anaphylaxis are usu-
reported that the majority (80.2%) of anaphylaxis ally sudden in onset and occur within minutes, or

up to a few hours, after exposure to the offending most patients, with a prolonged length of time for
antigen. The majority of children have uniphasic those with severe or protracted symptoms
reactions. Some children, however, experience a (Sampson et al. 2006; Lieberman et al. 2015).
biphasic reaction, which is defined as the return Anaphylaxis can range in severity from milder
of symptoms within 1–72 h (usually 8–10 h) after episodes to very severe reactions, progressing
the initial symptoms have resolved without any within minutes to respiratory or cardiovascular
further exposure to the trigger (Simons et al. compromise and death (Simons and Sheikh
2011). The reported incidence of biphasic reac- 2013). It is important to recognize that the clini-
tions in the literature ranges between 1 and 23% cal manifestations, as well as the severity of ana-
(Alqurashi et al. 2015). A recent Canadian study phylaxis, are unpredictable and may differ from
by Alqurashi et al. (2015) found the incidence of one patient to another and from one episode to
biphasic reactions to be 15% in their pediatric another in the same patient (Simons et al. 2011).
cohort, which was not significantly different In infants and young children, anaphylaxis may
from previously reported pediatric studies. The be difficult to recognize and diagnose for a num-
study also found that approximately 75% of these ber of reasons. Many of the signs and symptoms
reactions occurred within 6 h of the onset of the of anaphylaxis (itching, throat and chest tightness
initial reaction. Given the risk of a biphasic reac- and other subjective symptoms) cannot be
tion, it is recommended that children be observed described by infants. In addition, various signs
for a certain period of time following an anaphy- are nonspecific and are also seen in healthy chil-
lactic episode. There is no consensus regarding dren for other reasons; examples include flushing
the optimal duration of observation given that and dysphonia after crying, spitting up after feed-
there are no validated and widely accepted clini- ing, behavioural changes, such as irritability,
cal predictors of biphasic reactions (Sampson inconsolable crying, clinging to a caregiver and
et al. 2006; Alqurashi et al. 2015). As one of the incontinence (Rudders et al. 2011; Simons and
main objectives of their study, Alqurashi et al. Sampson 2015; Simons et al. 2011). A high index
(2015) identified five independent predictive fac- of suspicion is therefore often needed to make the
tors, which included: delay in presentation to the diagnosis in infants and younger children.
ED longer than 90 min after the onset of the ini-
tial reaction, children age 6–9 years, wide pulse
pressure at triage, treatment of the initial reaction Diagnosis
with more than one dose of epinephrine and
administration of inhaled beta-agonists in the The diagnosis of anaphylaxis is primarily based
ED. Overall, they found that the severity of the upon clinical signs and symptoms, as well as a
initial reaction appears to be associated with an careful and detailed description of the acute epi-
increased risk of biphasic reactions. Children sode, including the preceding events and any
presenting with severe initial anaphylactic epi- potential exposures (Simons et al. 2011). Specific
sodes would therefore benefit from a prolonged diagnostic criteria for anaphylaxis have been estab-
observation period. Furthermore, those with mild lished by a multidisciplinary panel of experts and
anaphylaxis who do not have any of the above continue to be widely used. Anaphylaxis is highly
risk factors could be considered for possible early likely when any one of the three following criteria
discharge from the ED (defined as less than 6 h are fulfilled: acute skin and/or mucosal involve-
from the onset of reaction). The authors recom- ment and at least one of the following: respiratory
mended that these clinical predictors be used compromise or reduced blood pressure or symp-
with caution prior to being validated in a large toms of end-organ dysfunction; two or more of the
prospective study (Alqurashi et al. 2015). The following that occur rapidly after exposure to a
majority of literature and current guidelines rec- likely allergen: skin/mucosal involvement, respira-
ommend that observation periods be individual- tory compromise, reduced blood pressure, gastro-
ized. A 4–8 h observation period is reasonable in intestinal s ymptoms; reduced blood pressure after

exposure to a known allergen (Sampson et al. Other conditions present with similar clinical
2006). Because the majority of anaphylactic reac- features to anaphylaxis and should be considered in
tions have cutaneous involvement, a large number the differential diagnosis. The most common enti-
of them can be identified by the first criterion. The ties in children include acute generalized urticaria
criteria have been shown to have excellent specific- associated with a viral infection, foreign body aspi-
ity and good sensitivity, and are believed to identify ration, acute asthma, vasovagal syncope and panic
more than 90% of cases of anaphylaxis (Sampson attacks or anxiety (Simons 2016). In infants, an
et al. 2006; Campbell et al. 2012). apparent life-threatening event, congenital abnor-
The patient’s history is an essential tool to malities of the respiratory or gastrointestinal tracts
help establish the cause of anaphylaxis. It should and food protein-induced enterocolitis syndrome
focus on the following key elements: recall of are important to consider (Simons and Sampson
exposure to potential triggering agents (such as 2015). Less common conditions include excess
foods, medications, insect stings) and events in histamine syndromes, postprandial syndromes, sei-
the hours preceding the onset of symptoms; the zures and nonorganic diseases such as vocal cord
time elapsed between exposure and symptom dysfunction (Simons 2016).
onset; description of clinical manifestations (such
as flushing, urticaria, airway involvement, gastro-
intestinal symptoms); progression of signs and Management
symptoms; and enquiry into any previous reac-
tions (Lieberman et al. 2005; Waserman et al. The treatment of suspected anaphylaxis begins
2010). with a rapid assessment of the airway, breathing,
Laboratory tests can be used to support a diag- circulation, and skin examination, with simulta-
nosis of anaphylaxis, but they are generally not neous administration of epinephrine (Waserman
required because anaphylaxis is primarily a clini- et al. 2010). Epinephrine remains the cornerstone
cal diagnosis. Increased levels of serum total of management (Lieberman et al. 2005). It should
tryptase and plasma histamine can be observed be given by intramuscular injection in the mid-
during or shortly after an acute anaphylactic epi- anterolateral thigh, as this route and location has
sode (Lieberman et al. 2010). Normal levels, been shown to have superior absorption in com-
however, cannot be used to rule out anaphylaxis parison to deltoid and subcutaneous injections
(Simons et al. 2010). Measurements of these (Simons et al. 1998, 2001). In children, the rec-
chemical mediators are often normal in children ommended dose is 0.01 mg/kg of a 1:1000 dilu-
and in food-triggered reactions (Simons 2016; tion, to a maximum of 0.15 mg in infants, 0.3 mg
Simons et al. 2010). They may be useful, how- in children and 0.5 mg in adolescents (and adults)
ever, if the diagnosis is unclear, or to distinguish (Simons 2016). The dose can be repeated every
anaphylaxis from other disorders that have over- 5–15 min as needed, depending on the patient’s
lapping clinical features, such as severe asthma. clinical response. Intravenous epinephrine is
Obtaining a tryptase level after an acute event rarely used, however may be necessary in those
once symptoms have resolved can be useful as a with uncompensated shock or cardiac arrest
screening test for systemic mastocytosis, where (Lieberman et al. 2005). There are no absolute
levels will remain elevated (Lieberman et al. contraindications to epinephrine and it should be
2010). Additional investigations may include given without any hesitation or delay to any indi-
skin prick tests and/or in vitro IgE tests to iden- vidual where anaphylaxis is diagnosed or strongly
tify the specific cause of anaphylaxis. These tests suspected (Waserman et al. 2010).
can determine the presence of specific IgE anti- Additional treatment measures should include:
bodies to foods, certain medications (such as removal of the offending trigger (if relevant, for
penicillin) and stinging insects. Skin testing is example, discontinuation of an intravenous
more sensitive and is generally the preferred medication); administration of supplemental

diagnostic method (Lieberman et al. 2010). oxygen and maintenance of an adequate airway;

placement of the child in a supine position with c omorbities (such as asthma) and access to care.
their legs elevated to optimize venous return to The recommended observation period for most
the heart and perfusion of vital organs; and estab- patients is a minimum of 4–8 h following the
lishment of intravenous access, preferably two reaction (Simons et al. 2011; Lieberman et al.
large bore IVs in the anticipation of the need for 2015). Prolonged observation periods or hospital
aggressive fluid resuscitation (Lieberman et al. admission may be necessary for those with
2010). Intravenous fluids should be administered severe or refractory symptoms (Waserman et al.
since massive fluid shifts may occur due to 2010).
increased vascular permeability associated with The principles of long-term management for
anaphylaxis (Lieberman et al. 2005). Patients patients who have experienced anaphylaxis
with hypotension and poor perfusion that are include: prescription of an epinephrine auto-
unresponsive to epinephrine and positioning may injector and instructions on how and when to use
require multiple fluid boluses of a crystalloid it; education on avoidance of precipitating trig-
solution, typically 20 mL/kg of normal saline gers; development of an anaphylaxis action plan;
(Lieberman et al. 2005; Cheng 2011). and referral to an allergist for further assessment
Adjunctive agents that may be considered in and ongoing management (Simons et al. 2011).
the management of anaphylaxis include antihista-
mines (H1 and H2 antagonists), corticosteroids
and bronchodilators. These therapies continue to
be used as second-line treatments since they do not
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Update in Pediatric Cardiology
3
Jane Lougheed and Jenna Ashkanase
ongenital Heart Disease: Current

C 2010). Again, the different rates are likely multi-
Changes in Epidemiology factorial, reflecting imbalances in access to pre-
natal screening and health care between
With ongoing advancements in prenatal screen- developed and developing nations (Moore and
ing, medical interventions, and surgical tech- Rouleau 2013; Bernier et al. 2010). In Canada,
niques, the epidemiology of congenital heart mortality rates associated with CHD in the pedi-
disease (CHD) in society has experienced several atric population have declined by 59% over the
key transitions in recent years. Canada has expe- past two decades (Khairy et al. 2010).
rienced a 21% decrease in the birth prevalence of Although overall mortality rates have
CHD from 1998 to 2009, from 10.7 to 8.5 per decreased, fetal deaths at an early gestational age
1000 total births (Moore and Rouleau 2013). have increased (Moore and Rouleau 2013).
Variations in rates amongst provinces and territo- Conversely, mortality rates are lower in late ges-
ries do exist, with the remote territory of Nunavut tation and in infancy (Moore and Rouleau 2013).
consistently having more than double the national This trend may be due to earlier prenatal diagno-
rate at approximately 22.9 per 1000 births (Moore ses and subsequent pregnancy termination, com-
and Rouleau 2013; Arbour et al. 2004). bined with improved outcomes for CHD live
Worldwide, the incidence is approximately 9.1 births when current post-natal management strat-
per 1000 live births as of 2011 (Van Der Linde egies are employed. Termination rates currently
et al. 2011). This international estimate almost range from an estimated 44–57% with a 1.4-fold
certainly underestimates the true total, as it is increased probability of termination following
restricted to live births and both diagnostic and prenatal diagnosis of CHD, most likely to occur
reporting capabilities in developing nations can when other congenital anomalies and/or genetic
be limited. Mortality rates also vary internation- syndromes are identified (Moore and Rouleau
ally with estimates of 20% in developing nations 2013; Tegnander et al. 2006; Tomek et al. 2009;
to 3–7% in developed nations (Bernier et al. Germanakis and Sifakis 2006).
Overall survival rates for CHD in the North
American population are now well over 90%
J. Lougheed (*) • J. Ashkanase (Marelli et al. 2007). The median age of patients
Division of Pediatric Cardiology, living with severe CHD has increased, from 11 to
Department of Pediatrics,
17 years from 1985 to 2000 (Marelli et al. 2007).
Children’s Hospital of Eastern Ontario,
University of Ottawa, Ottawa, ON, Canada The median age at death for patients with any
e-mail: jlougheed@cheo.on.ca form of CHD has increased from 60 to 75 years


62 J. Lougheed and J. Ashkanase
within the last few decades (Khairy et al. 2010). patients with coarctation of the aorta (CoA), pre-
For the subset of patients with severe CHD, the sumed to be secondary to arrhythmia. Of note,
median age at death also increased, from 2 to this population also had a high rate of non-CHD-
23 years. The most common types of CHD related deaths with a significant proportion of
afflicting both the adult and pediatric populations respiratory (17%) and neurological (14%) pathol-
are unchanged, with atrial septal defects (ASDs) ogy, highlighting the importance of monitoring
and ventricular septal defects (VSDs) accounting CHD patients for general health concerns.
for over 80% of diagnoses in Canada (Moore and As heart failure is frequently encountered as a
Rouleau 2013). In terms of severe lesions, complication in the CHD population, increasing
conotruncal anomalies such as Tetralogy of Fallot efforts to promptly identify and efficiently man-
and atrioventricular septal (canal) defects age this condition have been initiated. For
(AVSDs) still account for the majority of severe patients with CHD, making a diagnosis can be
CHD. challenging due to the complexity of the underly-
In summary, the recent epidemiologic data ing condition(s) contributing to heart failure and
reflect that CHD is becoming a chronic condition the evolving symptomatology that accompanies
with high survival rates, resulting in a greater further growth and aging (Kantor et al. 2013a).
proportion of adults living with CHD than chil- Scoring indices are often not applicable across
dren. This heralds a new era of management for age groups and are not validated to predict prog-
CHD patients in which late outcomes, including nosis for patients with complex congenital lesions
complications of CHD and/or surgical interven- (Kantor et al. 2013b). Guidelines for heart failure
tions, neurodevelopment outcomes, and quality in the pediatric population have been developed
of life outcomes become more significant, and by the Children’s Heart Failure Study Group in
thus merit further scrutiny and research. collaboration with the Canadian Pediatric
Cardiology Association (Kantor et al. 2013a).
These guidelines assert that while the New York
Late Outcomes of CHD Heart Association (NYHA)/Ross classification
can be used to stratify pediatric patients with
Pediatric CHD patients will undergo life-long established chronic heart failure, it is not neces-
monitoring by their primary care providers and sary for diagnosis or prognostication (Kantor
cardiologists for complications of their underly- et al. 2013a). Instead, clinical findings according
ing lesions and cardiac interventions. In order to to patient age and investigations including elec-
determine the most appropriate screening mea- trolytes, chest radiography (CXR), electrocardio-
sures, it is necessary to have an understanding of grams (ECGs), and echocardiograms are
the most common complications that contribute recommended. Brain natriuretic peptide (BNP)
to morbidity and mortality. or amino terminal (NT)-proBNP can be utilized
In a Finnish study of late causes of death fol- as confirmatory tests if needed, with elevated lev-
lowing cardiac surgery, 592/6024 (9%) patients els indicative of heart failure. Current medica-
died during the 45-year follow-up period. The tions utilized in the pediatric population for heart
majority of deaths with a cause identified (67%) failure mirror many of those used in the adult
were related to CHD, most often due to heart fail- population, including diuretics, angiotensin-
ure (40%) (Nieminen et al. 2007). Perioperative converting enzyme (ACE) inhibitors, beta-
death (within 30 days of a second, third, or fourth blockers, and aldosterone antagonists. Algorithms
operation), sudden death, and cardiovascular for a step-wise approach to initiating these medi-
complications (most prominently, stroke) were cal therapies have been developed based on cur-
also common causes of mortality. For patients rently available evidence (Kantor et al. 2013a)
with tetralogy of Fallot (TOF), surgery was the and patients should undergo continual, individu-
most frequently recorded cause of death, while alized assessment as treatment progresses.
sudden death was more common amongst Further randomized trials for heart failure man-

3 Update in Pediatric Cardiology 63
agement in the pediatric population are pending, school system, there has been an increasing
and will be critical to developing a comprehen- awareness of neurodevelopmental impairments
sive understanding of the risks and benefits of in this population. As a result, further analysis
currently available and new treatments. from both an imaging and a clinical perspective
Heart transplantation will become a necessity has been undertaken. We will review current
for a growing number of CHD patients as the findings broadly but urge readers to keep in mind
prevalence of heart failure in this population that prognostication must be individualized, as
increases (Attenhofer Jost et al. 2013). Of patients findings can vary based on the cardiac lesion,
requiring heart and lung transplantation, CHD type of repair, the mode of assessment, and the
was the leading underlying condition worldwide patient’s age at time of diagnosis and follow-up
between January 2000 and June 2012 (Yusen (Massaro et al. 2008).
et al. 2013). Typically, CHD patients spend a lon- Differences in central nervous system devel-
ger time on the transplantation waiting list, opment have been documented in CHD patients
potentially due to early identification of mild via magnetic resonance imaging (MRI) in both
stages of heart failure as these patients undergo the fetal and postnatal period, prior to surgical
serial monitoring by health care professionals. interventions (Ortinau et al. 2012; Limperopoulos
Higher perioperative mortality also plagues this et al. 2010). Overall, brain size in CHD patients
population of patients due to the complexity cre- has been observed to be smaller than that seen in
ated by previous procedures and increased bleed- the general population, particularly in the frontal
ing risks from prior sternotomy-related adhesions and brainstem regions (Ortinau et al. 2012;
(Attenhofer Jost et al. 2013). However, interna- Limperopoulos et al. 2010). These changes have
tionally, post-transplantation outcomes for been observed in the third trimester of pregnancy
patients with CHD have improved annually dur- with associated impairments in neuroaxonal
ing the past two decades (Chen et al. 2004; metabolism (Limperopoulos et al. 2010). Focal
Stehlik et al. 2012). In a retrospective review white matter signal abnormalities, usually of a
from a single centre, a decrease in mortality was mild nature, can occur in up to 42% of patients
associated with later year of transplantation with (Ortinau et al. 2012). Brain structures are also
mortality rates of 62.5% prior to 1990 decreasing more premature, by approximately 1 month at
to 12.5% after the year 2000 (Chen et al. 2004). baseline, in patients with hypoplastic left heart
Older age at transplantation was associated with syndrome (HLHS) and transposition of the great
better outcomes, with the highest mortality rates arteries (TGA) (Licht et al. 2009). Small studies
observed in neonates (57.1%) and the lowest have shown that in some populations, predomi-
rates in adults (23%). The mortality rate was con- nantly patients with TGA, brain volume can
stant amongst infants and children at 40%. The improve over time, particularly if cyanotic car-
increasing use of mechanical ventricular assist diac lesions have resolved (Ibuki et al. 2012).
devices may further change (decrease) mortality However, it is possible for structural differences
rates for patients on the transplantation waiting to persist through adolescence, particularly white
list in the years to come. matter injuries and significant volume loss (von
Rhein et al. 2011). If chronic changes remain on
imaging, they are commonly seen in association
Neurodevelopmental Outcomes with neurodevelopmental deficits.
in CHD As patients with CHD proceed to further inter-
ventions and surgery, there are further risks for
Parents in cardiology clinics often inquire about neurological injury posed by the potential for
the impact on intelligence and development for thromboembolism causing cerebral infarction
their infant or child following a new diagnosis of and ischemia-reperfusion injury resulting from
CHD. Indeed, as more patients with CHD are hypothermic cardiopulmonary bypass and/or
enrolled in daycare and progress through the total circulatory arrest (Su and Ündar 2010; Beca

et al. 2013). Post-operatively, transient risk who also have CHD. Smaller brain volumes have
factors such as hypotension, hypercarbia, and
been noted in patients with 22q11 microdeletion
inflammatory responses can also be detrimental syndrome and CHD as compared to those with
to neurodevelopmental outcomes (Bassan et al. 22q11 microdeletion without CHD (reduced by
2005; Gressens and Hagberg 2012). 16.9% vs. 6.9% compared to controls, respec-
With increasing data to support structural tively) (Schaer et al. 2010). In pediatric CHD
abnormalities of the central nervous system, it patients with Down syndrome, small studies have
becomes necessary to accurately evaluate clini- documented language delays (Alsaied et al.
cally meaningful, functional outcomes for CHD 2016) and/or motor delays (Visootsak et al. 2011)
patients. The International Cardiac Collaborative compared to patients with Down syndrome and
on Neurodevelopment (ICCON) recently pro- no CHD in infancy and as toddlers. However, by
vided a 14-year pooled analysis of outcomes fol- the time of preschool entry and extending into
lowing cardiac surgery in infancy for 1770 school age, differences in development have not
patients at the age of 14.5 ± 3.7 months using the been observed to be significantly different
Bayley Scales of Infant Development (Gaynor (Alsaied et al. 2016). These early delays coincide
et al. 2015). This scoring system incorporates with the usual timing of surgical interventions,
gross and fine motor skills through the and may reflect interruptions in developmental
Psychomotor Development Index (PDI) and progress during medical care with subsequent
parameters such as memory, problem solving, recovery.
language, and social skills through the Mental The risk of neurodevelopmental disability is
Development Index (MDI). Scores for both indi- closely linked to the type of CHD, with mild
ces in CHD patients were significantly lower than lesions such as ASDs or VSDs having a low prev-
those seen in the general population (p < 0.001), alence of neurodevelopmental disabilities. In this
but both slightly improved (by 5–6 points) during particular subgroup of CHD patients, over 80%
the study period. For patients with more complex have no disabilities whatsoever (Marino et al.
CHD, PDI but not MDI was lower. Several factors 2012). In contrast, patients with moderate (eg.
were identified as being associated with poor neu- AVSDs or TOF) or severe lesions (eg. TGA or
rodevelopmental outcomes including Caucasian single-ventricle lesions) have progressively
race, male gender, low birth weight, genetic syn- increasing rates of disabilities that correlate with
dromes, complex CHD, and low maternal educa- the degree of CHD severity. Less than 50% of
tion level. In addition, increased length of stay in those with severe CHD lesions experience nor-
hospital following cardiac surgery has been asso- mal developmental progress (Marino et al. 2012).
ciated with neurodevelopmental delays evident by The vast majority of patients with genetic syn-
the age of 8 years, including lower IQ with dromes will experience impairments, to a severe
reduced verbal IQ and math achievement extent in over 25% of patients. Following identi-
(Newburger et al. 2003). These effects persisted fication of these trends, the American Heart
even when outcomes were adjusted for periopera- Association has issued a scientific statement
tive events and perfusion times. (Marino et al. 2012) regarding the evaluation and
Several forms of CHD are commonly associ- management of CHD patients at risk for neurode-
ated with genetic syndromes, including Down velopmental delays. These guidelines state that
syndrome, 22q11 microdeletion syndrome patients should be risk-stratified with ongoing
(DiGeorge syndrome), Williams syndrome, and surveillance for developmental issues via age-
Noonan syndrome (Gaynor et al. 2015). appropriate screening tools. For high-risk
Neurodevelopmental delays are more prominent patients, ie. those with CHD and other comor-
in patients with genetic syndromes (Fuller et al. bidities, cyanotic lesions, and neonates requiring
2009), but imaging abnormalities and impaired open heart surgery, referral for a full develop-
developmental progress have also been identified mental assessment at baseline should be initiated.
as increased within this population for patients Low-risk patients will require ongoing periodic

screening with referral for developmental assess- in CHD patients. Based on parental report alone,
ment only if concerns are identified. there are perceived psychosocial issues in
With increasing numbers of CHD patients sur- 15–25% (Marino et al. 2012). A study conducted
viving into adulthood, it is likely that a larger in Portugal evaluating diagnostic outcomes in a
population of adult patients requiring additional cohort of 110 adolescents and young adults with
supportive resources will emerge. Further data various forms of CHD similarly found a lifetime
regarding long-term neurodevelopmental out- prevalence of psychopathology in 21.8%, higher
comes will be needed as the epidemiology of in female patients (Freitas et al. 2013).
CHD continues to change. Externalization (eg. aggression), internalization
(eg. social withdrawal), and symptoms of depres-
sion or anxiety were the most commonly diag-
Quality of Life in CHD nosed disorders based on self-report. A
meta-analysis examining psychological and cog-
Quality of life (QOL) measures in the pediatric nitive functioning in CHD patients found that
CHD population have also been scrutinized, with risks were higher only in older children and ado-
more data accumulating annually. Across all age lescents (mean age > 10 years) for internalizing
groups, up to 1 in 5 patients with CHD perceive a more so than externalizing behaviours (Karsdorp
lower QOL and detriment in psychosocial func- 2007). Symptoms of depression, anxiety, and dis-
tioning, even in those with mild cardiac condi- ruptive behaviour have been self-reported fre-
tions (Uzark et al. 2008). Lower QOL scores quently in adolescents with d-TGA, who also
have also been associated with having cyanotic have an increased risk of attention-deficit/hyper-
CHD and a history of cardiac surgeries, with an activity disorder (19% vs. 7% in the general pop-
inverse relationship between the number of sur- ulation) (Demaso et al. 2014). The effect of
geries and QOL scores (Areias et al. 2013). disease severity on psychosocial scores varies in
Children with CHD indicate lower scores for the literature, with some groups correlating more
physical well-being, financial resources, peer severe disease with higher rates of depressed
relationships, and autonomy than their healthy mood and lower self-esteem (Cohen et al. 2007)
age- and gender-matched peers (Amedro et al. and others demonstrating no correlation (Uzark
2015). Self-perception was significantly influ- et al. 2008; Karsdorp 2007). Patients with certain
enced by the severity of the cardiac condition, genetic syndromes may also be at risk for psy-
and parental perception of QOL was also lower chosocial impairments with a known association
in CHD patients. However, in a study of 59 post- between 22q11 microdeletion syndrome and
operative adolescents with CHD, lower peer- attention-deficit hyperactivity disorder, autism
relationship scores were noted but overall QOL spectrum disorder, and schizophrenia or schizo-
was not significantly lower than that of the gen- affective disorders (Niklasson et al. 2002).
eral population (Schaefer et al. 2013). A larger, Awareness of the increased risk of behavioural
multicenter cross-sectional study demonstrated and psychiatric problems for older children and
lower health-related QOL for patients with either adolescents with CHD, particularly those with
biventricular or univentricular CHD compared pre-existing risk factors, will be helpful in pro-
with healthy peers, with scores that paralleled moting early screening for disorders.
those of patients with other chronic diseases
(Mellion et al. 2014). Recent scoring systems
(Marino et al. 2012; Uzark et al. 2008) to evalu- Exercise in CHD
ate QOL specifically in cardiac patients will
enhance the current understanding of the chal- Exercise recommendations for CHD patients
lenges faced by this growing patient population. may differ depending on the specific cardiac con-
Behavioural and psychiatric issues can have a dition. Overall, most patients with minor, uncom-
profound impact on QOL and are also common plicated cardiac lesions should be able to tolerate

60 min of at least moderate physical activity daily recommendations for involvement in highly
with an increase to 70% of maximal heart rate competitive sports primarily for adult patients
(Brothers et al. 2016). Prior to initiating a new with a variety of forms of CHD, which can serve
exercise regimen it is ideal for patients to engage as a basic outline for patient counseling (Maron
in a discussion with their cardiologist to review et al. 2011).
their history and clinical findings and, in cases of Increasing awareness of sedentary lifestyles in
more complex CHD, undergo any individualized the adult CHD population (Chaix et al. 2015) in
screening investigations such as electrocardio- combination with increased obesity rates in the
gram (ECG), echocardiogram, or exercise test- pediatric population have prompted initiatives to
ing, if indicated. Studies have demonstrated that improve physical activity levels for these patients.
the perceived severity of heart disease by patients In 2013, the American Heart Association pub-
and parents is correlated with lower participation lished a scientific statement promoting physical
in exercise and sports (Cohen et al. 2007). Thus, activity for both pediatric and adult patients with
it is beneficial to ensure that CHD patients are CHD (Longmuir et al. 2013). These guidelines
aware of their current health status and given rea- state that discussion of appropriate forms of
sonable expectations for their involvement in physical activity should occur at each clinical
physical activity. assessment and provide a wide range of sugges-
For patients with more complex forms of tions to improve counseling for patients. Adult
CHD, functional limitations may be imposed not recommendations for exercise training in CHD,
only by the underlying pathology, but also by sur- categorized by the type of cardiac lesion, associ-
gical repairs, medications, or arrhythmias. In ated conditions, and the type of activity, were
particular, patients with the conditions listed in published earlier this year (Chaix et al. 2015).
Table 3.1 commonly require specific restrictions The authors readily acknowledge, however, that
to physical activity (Brothers et al. 2016). further research will be crucial in further delin-
However, alternate forms of mild to moderate eating which regimens are the most effective.
physical activity can be safely initiated if the Undoubtedly, further research in the pediatric
patient is motivated and aware that this is possi- population is needed to provide further data on
ble. The Task Force for Congenital Heart Disease which to base patient counseling.
from the 36th Bethesda Conference has provided An accurate depiction of each patient’s cardio-
vascular health status and exercise potential
should be obtained. For the overwhelming major-
Table 3.1 Cardiac conditions commonly requiring exer- ity of CHD patients, there are no restrictions to
cise restriction (adapted from Moss and Adams 2016) physical activity. Patients with more complex
Category Condition lesions should be counseled to focus on individu-
Left-sided • Severe/critical aortic stenosis alized activity adjustment, rather than avoidance,
obstructive • Severe aortic insufficiency to maintain a healthy, active lifestyle.
lesions
• Clinically significant bicuspid
aortic valve
Pulmonary • Pulmonary hypertension Pregnancy in CHD
vascular disease • Eisenmenger Syndrome
Genetic • Marfan syndrome with aortic
With improved longevity and survival, patients
syndromes root dilatation
with CHD now face decisions regarding family
Coronary artery • Anomalous origin of the left
abnormalities coronary artery from the right planning. CHD has been emerging as the most
sinus of Valsalva common form of cardiac disease impacting preg-
• Intramural coronary artery nancies as documented by the Canadian Cardiac
Arrhythmias • Uncontrolled Disease in Pregnancy (CARPREG) registry and
• Implantable cardioverter the European Registry on Pregnancy and Cardiac
defibrillator Disease (ROPAC) registry, with a prevalence of

74% and 66%, respectively (Siu et al. 2001; Discussions surrounding reproduction should
Roos-Hesselink et al. 2013). In order to meet the ideally be initiated with CHD patients well prior
needs of this patient population, an understand- to pregnancy, in late childhood or adolescence
ing of the physiology and risks involved during (Brickner 2014), especially since adolescents
pregnancy must be created. with CHD often demonstrate a limited under-
A series of hemodynamic changes occur during standing of their own health status (Greutmann
pregnancy, including an increase in heart rate and and Pieper 2015). Advice regarding contracep-
stroke volume with a decrease in peripheral vascu- tion should be individualized, as combined con-
lar resistance. The net effect is an increase in car- traceptives may be inappropriate for certain CHD
diac output to support growth of the placenta and patients at higher risk of thromboembolic events
fetus. Patients with CHD may have difficulties (Thorne 2006). When initiating discussions sur-
achieving sufficient cardiac output, especially rounding future pregnancies, any potential need
patients with the Fontan circulation or following to optimize clinical status, such as updating car-
insertion of conduits or baffles (Greutmann and diac investigations or weaning medications
Pieper 2015). Arrhythmias can interfere with should be outlined. In addition, in some forms of
coordinated intracardiac blood flow and pacemak- severe CHD, vaginal delivery may be contraindi-
ers may require new heart rate thresholds as the cated, and these patients should be counseled
physiologic changes accompanying pregnancy accordingly when formulating a birth plan
develop. Furthermore, obstetrical complications (Greutmann and Pieper 2015). It is also impor-
such as gestational diabetes, pre-eclampsia, and tant to include male patients with CHD in discus-
multiple gestations can further challenge hemody- sions regarding contraception and family
namic recalibration (Siu et al. 2001). planning as there can be an increased risk of
Significant risks are presented at both the CHD in the offspring of some male patients as
maternal and fetal level for patients with CHD. In well.
a prospective Canadian study of pregnant women Accurate characterization of risk level for
with CHD, primary cardiac events occurred in adverse maternal outcomes during pregnancy is
13% (80/599), with pulmonary edema, arrhyth- necessary. The most widely accepted guidelines
mias, and thromboembolic events being the most for pregnancy risk classification in CHD are the
common complications (Siu et al. 2001). The modified WHO criteria (Balci et al. 2014). Risk
same risks have been seen to persist even in level ranges from WHO Class I, in which there
lower-risk maternal populations (Balci et al. are no detectable increased risks of maternal
2014). When these conditions necessitate medi- morbidity or mortality (ie. for patients with
cal or surgical interventions, the risks for both repaired simple lesions) to WHO Class IV, in
mother and baby increase even further. Events for which the risks are so high that pregnancy is con-
offspring are seen in 20–30% of births (Siu et al. sidered contraindicated (ie. for patients with pul-
2001; Balci et al. 2014), most commonly related monary hypertension or severe aortic stenosis).
to growth restriction or premature birth and asso- Individuals at a significantly high risk of severe
ciated complications, such as respiratory distress complications can be promptly identified using
syndrome or intraventricular hemorrhage. these guidelines and counseled early regarding
Recurrence rates for CHD in offspring are esti- elective pregnancy termination if desired, which
mated to be between 3 and 8%, which can vary is generally considered to be safest in the first tri-
depending on conditions with gender predilec- mester (Regitz-Zagrosek et al. 2011). Guidelines
tions or genetic associations (Brickner 2014). for the overall management of adult CHD patients
The risk of fetal or neonatal death is also increased are available from several groups worldwide
in patients with CHD at approximately 2% (Siu including the Canadian Cardiovascular Society
et al. 2001), especially for those with more severe (CCS), the American College of Cardiology and
lesions and the related detriment in uteroplacen- American Heart Association (ACC/AHA), and
tal blood flow. the European Society of Cardiology (ESC)

(Regitz-Zagrosek et al. 2011; Silversides et al. time of presentation (Brown et al. 2006). Pulse
2010a, b, c; Warnes et al. 2008). oximetry has been studied as a screening method
With more CHD patients progressing into to improve detection of CCHD. This screening
adulthood, pregnancy-related concerns will method has been endorsed by experts in the US
undoubtedly become more common. A multidis- and Europe to become part of routine practice,
ciplinary approach involving obstetricians, cardi- with other countries including Canada following
ologists, family physicians, and genetic suit (Mahle et al. 2012).
counselors, as applicable, will be crucial to Although prenatal ultrasound is capable of
ensuring comprehensive care for this patient detecting most CCHD, the reality is that less than
population. 50% of CCHD is diagnosed prenatally (Trines
et al. 2013; Quartermain et al. 2015). This num-
ber is very region specific, with higher rates of
Neonatal Oximetry Screening diagnosis in larger, tertiary care level centres.
The routine newborn physical examination (in
Congenital heart disease is the most common the absence of oximetry) may detect CCHD, but
congenital malformation, with a prevalence of this is dependent on clinical expertise and experi-
6–9/1000 births worldwide (Van Der Linde et al. ence. There are higher rates of detection in cen-
2011). About 1/3 of these newborns will have tres with higher care level nurseries, but also a
critical congenital heart disease (CCHD), defined high false positive detection rate compared to
as severe heart disease requiring neonatal diagno- oximetry (Dawson et al. 2013). Pulse oximetry
sis and correction for optimal outcome. using a cut off saturation of 95% has a high speci-
Many of these lesions are ductal dependent, ficity of 99.9% and a moderately high specificity
and may only become apparent as the ductus of 76.5% for CCHD, in a recent systematic
arteriosus closes, usually in the first 24–28 h of review including over 225,000 newborns
life (Table 3.2). With routine earlier discharge of (Thangaratinam et al. 2012). Optimal timing for
newborns, there is a concern that more of these screening is between 24 and 48 h of age, with
lesions will clinically present after a baby is at higher false positives when screening is per-
home. Studies in the US and UK estimate that formed before 24 h. Most current recommenda-
25–30% of these lesions will present after dis- tions advocate for screening after 24 h of age,
charge or after 3 days of age (Wren et al. 2008; with saturations being checked in the right hand
Peterson et al. 2014a). Neonates with missed and one foot (Kemper et al. 2011) (Fig. 3.1). A
CCHD have increased morbidity and mortality, failed screen results in a full physical examina-
related to their degree of decompensation at the tion for evidence of congenital heart disease or
other causes for low saturations such as sepsis or
respiratory disease. If this does not clarify the
Table 3.2 Critical congenital heart disease lesions situation, then referral to pediatric cardiology
detectable with oximetry screening
and/or echocardiography is required to exclude
Usually cyanotic May be cyanotic CCHD. The anticipated screen positive rate is
Transposition of the great Coarctation of the aorta around 0.2% using this algorithm, with a cost of
arteries
under $5 US per newborn screened when reus-
Hypoplastic left heart Ebstein’s anomaly of the
syndrome tricuspid valve able probes are used (Peterson et al. 2014b).
Tetralogy of Fallot Single ventricles Implementation of screening involves devel-
Pulmonary atresia with Double outlet right oping a protocol, training of personnel, tracking
intact septum ventricle of abnormal results, and a plan for potential
Total anomalous Interruption of the aortic transfer of newborns to a site providing pediatric
pulmonary venous return arch echocardiography—however, the burden and
Tricuspid atresia cost of this is justified by not having these infants
Truncus arteriosus present back in critical condition.

Fig. 3.1 Algorithm for Child in well-infant nursery 24-48 h of age or shortly before
pulse oximetry discharge if<24 h of age
screening. With
permission from Kemper
et al., Strategies for
Implementing Screening
for Critical Congenital Screen
Heart Disease, Pediatrics
2011 (Kemper et al.
2011)
90%–<95% in RH and F or ≥95% in RH or F and

<90% in
>3% difference between ≤3% difference between
RH or F
RH and F RH andF
Repeat
screen
in 1 h

<90% in
RH or F
RH and F RH and F
Repeat
screen
in 1 h

<90% in
RH or F
RH and F RH and F
Positive screen Negative screen
Cardiac Imaging Cardiac MRI is now considered the ‘gold stan-

dard’ for both right and left ventricular volumet-
The Growing Role of Cardiac MRI ric quantification and has excellent inter-user
reproducibility (Mertens et al. 2008). In addition,
In the past decade, cardiac MRI has emerged as a extracardiac structures, particularly pulmonary
reliable, non-invasive form of assessment to fur- and systemic vascular structures and the aortic
ther detail cardiac anatomy, function, and hemo- arch, can be further delineated. These improve-
dynamics in more precise detail. One major ments in the imaging of key anatomic areas have
advantage is the further assessment of right ven- multiple applications in the pediatric population,
tricular volumes, which can be challenging on most significantly in evaluations for cardiomy-
standard echocardiographic views due to the opathy, pulmonary and systemic vein abnormali-
geometry of the chamber (Nies and Sekar 2013). ties, and aortic rings and slings (Nies and Sekar

2013). Both pre-operative planning and post- of pulmonary to systemic blood flow and pulmo-
operative monitoring for complications associ- nary vascular reactivity can be obtained, similar
ated with TOF, TGA, and single ventricle repairs to findings traditionally gained from diagnostic
can be supplemented with further anatomic catheterization studies (Nies and Sekar 2013).
details (Nies and Sekar 2013; Han et al. 2013). The three-dimensional (3D) imaging capabili-
Cardiac MRI is also beneficial in adolescents, ties of cardiac MRI have made complex visual
who can often have unclear echocardiogram reconstructions (Fig. 3.2) and 3D-printed ana-
imaging associated with changes in body habitus tomic models possible (Mertens et al. 2008;
(Krishnamurthy 2008). Myocardial viability can Costello et al. 2015). These innovative models
also be analyzed in cases of myocarditis or isch- can provide further details to cardiovascular sur-
emia with techniques such as delayed contrast geons for pre-operative planning and enhance the
enhancement (Nies and Sekar 2013). From a understanding of complex anatomy (Costello
hemodynamic standpoint, estimations of the ratio et al. 2015). 3D-printed models have the potential
a b
c d
Fig. 3.2 3D Echo images of the tricuspid valve (left) and mitral valve (right)arch

to give the opportunity to rehearse surgical tech- The use of cardiac MRI in the pediatric popu-
niques prior to entering the operating room, lation is projected to play an increasingly impor-
which carries an enormous potential to hone sur- tant role in characterizing anatomy, function, and
gical techniques in a risk-free environment and hemodynamics as imaging technology continues
ultimately, improve patient care. to improve. Guidelines and protocols for specific
Although the imaging advantages and lack of cardiac conditions are now under development
radiation make cardiac MRI a very attractive for both adults and children with CHD (Fratz
alternative to catheterization, there are some lim- et al. 2013).
itations (Han et al. 2013). For optimal results,
breath-holding may be required, which is not
always realistic in patients under the age of Updates in Echocardiography
6 years or for patients with developmental or
behavioural concerns. Sedation or general anaes- Echocardiography remains the workhorse of car-
thetic may be required to obtain optimal imaging. diac imaging and has undergone further enhance-
As well, both obtaining and processing the imag- ments in recent years. With high frequency
ing can be a time-consuming process requiring pediatric 3D transducers, it is now possible to go
expert interpretation, which is not available at all beyond the standard two-dimensional (2D)
cardiac centres (Krishnamurthy 2008). Full ana- images and create 3D reconstructions from
tomic details may not be possible depending on volumetric echocardiogram datasets that can be
tissue imaging planes and the limitations of cur- manipulated in multiple planes (Fig. 3.3)
rent technology, such that further imaging such (Mertens et al. 2008). An increasing amount of
as cardiac catheterization may still be required. detail regarding the myocardial surface contour,
Fig. 3.3 Three-dimensional echocardiogram images of the tricuspid valve and mitral valve

valve morphology, and chamber volumes can Extracardiac vascular structures including aortic
bolster pre-operative knowledge and is becoming rings and slings can also be well visualized using
more routine practice (Mertens et al. 2008). this modality. CT studies are typically much
However, as with any imaging modality, the qual- shorter in duration than echocardiograms or
ity of the information gained is directly related to MRI’s, and due to this, in some instances the
operator technique and experience with this tech- need for sedation can be eliminated. However,
nology is still developing. Optimizing the 3D the risks inherent to the radiation involved in CT
images can also be a very time-consuming pro- imaging must balance the potential benefits.
cess and standard protocols for specific forms of Weight-based protocols can help to ensure that
CHD have not yet been finalized (Mertens et al. the lowest possible dose of radiation is used and
2008). techniques such as prospectively-gated ECG CT
Ventricular functional analysis has also imaging can decrease the amount of radiation
expanded in echocardiography due to techniques administered by at least 64% (Young et al. 2011).
such as tissue Doppler, strain, and strain rate Young children with elevated heart rates and/or
imaging (Mertens et al. 2008). These methods patients with arrhythmias can also present chal-
are able to describe the velocity of movement lenges to the acquisition of ECG-gated CT imag-
within the myocardium as well as both the per- ing, and thus specialized adjustments may be
centage and rate of deformation of myocardial required to ensure accurate data capture (Young
segments, respectively, to better characterize et al. 2011).
regional myocardial function. These methods are As modern technology continues to advance,
highly applicable to patients with cardiomyopa- new applications of these standard cardiac imag-
thies, anthracycline-induced cardiotoxicity, or ing techniques will undoubtedly progress even
post-operative myocardial dysfunction (Mertens further. Uncovering an increasing amount of
et al. 2008). information regarding cardiac structure and func-
Criteria for the appropriate use of transtho- tion in multiple forms of CHD will prompt new
racic echocardiography in the outpatient setting standards for cardiac measurements and imaging
have been developed in recent years in response protocols to keep pace with this expanding body
to a growing demand for high-quality studies of knowledge.
with a limited number of trained pediatric sonog-
raphers to perform them (Campbell et al. 2014).
Recommendations are grouped by indications for Catheter Based Interventions
the study, which focus on common patient pre-
sentations such as chest pain and syncope. By The treatment of congenital heart disease has
applying these guidelines, resources and more changed significantly over the past two decades
specialized studies can be directed towards the with the rapid growth of interventional cardiol-
patients with the highest risk of pathology. ogy and catheter based therapy. Congenital heart
diseases that are now frequently treated non-
surgically with interventional cardiac catheter-
he Role of Cardiac Computed
T ization include secundum atrial septal defect
Tomography (CT) (ASD), patent ductus arteriosus (PDA), coarcta-
tion of the aorta, pulmonary and aortic valve ste-
With advancements in echocardiography and the nosis, pulmonary artery stenosis and pulmonary
expanding role of cardiac MRI, understanding regurgitation. Avoiding sternotomy and
the applications for cardiac CT merits a brief dis- cardiopulmonary bypass in these cases often

cussion. Overall, one of the main benefits for this results in lower morbidity, shorter hospital stays
imaging modality comes in the form of improved and lower health care costs.
coronary artery assessment, in some cases above Catheter repair of secundum ASD (Fig. 3.4a)
that offered by cardiac MRI (Mertens et al. 2008). began in the 1990s, with changes in device

a b
Fig. 3.4 (a) Secundum ASD device closure, (b) stent placement for coarctation of the aorta
construction taking place in the last decade to s uccess rate of this procedure is near 100% with
improve device stability. The earlier ASD devices very low complication rates (El-Said et al. 2013).
had some complications of structure fracture Closure by this technique is standard in the non-
which are improved with the new design of neonatal population. However new devices and
devices. The most commonly used devices are techniques are now allowing for the possible
the Amplatzer device and the Gore Septal extension of this procedure into the premature
Occluder device, although there are other devices neonate population (Francis et al. 2010).
in development for pediatric use. The successful Although there is continuing debate regarding
implantation rate is over 98%, including long- the indications for PDA closure in the premature
term freedom from re-intervention (Du et al. neonate population, the ability to non-surgically
2002). The age and size of child suitable for close this lesion avoids the possible post-
device closure depends on the anatomy and size operative complications of vocal cord palsy (9%),
of the ASD, but the majority of secundum ASD’s pneumothorax, chylothorax and need for transfu-
can be closed by the age of 3–5 years or weight of sion. With further experience and studies, it may
15 kg. Longterm follow-up reveals rare but become standard to offer this as an interventional
potentially serious complications, including ero- procedure rather than surgery in this newborn
sion with cardiac perforation (0.1%), endocardi- population.
tis, thrombosis and arrhythmia, the highest risk Coarctation of the aorta is also a lesion which
of which is in the first year after implantation is amenable to catheter intervention (Fig. 3.4b).
(Moore et al. 2013). This highlights the need for Primary treatment of non-neonatal coarctation
continued longterm surveillance of patient out- (over 6 months of age) by interventional catheter-
comes. Compared to surgical closure, there is ization is standard for many anatomical forms of
equal efficacy of both procedures with lower coarctation. The effectiveness of angioplasty of
complication rates, shorter hospital stays and native coarctation and recurrent post-operative
lower cost with device closure, making this a safe coarctation is high, with the main complication
and effective alternative to surgical therapy for being need for eventual repeat dilation in up to
secundum ASD (Du et al. 2002; Butera et al. 25% of patients (Tynan et al. 1990; Yetman et al.
2011). 1997). Stent placement decreases the rate of
Closure of hemodynamically significant PDA recoarctation, however in growing children, care
by transcatheter approach may be performed needs to be taken to ensure that an adequate sized
using either vascular coils or a device. The stent is placed to allow for repeat balloon dilation

with growth (Forbes et al. 2011). Neonatal pri- unknown etiology are increasingly being attrib-
mary coarctation catheter intervention is not as uted to genetic mutations. As this is a rapidly
universally performed compared to surgery, due advancing field, it is important to periodically re-
to concerns regarding higher recoarctation rates evaluate patients with prior negative genetic test-
and higher rates of vascular injury (Fiore et al. ing, as they may subsequently test positive for a
2005). Anatomy of the coarctation site, presence newly discovered mutation. While most of car-
of aortic arch hypoplasia and other associated diac screening and genetic testing remains in the
congenital heart lesions influence choice of bal- realm of pediatric cardiologists and geneticists, it
loon dilation, with or without stent placement, is important for referring physicians and caregiv-
versus surgery. ers to be aware of these advances, so that evalua-
The most recent interventional catheterization tion and screening of appropriate individuals
procedure to become available to a significant may occur.
number of congenital heart patients is percutane-
ous implantation of the pulmonary valve. Surgical
repair or revision of Tetralogy of Fallot and other Hypertrophic Cardiomyopathy
repairs involving the right ventricular outflow
tract often involve placing a valved conduit in the Hypertrophic cardiomyopathy (HCM) has long
pulmonary valve position. These valves are prone been recognized as having inheritance patterns
to progressive stenosis and regurgitation, result- suggestive of a genetic cause. It is now recog-
ing in the need for recurrent surgical replace- nized as being the most common of the genetic
ments. Since the mid 2000s there has been cardiac diseases (Maron et al. 1995; Zou et al.
significant progress in the development of percu- 2004). Mutations in at least 11 genes encoding
taneously placed pulmonary valves, implanted proteins of the cardiac sarcomere have been
over a balloon and in the framework of a stent. identified, with varied clinical expressions of
Current technology allows successful placement these mutations (Maron et al. 2012). HCM may
of these valves in larger children (over 20 kg) present from infancy through adulthood,
with pre-existing medium to large conduits (over although the majority of cases present in adoles-
16 mm) (Lurz et al. 2009; Vezmar et al. 2010). cence to early adulthood. Causes presenting in
There is ongoing research to develop a percuta- infancy and childhood tend to represent meta-
neous valve procedure suitable for post-operative bolic causes including glycogen storage disease
Tetralogy of Fallot patients with dilated outflow (Pompe’s disease) and mitochondrial myopa-
tracts who have not yet had their first valve thies, as well as Noonan syndrome. Most other
replacement (Boudjemline et al. 2012; Momenah forms are latent until adolescence or adulthood.
et al. 2009; Wilson et al. 2015). This represents a HCM is the most common cause of sudden
large group of patients and involves techniques to death in young people and is often silent, with
downsize the outflow tract to be able to anchor a the typical murmur, indicating outflow tract
percutaneous valve. Current clinical trials con- obstruction, or any other signs absent in up to
tinue to refine this technique. 2/3 (Members et al. 2011).
Genetic inheritance of HCM follows an auto-
somal dominant pattern. Seventy percent of iden-
enetic Testing in Pediatric
G tified mutations are for components of
Cardiology beta-myosin heavy chain or myosin binding
protein C. The majority of patients with disease-
Over the last 5–10 years, there has been an explo- causing mutations will develop HCM by early
sion in the knowledge and available testing for adulthood. The challenge is that with current test-
heritable causes of cardiac disease. Diseases that ing panels, only 1/3 will have disease-causing
were previously labelled as idiopathic or of mutations, with the remaining 2/3 negative or

with ambiguous results. This will remain a chal- cardiology screening throughout childhood if
lenge for diagnosis until all genes for HCM are genetic testing is positive, versus screening every
identified. To add to this challenge, thus far there 3–5 years in the absence of testing.
is minimal data to allow prediction of clinical
course and sudden death risk based upon genetic
test results (Maron et al. 2012). I nherited Arrhythmias, Including
Given this information, it is important that Sudden Cardiac Death
first degree family members of patients with
HCM be aware of the genetic link, and be consid- Sudden death in a young person is infrequent,
ered for referral to specialist assessment regard- occurring in about 1 in 10,000 of those between 1
ing cardiac screening and/or genetic testing. and 18 years of age. A cause for the sudden death
is found on autopsy in up to 50% of these, with
most common diagnoses being hypertrophic car-
Dilated Cardiomyopathy diomyopathy, arrhythmogenic right ventricular
cardiomyopathy, congenital coronary anomalies
Dilated cardiomyopathy (DCM) is the most and myocarditis (Puranik et al. 2005; Liberthson
common cardiomyopathy in children (Towbin 1996). There is no identifiable abnormality found
et al. 2006). This diagnosis carries a high risk of at autopsy in the remainder (sudden unexplained
morbidity and mortality, with a significant num- death or SUD), and these are presumed to be
ber of patients requiring advanced heart failure arrhythmia syndromes (Van Der Werf et al. 2010;
support including mechanical support and heart Chugh et al. 2000). Causes of SUD not identifi-
transplantation. DCM in the pediatric popula- able on standard autopsy include long QT syn-
tion has been traditionally described as idio- drome and other cardiac channelopathies. After
pathic in the majority of patients (Towbin et al. clinical evaluation of first degree family mem-
2006). This is in contrast to adult patients, in bers, a diagnosis can be made in about one third
whom ischemic and hypertensive causes are of these. A further 20% may be diagnosed by
common. Other causes of DCM in infants and genetic evaluation of the deceased (molecular
children include inflammatory causes (myocar- autopsy). While beyond the scope of this chapter
ditis), neuromuscular diseases, anthracycline to fully discuss these disorders, it is important
chemotherapy, metabolic and mitochondrial that referring physicians be aware of the presen-
diseases. Forty percent of patients are diagnosed tation of, inheritance patterns and availability of
in the first year of life, and the majority at all genetic testing for these channelopathies. The
ages present with clinical congestive heart fail- younger the patient who has died is, the more
ure at diagnosis (Towbin et al. 2006). Age at likely it is that the autopsy is negative (Van Der
diagnosis of 6 years or older is associated with a Werf et al. 2010). There is often a positive family
higher risk of death or transplant compared to history of young SUD or a history of prior syn-
infants (Alvarez et al. 2011). cope in the deceased patient (Van Der Werf et al.
Increasingly, a genetic basis to DCM is being 2010).
identified. At present, sarcomeric or cytoskeletal Cardiac channelopathies describe a number of
gene mutations can be identified in an increasing disorders affecting the ion channels of the heart.
number (20–35%) of patients with DCM (Kindel These include long QT syndrome (LQTS), cate-
et al. 2012; Møller et al. 2009). Genetic testing cholaminergic polymorphic ventricular tachycar-
panels for DCM have become commercially dia (CPVT) and Brugada syndrome. The
available and have over 40–50% diagnostic yield presenting symptoms of these disorders are most
(Kindel et al. 2012). Identification of a disease- commonly syncope, seizures or sudden death.
causing mutation will guide management of the There is often overlap both in the presenting
family. Current recommendations are for yearly symptoms, clinical findings and genetic testing

for many of these disorders. CPVT is usually pediatric cardiologist for further evaluation, as
caused by an abnormality in calcium movement this may be the only warning of a significant car-
within the cardiac cell through the ryanodine diac diagnosis.
receptor. Most of these have autosomal dominant
inheritance (Laitinen et al. 2001; Priori et al.
2001), and present as exercise or stress induced ediatric Chest Pain: Cardiac
P
ventricular arrhythmias, often manifest as syn- Features
cope or sudden death during exercise. For LQTS,
16 genes have been implicated to date, with hun- Chest pain is a common complaint in children
dreds of mutations involving mostly the sodium and adolescents, prompting many Emergency
and potassium cardiac channels (Splawski et al. Room visits. The vast majority of pediatric chest
2000; Tester et al. 2016; Tester and Ackerman pain symptoms are secondary to non-cardiac
2011). The majority (>90%) are caused by just causes, which is very distinct from the causes of
three of these—LQTS 1–3. Most have autosomal chest pain in adults. However, the majority of
dominant inheritance. Genetic testing has a yield patient, caregiver and health care provider anxi-
of over 70–80% if the diagnosis is suspected clin- ety surrounding pediatric chest pain is related to
ically (Tester et al. 2006). However, expertise in potential cardiac causes. History and physical
interpretation of both clinical and genetic testing examination are key in determining the cause of
is critical, to avoid false labelling of the patient or chest pain. In large studies evaluating pediatric
family member with or without disease. patients presenting with chest pain, a cardiac eti-
Treatment for channelopathies is available with ology was determined in only 1–4%, with most
significant reduction in symptoms and mortality. cases attributable to musculoskeletal, gastroin-
Therapeutic choices include medication (fre- testinal, respiratory or idiopathic causes (Lin
quently beta-blockers), pacemaker therapy and et al. 2008; Saleeb et al. 2011; Angoff et al.
implantable defibrillators. In some situations, the 2013). Cardiac chest pain is more likely with
genetic testing result may help guide the thera- gradually increasing chest pain with exertion, or
peutic approach. chest pain associated with fever, palpitations,
It is important to remember that the vast syncope or pre-syncope. Although cardiac tropo-
majority of syncopal episodes in the pediatric age nin levels are important in screening and diag-
range are benign vasovagal syncope. Classic fea- nosing ischemia in adults, the use of troponin
tures of vasovagal syncope are syncope occurring screening in children with chest pain is of mini-
in an upright position or with exposure to pain or mal benefit unless associated with fever (perimy-
stress, with prodromal symptoms of diaphoresis, ocarditis) or ECG changes (Liesemer et al. 2012).
warmth, visual change, and pallor, followed by Pediatric chest pain is usually not an indication
fatigue following the episode. Less than 5% of for referral to a pediatric cardiologist or for echo-
pediatric syncope cases have cardiac pathology, cardiography unless cardiac features are present
and the most useful way to differentiate these (Campbell et al. 2014).
cases from benign vasovagal syncope is by care-
ful history taking (Ritter et al. 2000; Steinberg
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Update in Child Maltreatment
4
Michelle G.K. Ward, Amy E. Ornstein,
Tanya Deurvorst Smith, and Karla Wentzel
Introduction In the United States, an estimated 3.6 million

referrals involving 6.6 million children were
Every child has the right to grow up in a safe, made to child protection services in 2014 and in
healthy, and nurturing environment that helps greater than 700,000 cases, child maltreatment
them to meet their greatest potential. However, was substantiated. This indicates that 9.4 per
globally at least a billion children experience 1000 children in the United States are victims of
physical, sexual, emotional, or multiple types of substantiated maltreatment and greater than
violence. This includes greater than 50% of chil- 240,000 children receive foster care services
dren living in North America (Hillis et al. 2016). (U.S. Department of Health, and Human Services,
Child maltreatment (abuse, neglect, and exposure Administration on Children, Youth and Families,
to family violence) normalizes violence, under- Children’s Bureau 2016). However, some studies
mines the health and development of children, suggest that up to one quarter of children in the
and is linked with multiple negative physical and US experience some form of child maltreatment
mental health outcomes in adulthood. It is hard to (Finkelhor et al. 2013, 2015). In Canada, approx-
imagine a current health problem that has a imately 1.4% of children are the subjects of
greater effect on our population, than does vio- reports to child protection services that go on to
lence, with child maltreatment representing vio- be substantiated for abuse or neglect (Public
lence that occurs within the context of a Health Agency of Canada 2010). However, popu-
caregiving relationship. lation studies demonstrate that up to 32% of
M.G.K. Ward, M.D., F.A.A.P., F.R.C.P.C. (*) Department of Pediatrics, Dalhousie University,
Division of Child and Youth Protection, Halifax, NS, Canada
Department of Pediatrics, Children’s Hospital of e-mail: amy.ornstein@iwk.nshealth.ca
Eastern Ontario, 401 Smyth Rd, Ottawa K1H 8L1,
T.D. Smith, M.N., N.P.-Paediatrics • K. Wentzel,
Ontario, Canada
M.N., N.P.-Paediatrics
Associate professor, Department of Pediatrics, The Suspected Child Abuse and Neglect (SCAN)
Faculty of Medicine, University of Ottawa, Program, The Hospital for Sick Children,
Ottawa, ON, Canada Toronto, ON, Canada
e-mail: mward@cheo.on.ca
Lawrence S. Bloomberg Faculty of Nursing,
A.E. Ornstein, M.D.C.M., M.Sc., F.R.C.P.C, F.A.A.P. The University of Toronto, Toronto, ON, Canada
Department of Pediatrics, IWK Health Centre, e-mail: Tanya.smith@sickkids.ca;
Halifax, NS, Canada Karla.wentzel@sickkids.ca


84 M.G.K. Ward et al.
women and men report physical abuse, sexual which authorities can or must respond and these
abuse, and/or exposure to domestic violence as are usually categorized as physical abuse, sexual
children (Afifi et al. 2014). This implies that cli- abuse, emotional abuse, and neglect. Many juris-
nicians who are seeing children and youth regu- dictions also consider exposure to intimate part-
larly are likely encountering victims of ner violence (also called domestic violence) as
maltreatment on a monthly, if not weekly or daily maltreatment for children because it places them
basis. at risk of harm in their home environment and
Although many clinicians feel poorly pre- because they often experience many of the same
pared to deal with cases of suspected abuse or negative outcomes as children who are victims of
neglect, they are in a unique position to identify direct maltreatment (Afifi et al. 2014; Rankin and
concerns of maltreatment and to assist children Ornstein 2009).
and families. They also have an ethical responsi- Physical abuse is characterized by the use of
bility, and in many jurisdictions a legal duty, to physical force by a caregiver that results in harm
report concerns of maltreatment to authorities. or risk of harm to the child’s health, safety or
Clinicians can take a standard clinical approach well-being.
to this issue by generating a differential diagno- Sexual abuse occurs when a caregiver or
sis, completing a history and physical examina- another person in a position of power, engages in
tion, assessing with laboratory and radiographic any activity with a child for sexual purposes. This
testing, and synthesizing the information to arrive includes sexual contact (e.g., oral, anal, genital),
at a conclusion. Following this type of objective, and activities without physical contact, such as
structured approach will be familiar to clinicians exploitation (eg. trafficking or facilitating prosti-
and can provide a framework for assessment, tution or pornography), voyeurism, and exhibi-
during a time that may be emotional for all tionism. Different jurisdictions may have
involved. additional definitions and laws regarding the defi-
This chapter will provide a review and practi- nition of sexual abuse, such as age-based laws for
cal medical approach to the most common child consent.
maltreatment problems encountered by clini- Neglect is generally viewed in the child pro-
cians: physical abuse, sexual abuse, and neglect. tection system as a pattern of omissions of care
by a parent or caregiver that leads to harm or a
risk of harm for a child. However, neglect has
What Is Child Maltreatment? also been defined from a child’s perspective, as
the child’s needs not being met, whatever the
The World Health Organization defines child cause (Dubowitz et al. 2005).
maltreatment as “…the abuse and neglect that In addition to legal and clinical definitions of
occurs to children under 18 years of age. It child maltreatment, culture plays a key role in
includes all types of physical and/or emotional defining child maltreatment. Parenting philoso-
ill-treatment, sexual abuse, neglect, negligence, phies, methods, norms, disciplinary practices,
and commercial or other exploitation, which and expectations of children’s behaviour vary
results in actual or potential harm to the child’s widely within and between different populations.
health, survival, development or dignity in the These are often culturally-determined. As a
context of a relationship of responsibility, trust or result, there is variability in what is deemed
power” (World Health Organization 2016). In acceptable in child rearing and what constitutes
other words, child maltreatment refers to the abuse or neglect. Notwithstanding these differ-
actions or inactions of a caregiver that result in ences, clinicians should always advocate for par-
actual or potential harm to a child’s health or enting practices that are safe, healthy, and
well-being. beneficial to helping children reach their best
In many countries, child protection and/or physical, developmental, and emotional potential
criminal laws outline the types of maltreatment to (Ward et al. 2014).

4 Update in Child Maltreatment 85
ow Does Maltreatment Affect

H state the certainty of the medical information that
Children? the finding in question was caused by maltreat-
ment. The clinician should also be aware that
In recent decades, a robust medical literature has some words carry unintended meaning for the
demonstrated the negative effects of adverse legal system, which may place greater emphasis
childhood events, such as child abuse and neglect, on the intent behind an individual’s actions.
on the long-term physical and emotional health Many different terms have been used to dif-
of adults. These early childhood experiences are ferentiate causes of injuries including the follow-
associated with stroke, cancer, heart disease, ing pairs of terms: non-accidental and accidental,
hypertension, diabetes, depression, suicide, sub- abusive and non-abusive, intentional and non-
stance abuse and other poor outcomes (Maguire intentional, inflicted and non-inflicted.
et al. 2015). Moreover, disruptions in early child- For the purposes of this chapter, the term
hood attachment and exposure to a stressful and “accidental” will be used to refer to injuries or
unpredictable environment lead children to have health effects that occur as a result of common
maladaptive behaviours, difficulties regulating minor life events (eg. bumps and falls), usually
emotions and understanding social interactions, through the child’s own actions. For example,
and an exaggerated stress response to normal bruising on the shins of a school age child that
minor life events, with subsequent high rates of occurs through playing outdoors and bumping
mental health problems in adulthood (Afifi et al. against the play structure at the park would be
2014; Maguire et al. 2015). In the clinic, com- considered “accidental”. Similarly, a buckle frac-
munity, or classroom, this often demonstrates ture of the radius that occurs from falling from a
itself as aggression, anger, depression, or diffi- swing at the park would be considered “acciden-
culty sustaining attention. Once established, tal”. It is acknowledged that injury prevention
these behavioural patterns may be difficult to specialists typically do not use “accident” as even
manage using typical behaviour modification the actions above may be viewed as preventable
strategies because of the alteration in the child’s events.
neural physiology and their priming of the stress The term “inflicted” will be used to refer to
response. As a result, prevention and early inter- injuries or health effects that occur as a result of
vention are essential, while promoting effective the direct actions of another person. For example,
treatment for those already affected. bruising on the back caused by an adult hitting a
child with a belt would be considered inflicted.
Similarly, if a parent grabbed their child by the
Terminology and Definitions elbow to stop them from running into traffic and
this resulted in bruising, this would be considered
When maltreatment concerns are raised for a inflicted. Used in this way, the term does not
child, a variety of professionals may become determine the intent of the action that caused
involved including those from health care, child injury, as the medical information alone (mark
protection, law enforcement, social services, and/ seen on the back or bruises on the elbow) is not
or the justice system. As a result, it is imperative able to determine the intent of the adult’s action or
that the language used by clinicians be objective, to verify the circumstances surrounding the event.
clear, and understandable to those within and out- The term “abuse” is used to refer to a legal deter-
side of the health care system. mination that injuries or effects that occurred as a
Clinicians need a way to communicate that result of the direct actions of another person were
they are concerned that a specific injury or health intended and harmful. The determination of abuse
effect is related to maltreatment as opposed to typically occurs after an investigation by child pro-
being related to a medical illness or common tection and/or legal authorities, but the investiga-
childhood event (bump, fall etc.). At the same tion may be initiated by concerns for abuse raised
time, they must use language that does not over- by a health professional. For the purposes of this

chapter, “abuse” will also be used to refer to find- with a reasonable traumatic or medical expla-
ings in the literature that were deemed to be asso- nation and may be explained by maltreatment.
ciated with abuse (whether determined medically, • Pattern of growth, development, behaviour, or
multi-disciplinarily or legally). emotional problems that is outside the norm
and may be due to a caregiver’s actions or
inactions.
Identifying Maltreatment • Pattern of non-adherence with medical, dental
or psychological care recommendations such
Although child maltreatment is common, it often that the child experiences (or is at risk of) harm.
goes unrecognized in health care settings. In • Pattern of a child’s physical, emotional, devel-
many cases it is difficult to recognize because the opmental or educational needs not being met.
signs and symptoms may be non-specific and/or • Pattern of injuries or harm related to inade-
the child may be pre-verbal, unable or unwilling quate supervision.
to disclose the maltreatment. Clinicians are
trained to begin their assessment by taking a his-
tory. However, in these cases, the history pro- linical Approach to Physical Injuries
C
vided by the caregiver may be incomplete, That May Be due to Maltreatment
incorrect, or unknown to the person providing the
information. General Approach
The following general concepts on assessment Questions of child maltreatment should be evalu-
should prompt the clinician to carefully consider ated using a standard medical approach including
maltreatment as a possible cause, while also con- a thorough pediatric history, full physical exami-
sidering other traumatic possibilities (eg. acci- nation (including vital signs, growth parameters,
dental, birth, inflicted or self-inflicted injury) and and examination of the full skin surface, with a
medical conditions in the differential diagnosis, chaperone present when possible), laboratory test-
as appropriate. More specific “red flags” for dif- ing and/or imaging when indicated, and synthesis
ferent types of maltreatment are included in the of the relevant clinical information with the clini-
sections below. cian’s understanding of the issues from current
literature and experience. The clinician should
• Disclosure of maltreatment by a child, a wit- approach this task without bias, with objectivity,
ness, or someone else. and with an open mind regarding the cause of the
• No explanatory history or unknown history injuries. Clinicians should demonstrate the same
for a significant, uncommon, or unexpected compassion, empathy, professionalism, and col-
traumatic injury. laboration with caregivers in this clinical scenario
• Injuries with characteristics that are more as they do in all other situations.
often associated with inflicted injury and/or In determining the likely cause of the injury,
physical abuse than with other injury mecha- the health care provider should consider a broad
nisms and a history that does not clearly differential that includes medical causes and trau-
explain the injury. matic causes for injuries or symptoms. Working
• Explanatory history for a traumatic injury(ies) through the differential diagnosis in a systematic
that does not appear compatible with the way is recommended. Although health care pro-
observed injury because of factors related to fessionals are used to using information gathered
the child (eg. age and developmental abilities) on history to guide their evaluation on physical
or the injury (eg. severity, number, type and/or exam, laboratory testing and imaging, in cases of
approximate age of the injury). possible maltreatment, the history of the injury
• Pattern of injuries or medical issues (such as event and symptoms may be incorrect, incom-
fractures, growth problems, genito-urinary plete, or misleading. This is sometimes also true
symptoms) that does not appear compatible of non-maltreatment cases.

History The clinician should ask about allergies,

A standard pediatric history should be taken. In immunization status, and whether the child takes
general, when maltreatment is being considered a any medications or uses alternative therapies.
detailed History of Presenting Illness (HPI) is A developmental history is important in order
required. Although, in most circumstances, it is to understand a child’s level of mobility, indepen-
not the role of the clinician to take a forensic his- dence and/or any need for assistance with daily
tory (unless they are specifically trained to do so), activities. These may need to be compared to the
the clinician must take enough history to be able history that is presented (eg. the child crawled off
to assess and assist the child and family medi- the bed) to determine whether they are compati-
cally, and to determine if the concerns require a ble. Developmental problems are common in
report to legal authorities. The clinician should be children who have experienced maltreatment
aware of relevant child protection laws, including and/or suboptimal parenting. In particular, prob-
mandatory reporting duties, for their lems in the development of speech and language
jurisdiction. and in social skills are more sensitive to the
On history, the clinician should take sufficient child’s environment and the degree and quality of
information in the initial assessment in order to caregiver stimulation. These can be screened for
answer the following questions: using a developmental history and/or a standard-
ized and validated developmental screening tool.
1. What injuries or health effects are present? Motor skills tend to be less sensitive to the child’s
What associated features of maltreatment, environment and level of caregiver interaction
trauma, or a medical condition might be pres- but can also be affected if the child is not chal-
ent? What medical assessment, testing and lenged to move and/or given appropriate oppor-
management are indicated for this child for tunities to practice motor skills.
health purposes? How urgently are testing Clinicians should make a special effort to ask
and/or treatment needed? about child behaviour, parental expectations, and
2. Does the information suggest harm or risk of discipline practices since most physical abuse
harm to the child, such that a report to child occurs in the context of physical or corporal pun-
protection/legal authorities is advisable accord- ishment. Clinicians can initiate this discussion as
ing to regional legislative requirements? part of the developmental history or ROS when
3. Is there any indication for forensic samples to behaviour is reviewed. This is an opportunity for
be collected (eg. sexual assault forensic evi- the clinician to convey their openness to discuss-
dence kit)? ing these issues. The clinician can also provide
anticipatory guidance and counselling on these
If the child has a physical finding such as a issues that are of importance to most parents.
bruise or fracture, the HPI, Review of Systems Risk factors for the use of physical punish-
(ROS) Past Medical History (PMHx) including ment include parental approval of physical pun-
pregnancy and birth history, and Family History ishment, parental anger in response to conflict
(FHx) should include specific questions about the with their child, parental history of physical pun-
finding in question. The purpose is to understand ishment as a child, and parental assessment of
the course and effect of the finding (eg. is this the child misbehaviour as intentional or serious
child’s first episode of significant bruising, does (Ateah and Durrant 2005; Durrant et al. 1999;
the child have other symptoms of bleeding or is Bower-Russa et al. 2001; Durrant and Ensom
there a family history of such), as well as to look 2004). Increased family stress with the presence
for possible underlying acute or chronic medical of parental conflict or violence, greater number
conditions that could predispose to the finding of children, and parental mental health or addic-
(eg. bleeding disorder or systemic illness). See tion problems are also linked to greater use of
below for specific questions to include for differ- physical punishment. Possible protective factors
ent types of physical findings. include a warm and positive parental relationship

(especially if one parent experienced childhood Physical Examination

violence), an appropriate source of parenting A head to toe evaluation, beginning with vital
advice, and parents who are empathetic (Durrant signs and the child’s general appearance (hydra-
and Ensom 2012; Afifi and MacMillan 2011). tion, nourishment, clothing, general health sta-
Using a non-judgemental and supportive style, tus) is recommended whenever child maltreatment
clinicians should encourage parents to talk about is suspected. The clinician should observe for
their challenges in parenting and help them make features that might suggest an underlying genetic
a concrete plan for dealing with the issues the condition. The weight and height should be plot-
next time they arise. They can also refer to appro- ted on a standardized and validated growth chart
priate supports in the community. The following (eg. WHO, CDC) at each visit in order to appreci-
are questions that may help the clinician to under- ate trends that might not otherwise be seen. The
stand the parent’s views and practices on child head circumference should be plotted for all chil-
behaviour and physical discipline, and assess for dren under the age of 2 years as a rapidly increas-
the above risk factors: ing head size may be the first clue to an intracranial
injury and stagnating head growth is an important
• What is your child’s behaviour like most of health issue for a child with inadequate nutrition
the time? Do you think it is appropriate for and/or prior trauma. These parameters may also
their age? How do you usually guide your highlight conditions that can contribute to or
child’s behaviour? mimic injuries from maltreatment such as skele-
• All children have moments when they misbe- tal dysplasias and metabolic conditions (eg. glu-
have or don’t listen. Can you tell me about taric aciduria).
what your child is like at those times? When Particular attention should be paid to the head
was the last time this occurred? Was this the and neck exam. The dentition often reflects envi-
“worst” time? What did you do? How were ronmental and caregiving factors such as feeding
you feeling? The next time this occurs, would practices (eg. bottle caries), hygiene, and quality
you do anything differently? of nutrition, and may also be a clue to underlying
• Has your child’s behaviour ever been so bad conditions (eg. dentinogenesis imperfecta).
that you felt you had to spank, hit or do some- During an evaluation, if the clinician notes speech
thing physical to him/her? How often does and language delays and poor dental hygiene,
this occur? Did your child ever get hurt as a further information should be sought about care-
result? If this scenario occurred again, would giving practices, daily routines and the home
you do anything differently? environment. This combination of findings is
• Did your parents ever hit, spank or use physi- often seen in children who live in suboptimal
cal punishment with you as a child? What do environments.
you think about that now? The general physical examination may include
an external genital examination. It is appropriate
As there is now ample evidence that physical to examine the genitals when the presenting con-
discipline is not effective and can be harmful to cern or symptoms involve the gastro-intestinal or
children in the short and long-term, clinicians genito-urinary system but it is often also appro-
should advise against all forms of physical dis- priate to examine the genitals as part of the com-
cipline (Durrant and Ensom 2004, 2012). plete pediatric assessment. The health care
Clinicians should guide parents on the use of provider can convey, in age-appropriate lan-
positive parenting including safe, effective and guage, and using correct anatomical terms (or the
healthy forms of guidance for children’s behav- terms that the child already knows and uses) that,
iour. Many excellent resources for clinicians like the other areas already examined, the geni-
and parents exist including those by the tals are another part of the body that should be
American Academy of Pediatrics and the examined periodically by a physician to ensure
Canadian Paediatric Society. that they are healthy. The clinician should

acknowledge that the genitals are a private area the sections below. The reader is referred to
of the body. This offers an opportunity to model a sources for further information about documenta-
discussion with the child about privacy and safety tion and legal considerations (Ornstein 2013).
in front of the caregiver. The child’s permission
for this part of the exam should be sought and
respected. Gloves should be worn by the clinician Physical Abuse
when examining the genitalia or anus. Every
effort should be made to help the child feel com- Clinicians may be the first to identify concerns
fortable with this exam, including draping the for physical abuse because of a specific physical
child, taking more time for the exam, and having finding or they may be asked to assess a child to
a supportive caregiver with the child. Further provide an opinion on whether there are signs of
details of the genital exam are included in the physical abuse. When presented with these sce-
section below on sexual abuse. narios, clinicians should be cautious to follow
their usual objective, empiric approach and to
Documentation recognize both the breadth and limitations of
When a clinician is asked to evaluate a child for a their roles as a medical professional. The follow-
child maltreatment concern, or when one is iden- ing key points should be borne in mind:
tified in the course of an evaluation, special atten-
tion should be given to documentation. In • On medical assessment, no injury on its own
addition to the usual notations made in the record, is pathognomonic for physical abuse
the clinician should include the time and length • All physical findings have a differential diag-
of the assessment, who accompanied the child, nosis which may include a variety of traumatic
the reason for the assessment, and what informa- and medical causes
tion was provided prior to the assessment. • Medical conditions and trauma are not mutu-
The clinician should use descriptive (and not ally exclusive. The presence of one does not
interpretive) language throughout such as “the exclude the possibility of the other
mother reports concerns of …..” or “the father • In most cases of suspected physical abuse, the
states that…..”. The diagnosis should be recorded objective medical findings, on their own, can-
as an objective medical determination (eg. bruis- not determine the exact mechanism and
ing, fracture, head injury, alleged sexual assault). circumstances of injury or the precise timing
Where it is important to capture the context of the of injury
situation, the clinician can record “child maltreat- • The current understanding of the scientific
ment assessment” or other descriptor (eg. unex- basis of injuries, coupled with clinical experi-
plained bruising instead of bruising) but should ence, often can raise concern about physical
avoid making a “diagnosis” of abuse based on abuse. Physicians with appropriate training,
medical information alone. skills, and experience can identify concerns
The information given to the family, child pro- for maltreatment and provide an opinion on
tection worker or others should be recorded. the likely cause or mechanism of injury and
Reviewing the documentation for legibility, approximate time of injury. Physicians with-
accuracy and completeness is good practice as out this expertise should be cautious about
this documentation may be used for legal pur- providing an opinion that will be used for
poses and may be the only record by a profes- legal purposes
sional. If the clinician is called to testify in the
case in the future, they will need to rely on their
written record. Bruising
Special documentation of skin and genital
findings by drawing or photography should also Bruises are common in childhood and usually
be included when appropriate and is described in represent no significant health concern. However,

bruising is also the most common injury sus- considered “normal childhood bruising”
tained from physical abuse (Public Health (Maguire and Mann 2013; Maguire et al. 2005a;
Agency of Canada 2010) and can sometimes be Pierce et al. 2010; Labbe and Caouette 2001;
the first indication of an underlying medical ill- Dunstan et al. 2002; Lux 2000; Sugar et al. 1999;
ness. As a result, health care providers may be Carpenter 1999; Harris and Flaherty 2011; Kemp
asked to provide an opinion on the likely cause of et al. 2015). Many studies have shown that the
bruising on a child or they may be the first to amount of bruising on children is directly corre-
raise concern for physical abuse or a medical ill- lated with the child’s level of mobility. While
ness as a result of their physical examination. non-mobile infants or children can sustain bruises
Bruises are skin injuries that are the result of (eg. a baby who is dropped or rolls from a change
bleeding beneath the skin. They can be caused by table), any unexplained bruising in young infants
an impact, compression, crushing or penetrating should be viewed as concerning and warrants fur-
force that damages the blood vessels, leading to ther assessment for both the possibility of
bleeding into subcutaneous tissue layers. In chil- inflicted injury as well as an underlying medical
dren, bruises are usually caused by impact condition.
between a part of the body and a hard surface or In some cases, a question regarding the mech-
object. Petechiae can also be seen on their own or anism of injury may arise when the size, pattern,
in association with bruising. location or other features of the bruising do not
Through active play, mobile children often appear compatible with the explanation provided.
sustain “normal childhood bruising”. This type of Numerous studies have outlined the most com-
bruising is typically characterized by small, mon locations and characteristics for “normal
round-oval bruises over bony prominences on the childhood bruising” versus bruising seen in phys-
front of the body and is considered “accidental”. ical abuse. However, the clinician should be cau-
These are most commonly seen on the forehead, tious in drawing firm conclusions based on this
knees, and shins and usually result from minor data alone. The following “red flags” are pro-
impacts against objects or the ground as a result vided for health care providers to use in the con-
of the child’s own activities (ie. bumps and falls text of unexplained bruising or bruising that does
through play). Areas with greater subcutaneous not appear to fit with the explanation provided.
tissue (eg. buttocks, thighs, soft part of the These “red flags” should prompt clinicians to
cheeks) are less likely to bruise because of the conduct a thorough history and physical as out-
cushioning effect of the tissues. “Normal child- lined above for the possibility of physical abuse
hood bruising” usually does not have a defined as well as for an underlying medical condition
shape or pattern (Maguire and Mann 2013; (Table 4.1).
Maguire et al. 2005a; Pierce et al. 2010; Labbe The colour of bruises has been used to esti-
and Caouette 2001; Dunstan et al. 2002; Lux mate their age and bruises of different ages are
2000). Of course, children are sometimes sometimes interpreted as a “red flag” for trauma
involved in more significant trauma (eg. falls occurring on multiple occasions. However, the
from a height, sports injuries, motor vehicle col- dating of bruises is now known to be inaccurate
lisions) and the resultant bruising may show and the colour of bruises should not be used as
characteristics that are not in keeping with “nor- evidence (on its own) to confirm that injuries
mal childhood bruising”. These bruises usually occurred at different times (Maguire et al. 2005b;
do not pose a problem for health care providers in Stephenson and Bialas 1996; Grossman et al.
determining their cause as these events are often 2011; Schwartz and Ricci 1996; Langlois and
witnessed and/or verifiable. Gresham 1991; Pilling et al. 2010; Bariciak et al.
As “normal childhood bruising” occurs in 2003).
children who are mobile and who cause skin The overall assessment and opinion on the
injury through their own actions, bruising in very possible cause(s) of bruising should be arrived at
young and/or non-mobile children should not be using an objective structured approach whereby

Table 4.1 Bruise characteristics that are “red flags” for to those that are required for health purposes.
possible physical abuse
Laboratory testing may also be indicated to rule
Characteristic “Red flags” out an inherited or acquired coagulopathy, as
Age/mobility Unexplained bruises in infants and well as other illnesses. Imaging may be indicated
young children who are not yet to look for features of an underlying condition or
mobile (ie. not crawling or cruising)
for occult injuries in very young children.
Location Bruises on the ears, neck, hands, feet,
buttocks or torso (torso includes chest,
back, abdomen, genitalia). Bruises on Differential Diagnosis
other “fleshy” areas of the body Traumatic mechanisms, medical conditions, and
Size Bruises that are unusually large mimics of bruising (eg. phytophotodermatitis,
Shape Bruises that have a recognizable dyes) should be considered as possible causes of
shape (eg. outline of a shoe, hand, or
belt)
bruising. While the clinician should carefully
Pattern Bruises that occur in clusters or have
assess for medical causes, they should also rec-
a defined shape that is repeated on ognize that in many situations (eg. infants with
various body surfaces bruising) medical conditions resulting in bruising
Number Bruises that are more numerous than are rare. Bruising from inflicted injury is more
typically seen (especially during common than many of the conditions listed.
winter months or when children have
less active outdoor play) Types of medical conditions that should be con-
Explanation Significant bruises with no sidered include:
explanation or an explanation that
does not appear compatible with the • Coagulation disorders (eg. idiopathic throm-
bruise characteristics bocytopenic purpura (ITP), von Willebrand
disease, hemophilia, platelet disorders)
• Connective tissue disorders (eg. Ehlers
the health care provider assesses the location(s), Danlos, Osteogenesis imperfecta), infections
size(s), shape(s), pattern(s), and number of (eg. meningococcemia)
bruises relative to what is considered “normal” • Malignancies (eg. leukemia, neuroblastoma)
within the child’s developmental abilities and the • Nutritional deficiencies (eg. vitamin K or C
context of the history provided. The presence of deficiency)
one or more of these red flags may be sufficient to • Autoimmune and inflammatory disorders (eg.
report concerns to child protection authorities but Henoch-Schonlein purpura)
should not be taken, on its own, as proof of physi- • Other severe systemic illnesses (eg. dissemi-
cal abuse. The medical information, on its own nated intravascular coagulation)
usually can determine whether the bruises are
likely related to trauma, but is limited in its abil- History
ity to determine precisely how the skin was The history for a presenting concern of bruising
impacted or otherwise injured by another object, should include specific questions to evaluate for
surface, or person (ie. whether the impact was a the diagnoses above, as well as a thorough bleed-
result of the child’s own actions or the actions of ing history. It should also include a comprehen-
another person). sive general history with attention to factors such
When concerns for physical abuse are raised as the use of vitamin K at birth, feeding history,
because of bruising on a child, the physician’s recent symptoms, and family history suggesting a
role is to assess for possible causes including bleeding disorder. Key symptoms on history
medical conditions. This requires taking a com- (HPI, PMHx and FHx) for coagulopathy are
prehensive history and doing a physical examina- dependent on the child’s age and are listed below.
tion. As discussed above, it is generally not the These are drawn from the standardized Pediatric
role of the health care provider to take a forensic Bleeding Questionnaire, which can be used as a
history. The clinician should limit their questions guide (Mittal et al. 2015).

Index child or family such as bruises, lacerations, abrasions, areas of

Infant members hyper or hypopigmentation, birth marks etc. For
Postcircumcision bleeding Spontaneous, easy or example, the clinician can draw the skin finding
Birth cephalohematoma excessive bruising
and note “3.0 × 1.5 cm irregular oval blue-green
Umbilical stump bleeding Mucocutaneous
or delayed stump bleeding (eg, gingival non-blanchable bruise on the mid forehead”.
separation bleeding) Photos can be taken but this is best done by a
Postvenipuncture bleeding Epistaxis that is trained forensic photographer, where possible.
Macroscopic hematuria spontaneous, lasts
Written consent from the legal guardian or child
Petechiae at clothing line >10 min or requires
pressure sites medical treatment themselves may be required, depending on
Bruising at sites of object Bleeding from minor regional laws and practices. Colour balance pal-
pressure, such as infant car wounds that lasts ettes and standardized rulers should be used.
seat fasteners >15 min or recurs
Photos must be stored in a secure fashion, linked
within 7 days
Prolonged bleeding to the child’s medical record.
after surgical
procedures Medical Testing
Bruises with palpable
While not all cases of bruising require laboratory
lumps beneath them
Joint swelling with testing or imaging, various professional groups and
minor injury authors have recommended testing when it is indi-
Blood in the stool or cated for clinical or legal purposes (Ward et al.
urine
2013; Anderst et al. 2013; Royal College of
Menorrhagia
Unexplained anemia Paediatrics and Child Health 2006; Khair and
History of blood Liesner 2006; Liesner et al. 2004; Minford and
transfusion Richards 2010). Testing may be done to evaluate for
specific conditions or to evaluate for other injuries.
Bloodwork that is recommended to screen for
Physical Examination bleeding disorders includes:
The physical examination should be thorough
and complete with visualization of all skin sur- • Complete blood count (including platelet
faces. The health care provider should look for count)
signs of other injuries including in the mouth (eg. • Peripheral blood smear
torn frenulum) and by palpation and observation • Prothrombin time (PT)/International normal-
of the bony structures of the head, chest, back, ized ratio (INR)
and extremities. Special attention should be paid • Activated partial thromboplastin time (aPTT)
to signs of any of the medical conditions dis- • Fibrinogen
cussed above, which should include examination • Von Willebrand studies (antigen and activity)
of the liver, spleen and lymph nodes, joints for • Factor VIII level
effusions or hyperlaxity, and facial features for • Factor IX level
dysmorphisms. • Blood group (for interpretation of von
Willebrand levels)
ocumentation of Physical Findings
D • Liver function tests (for secondary platelet
When possible, the skin findings should be dysfunction)
described in the written record in words and • Renal function tests (for secondary platelet
using a visual representation. For accuracy, skin dysfunction)
marks can be measured. Clinicians can use a
body diagram to draw the size and shape of The above listed tests, and others that are
bruises, scars, and other skin marks, indicating available, should be tailored to the clinical situa-
measurements, shape, and colour. Where possi- tion. Consultation with a child maltreatment
ble, clinicians should name the skin findings, pediatrician and/or hematologist may be helpful

in determining which tests to do. A hematologist imaging. In most cases, a CT scan is recom-
may also be helpful in interpreting abnormal mended, although MRI can also be used if the
results and making recommendations on whether traumatic event is non-acute (ie. more than
further assessment or testing is needed. 3 days prior to time of imaging). Head ultra-
sound is an insufficient test for the evaluation
esting for Occult Injuries
T of possible head trauma and should not be
Testing may be indicated to evaluate for other relied upon to rule-out traumatic findings
possible injuries when bruising raises a concern (American Academy of Pediatrics Section on
for physical abuse. A recent prospective study Radiology. 2009). If a significant head injury is
demonstrated that 50% of infants who presented demonstrated on imaging, an eye exam should
with apparently isolated bruising and were evalu- be performed by a trained ophthalmologist to
ated by a child abuse pediatrician had at least one evaluate for retinal trauma. Please see section
additional serious injury (fracture, abdominal on head trauma for further details.
trauma, head trauma) (Harper et al. 2014).
Clinicians should consider whether the following When in doubt, consulting with a child abuse/
types of injuries may be present and evaluate maltreatment pediatrician, or another medical
appropriately (Christian et al. 2015): expert can be helpful.
• Abdominal injury: When bruising occurs over roviding an Opinion on the Cause

P
the abdomen or the child is non-verbal, screen- of Bruises
ing tests for abdominal injury should be con- When concerns for physical abuse arise as a
sidered. These include ALT, AST, lipase and/ result of bruising, the health care provider should
or amylase and urinalysis for red blood cells. report these concerns to the appropriate authori-
Additional testing includes CT of the abdo- ties, per their regional laws, and explain the sig-
men with IV contrast (and oral contrast when nificance of the findings. The clinician should
indicated). Please see section below on also outline the limitations of the medical infor-
abdominal trauma for further details. mation to confirm or disprove the possibility of
• Skeletal injury: When there is concern for abuse. Clinicians can help child protection
physical abuse and the child is less than authorities to understand that bruises usually rep-
2 years old and/or not routinely seen in the resent trauma to the skin and can be caused in a
community by people other than the primary variety of ways. They should indicate whether a
caregiver, and/or is non-verbal, a skeletal sur- medical condition is likely to explain the find-
vey is indicated to evaluate for occult bone ings. Clinicians can articulate their level of con-
injury. Please see section below on fractures cern for inflicted injury or physical abuse based
for further details. on the characteristics of the bruising as described
• Head injury: When there is concern for physi- above. If asked to provide an opinion on the
cal abuse and head trauma is a possibility, the mechanism of injury for the bruising, the clini-
clinician should consider completing head cian should be cautious about offering a specific
imaging. For children less than 6 months of mechanism unless they have the appropriate
age (ie. non-mobile infants with unexplained training and expertise to do so.
bruising), head imaging should be performed.
For children aged 6–12 months of age, head
imaging is recommended in most cases. For Fractures
children 12–24 months of age, head imaging
should be considered. At any age, significant Fractures are a relatively frequent finding in
bruising on the face or head or clinical con- young children evaluated for physical abuse and
cerns for head injury, such vomiting or lethargy, are also a frequent finding in urgent care health
should prompt the clinician to complete head centers and emergency departments. Determining

which of the many fractures assessed should raise Differential Diagnosis

concern for physical abuse can be a challenge. Fractures are generally caused by a traumatic
Furthermore, many fractures diagnosed in the event that involves forces being applied to the
context of maltreatment are not the presenting area of the body in question. Fractures result
complaint, may not be clinically obvious, and are from a variety of types of forces exerted on the
often only identified because of standard screen- bone including impact (eg. against an object or
ing x-rays (usually a skeletal survey). When mul- surface), torsion or twisting, bending, compres-
tiple fractures are seen, the clinician will need to sion, tensile or pulling, or a combination of these.
evaluate for both traumatic causes and an under- As described elsewhere in this chapter, these
lying bone condition predisposing to fracture. forces can be applied to the child’s body in a vari-
Certain types and characteristics of fractures ety of ways including through the birth process,
are seen more commonly with either physical medical interventions, or by inflicted, self-
abuse or medical conditions. No one type, loca- inflicted, or accidental means.
tion, or characteristic of fracture is pathognomonic Certain normal anatomic variants can some-
for physical abuse. However, certain features are times be mistaken for a fracture in a child. These
more likely to be seen with physical abuse than include metaphyseal spurs and collars, physio-
with accidental trauma or medical conditions logic periosteal reaction in infants, normal or
(Kemp et al. 2008; Pierce et al. 2012; Leventhal accessory cranial suture lines, and accessory cen-
et al. 2008; Maguire et al. 2013a). These features, tres of ossification. It is therefore important that
or “red flags” are indicators to consider carefully the diagnosis of fracture be confirmed by a radi-
whether physical abuse is a possible cause, while ologist with knowledge of normal pediatric
also considering other causes, both traumatic and variants.
medical. While these features are not pathogno- Certain illnesses or conditions can predispose
monic for physical abuse, they may be sufficient to to developing a fracture with a lesser degree of
report concerns to child protection authorities. trauma and, in some cases, with no significant
In the absence of a clear trauma history to trauma. Medical conditions that may contribute
account for the injuries, “red flags” for possible to a predisposition to fractures include bone, con-
physical abuse when evaluating fractures include nective tissue, and systemic diseases such as
the following: those listed below:
• Any fracture in an infant or young child who • Metabolic bone disorders related to osteoma-
is not yet walking lacia (softened bones) (eg. vitamin-D defi-
• Rib and long bone metaphyseal fractures, ciency rickets or hypophosphatemic rickets)
especially in infants and toddlers • Genetic/inherited bone fragility disorders (eg.
• Fractures of the scapula, sternum, vertebral osteogenesis imperfecta, osteopetrosis, hypo-
spinous processes or vertebral bodies, espe- phosphatasia, or Menkes syndrome)
cially in infants and toddlers • Structural bone abnormalities (eg. certain
• Femur or humerus fracture in a child skeletal dysplasias)
<18 months old • Focal bone abnormalities related to disease
• Multiple fractures without an apparent under- (eg. bone infection or malignancy)
lying medical cause • Systemic medical conditions that secondarily
• Fractures that are clearly of different ages (eg. affect bone (eg. significant prematurity, nutri-
acute symptomatic femur fracture and healing tional deficiencies such copper deficiency or
rib fractures) vitamin C deficiency, malabsorption, leuke-
• Fractures that occur by an unusual mecha- mia, cholestatic liver disease, metabolic or
nism, a mechanism that does not make biome- kidney diseases that cause calcium wasting)
chanical sense, or a mechanism that does not • Conditions resulting in low bone mass from
fit with the child’s developmental level decreased use, movement and/or weight

bearing (eg. neuromuscular disorders, spina tissue and bone disorders should be asked. The
bifida, cerebral palsy, or prolonged clinicians should also obtain information about
immobilization) medications, vitamins, or other supplements that
• Certain toxins and medications (eg. glucocor- the child may be taking.
ticoids, some diuretics, methotrexate, lead) The FHx is particularly helpful in evaluating
for inherited disorders that may predispose to
History fractures. A detailed history of fractures, hearing
The history for a presenting concern or finding of loss, dental problems, spontaneous fetal losses,
a fracture should include a detailed HPI to under- short stature, gastrointestinal, liver, renal, bone,
stand the events surrounding the time of injury, connective tissue and other childhood diseases
the types of forces that were likely exerted on the should be sought for at least the child’s parents,
bone during the injury event, and the symptoms siblings, grandparents, and 1st degree cousins.
and signs since that time. For example, if the his-
tory is of the child falling down stairs, the clini- Physical Examination
cian should take enough information to be able to A general pediatric physical examination with
form a picture of the event in their mind. This vital signs, growth parameters, and visualization
would include details about the stairs (how many, of the full skin surface is recommended. The limb
how high, carpeted or hardwood etc.), the event or area of the body with a fracture should be care-
(how the child fell, the direction of the fall, the fully examined by observation and palpation,
movements during the fall, whether there was noting the neuro-vascular status. Accompanying
impact with various parts of the stairs, and the swelling, bruising, deformity, or other sings of
position of landing), and the child (their reaction injury should be documented.
immediately and afterwards). Specific informa- The clinician should note physical features
tion about the related symptoms (eg. swelling, that may suggest a genetic disorder (eg. short
redness, bruising, pain, reduced movement) and stature, blue-grey sclerae, triangular shaped face,
their management by the family or other health dental anomalies). Special attention should be
care providers, should be sought. This informa- paid to the general examination of the joints (eg.
tion is needed for the clinician to decide whether for swelling or hyperlaxity), skin (eg. for bruises,
the injuries are likely to be compatible with the stretchy and fragile skin), and extremities, as well
described event. The clinician should also ask as the neuromuscular exam. When appropriate,
about other past injuries including fractures, signs of Rickets should be checked for, including
unexplained bruises, burns or head injuries. craniotabes, a rachitic rosary on palpation, bow-
Although children commonly have falls, low ing of the legs in an ambulatory child, and widen-
level falls (eg. falls from beds and couches) rarely ing of the ends of the long bones (eg. at the
cause a fracture. When a fracture does occur, it is wrists).
most likely to be a clavicular fracture or simple
linear parietal skull fracture). Clinicians should Medical Testing
be aware that spiral fractures of the tibia in newly In most cases, children presenting with a trau-
ambulatory children (ie. “toddler’s fracture”) are matic fracture will not require bloodwork or
not uncommon. imaging beyond what is required to make the
The PMHx should include pertinent preg- fracture diagnosis. However, when the cause of
nancy and birth history and whether the child has the fracture is unclear or unusual, or there is a
had any other fractures, in addition to a general specific concern that the injury may have resulted
review of the child’s prior health. from physical abuse, it is beneficial to do further
The ROS should include a feeding and nutri- testing.
tional history, history of exposure to sunlight, and Laboratory testing that is recommended to
symptoms that relate to the differential diagno- screen for an underlying medical predisposition
ses. Specific questions regarding connective to fractures includes (Flaherty et al. 2014):

• Complete blood cell count • Infants and young toddlers with unexplained
• Serum calcium, phosphate, magnesium, alka- intracranial injuries
line phosphatase, 25-hydroxy-vitamin D, • Infants and siblings <2 years and household
parathyroid hormone contacts of an abused child
• Alanine aminotransferase (ALT), aspartate • Twins of abused infants and toddlers”
aminotransferase (AST), bilirubin, albumin
• Blood urea nitrogen (BUN) and creatinine Because not all pediatric fractures may be vis-
ible acutely on X-ray, it is recommended that the
Other tests that can be helpful include serum skeletal survey be repeated approximately
copper and ceruloplasmin, Vitamin C level, uri- 2 weeks later (Christian et al. 2015). Rib and
nalysis, urine Calcium – Creatinine ratio, and metaphyseal fractures are particularly difficult to
genetic testing for osteogenesis imperfecta and diagnose acutely and repeating a skeletal survey
specific connective tissue disorders (eg. Ehlers has been shown to increase the identification of
Danlos Syndrome) (Flaherty et al. 2014). fractures by up to 25% (Kleinman et al. 1996).
The laboratory tests chosen for an individual Even when the initial imaging is normal, the fol-
patient should be tailored to their specific clinical low-up imaging may yield forensically important
situation. Consultation with a child maltreatment results (Bennett et al. 2011).
pediatrician, a general pediatrician, an endocrinol- Testing may also be indicated to evaluate for
ogist, geneticist, or orthopedist may be helpful. other possible injuries when a fracture raises a
Additional imaging may be indicated to evalu- concern for physical abuse. Clinicians should
ate for medical causes and/or occult fractures. consider that abdominal and head injuries may
The most common additional imaging study is a also be present and occult. Please refer to the
skeletal survey. The American College of “testing for occult injuries” section within the
Radiology and the Society for Pediatric bruising section above and the appropriate sec-
Radiology have set out the standards in regards to tions below for an approach to the evaluation for
technical aspects of completing a skeletal survey occult injuries. Head imaging should be consid-
and recommend the following as indications for a ered for young infants in whom there is concern
skeletal survey (American College of Radiology for physical abuse.
and Society for Pediatric Radiology 2014):
roviding an Opinion on the Cause
P
• “Known or suspected physical abuse in infants of a Fracture
and young children. When a fracture raises concerns for physical
• Known or suspected skeletal dysplasias, syn- abuse, this should be reported to the appropriate
dromes, and metabolic disorders. authorities, per jurisdictional laws. The clinician
• Known or suspected neoplasia and related should clearly express the reasons for their con-
disorders.” cern based on the fracture characteristics, his-
tory, associated physical findings, and/or other
The American Academy of Pediatrics’ factors. They should also articulate the limita-
Committee on Child Abuse and Neglect recom- tions of the medical information to determine the
mends that a skeletal survey be completed for precise cause and circumstances of the fracture.
(Christian et al. 2015): The clinician should discuss the differential
diagnosis as including both traumatic and medi-
• “All children <2 years with obvious abusive cal causes, when appropriate, and the informa-
injuries tion or testing that is relevant to this question.
• All children <2 years with any suspicious The health care provider can play an important
injury role in identifying a concern for maltreatment
• Infants with unexplained, unexpected sudden and in assessing and managing the medical
death aspects of the situation.

Head and Spine Injuries quences. However, it is also widely recognized

that other mechanisms of injury (eg. impact on its
Head injuries from physical abuse represent a own or in combination with shaking) may cause
small proportion of child maltreatment cases but similar injuries. Many have advocated for a term
carry the highest morbidity and mortality. Crying that is more accurate (eg. “baby” is not the only
(ie. parents’ or caregivers’ response to crying) is a age group affected by such injuries) and does not
known risk factor for inflicted head injuries in predetermine the cause or mechanism of injury.
young children (Barr 2012, 2014; Barr et al. In 2009, the American Academy of Pediatrics
2006). Infants, males, and children who are born recommended the term Abusive Head Trauma
prematurely or as multiple births are described to and this has been widely adopted (Christian et al.
be at higher risk for this form of maltreatment 2009). However, this term has also been criti-
(Xiang et al. 2013; Parks et al. 2012; Sieswerda- cized for implying intent, something that is not
Hoogendoorn et al. 2013; Keenan et al. 2003; typically determined by the medical assessment.
Lopes et al. 2013; Niederkrotenthaler et al. 2013). An alternative for clinicians is to describe the
Up to 1/3 of identified victims die from their inju- injuries in a specific case using objective terms
ries, and up to 2/3 of survivors have significant such as “traumatic head injury”, followed by a
neurological sequelae (King et al. 2003; Barlow descriptor or opinion, such as “most likely due to
et al. 2004, 2005; Lind et al. 2016; Acker et al. physical abuse/maltreatment/inflicted injury”. In
2015). While subdural and retinal hemorrhages this way, the medical findings and the clinician’s
have historically been closely tied to traumatic opinion can be viewed separately. The choice of
head injuries due to physical abuse, it is impor- terminology will vary and may be informed by
tant to recognize that each of these findings has a the local context and case specific details.
differential diagnosis that includes both traumatic Head injuries due to physical abuse are often
and medical causes. These findings often are the difficult to recognize. This is especially true
first indication of an underlying head injury, because they usually present in non-verbal chil-
however, the hemorrhages on their own are rarely dren and with non-specific symptoms. For exam-
the cause of significant symptoms. In the way ple, infants may present with poor feeding,
that a fever is an indicator of underlying illness respiratory difficulties, vomiting, lethargy or irri-
(due to infection, malignancy etc.) and usually tability. More overt signs of head injury include
does not cause harm itself, these findings are usu- seizures, apnea and decreased level of conscious-
ally indicators of a prior trauma. The associated ness. As a result, clinicians need to remain alert
morbidity and mortality usually relates to the to this possibility and should consider head
parenchymal injury (eg. edema, hypoxia and/or trauma with the signs and symptoms listed above,
ischemia) to the brain and/or brain stem which even when the child appears well. The most com-
may have occurred at the time of the initial injury mon misdiagnosis is gastroenteritis and most
(primary injury) or may be caused by the body’s infants present on more than one occasion before
response to the injury (secondary injury). a health care professional recognizes the true
In the past, head injuries from physical abuse cause of the symptoms (Jenny et al. 1999). A nor-
were typically referred to as Shaken Baby mal neurological examination does not exclude
Syndrome. This term has fallen out of favour for the possibility of head injury, especially in very
a variety of important reasons. Health profes- young children (King et al. 2003; Rubin et al.
sional organizations such as the World Health 2003).
Organization, the Center for Disease Control, the As with other types of injuries discussed
American Academy of Pediatrics, the Canadian above, no single head injury finding is pathogno-
Paediatric Society, and the Royal College of monic for physical abuse either on its own or in
Paediatrics and Child Health, and others agree combination with others. This relates to the fact
that shaking an infant forcefully can cause sig- that injuries are a result of specific forces exerted
nificant head injuries with long-term conse- on the tissues and that these forces can be

generated in a variety of ways. However, the sci- • Bleeding disorders (eg. thrombocytopenia and
entific literature has linked certain physical find- platelet function disorders, disseminated intra-
ings more strongly with head injury due to vascular coagulopathy, hemorrhagic disease of
maltreatment than with other traumatic causes the newborn, acquired vitamin K deficiency,
(Maguire et al. 2009; Kemp et al. 2011; Piteau hemophilia, von Willebrand disease, congenital
et al. 2012). These findings, on their own, may be afibrinogenemia, and factor XIII deficiency)
sufficient to raise concerns for physical abuse and • Infections (eg. meningitis and viral encephali-
report these concerns to the appropriate tis, especially HSV)
authorities. • Metabolic disorders (eg. glutaric aciduria
These “red flags” include: type 1, other inborn errors of metabolism
resulting in cerebral atrophy)
• Intracranial subdural hemorrhages (especially, • Vasculopathies and cerebral vessel abnormali-
those that occur without a specific injury ties (eg. malformations, aneurysms)
history) • Malignancies (eg. various CNS tumours)
• Skull fracture accompanied by an intracranial • Certain genetic conditions (eg. Menkes syn-
injury drome, Alagille syndrome)
• Head injury and rib fractures
• Head injury and classic metaphyseal lesions Subdural hemorrhages may also result from
• Head injury and cerebral ischemia re-bleeding of a prior bleed and may be seen more
• Retinal hemorrhages that are numerous, multi- commonly with increased extra-axial fluid spaces
layered and which extend to the periphery of (eg. benign external hydrocephalus in infants). In
the retina(s) most cases, trauma is required to cause subdural
• Retinoschisis (splitting of the layers of the hemorrhages even with the presence of a medical
retina, forming a pocket that fills with blood) condition. However, hemorrhage may occur with
• Spinal subdural hemorrhages a lesser degree of trauma and/or the hemorrhage
may be more extensive when a predisposing med-
Other injuries that can be seen with head ical condition is present.
injuries from physical abuse include scalp A variety of traumatic causes should also be
hematomas, skull fractures with no intracranial considered in the differential diagnosis for sub-
injury, facial bone fractures, head and/or facial dural hemorrhage. Subdural hemorrhage can be
bruising, orbital injury, neck injuries, spinal caused by birth trauma. This is more common in
fractures, subconjunctival hemorrhages, vitre- vacuum and forceps assisted vaginal deliveries
ous hemorrhages, cerebral contusions, as well but can also be seen in Cesarean-section deliver-
as subgaleal, epidural, subarachnoid, and intra- ies following labour and in normal vaginal deliv-
parenchymal hemorrhages. Associated injuries eries (Rooks et al. 2008).
also include bruising on other parts of the Subdural hemorrhages can also be seen from
body, rib fractures and fractures of the long focal impact, such as may occur with a fall. Even
bones, including metaphyseal fractures low level falls have been shown to cause subdural
(Maguire et al. 2009; Kemp et al. 2011; Piteau hemorrhages. These tend to be small, focal hemor-
et al. 2012). rhages, often underlying a scalp hematoma and
skull fracture, with a low likelihood of significant
Differential Diagnosis symptoms or sequelae (Ibrahim et al. 2012;
The most common finding to prompt concerns Vinchon et al. 2004, 2005; Tung et al. 2006;
for traumatic head injury due to child maltreat- Ewing-Cobbs et al. 1998). Signs of impact may or
ment is subdural hemorrhage. This has a differen- may not be easily visible on the scalp and there-
tial diagnosis that includes medical and traumatic fore the absence of scalp swelling or bruising does
causes. Medical conditions that may cause or not definitively exclude the possibility of impact
contribute to subdural hemorrhages include: as the mechanism of injury (Ibrahim et al. 2012).

Inertial trauma, caused by acceleration- ing, and vomiting (Kodikara and Pollanen 2012).
deceleration or sudden deceleration of the head, Cardio-pulmonary resuscitation has rarely been
as may occur with shaking, whiplash or the head associated with retinal hemorrhages, and in many
stopping abruptly against a surface (eg. bed) is of the cases, the child also had an underlying
another mechanism that may cause head injury, bleeding disorder. Increased intracranial pressure
including subdural hemorrhages and retinal hem- has also been described to cause a few intrareti-
orrhages. In these circumstances, signs of impact nal or preretinal hemorrhages in the posterior
may not be seen and the subdural hemorrhage is pole, especially around the optic nerve (Levin
often diffuse. 2010). In most cases, retinal hemorrhages from
Crushing head trauma can also cause subdural these causes result in a pattern of a few hemor-
hemorrhages and retinal findings. These are typi- rhages, in specific locations, and/or with other
cally associated with complex skull fractures. associated retinal findings.
Significant head and facial swelling, as well as A variety of traumatic mechanisms can also
cranial nerve injuries, may be seen. Cases of lead to retinal hemorrhages. Trauma resulting
crushing head injury with subdural and retinal from the birth process in vaginal deliveries, with
hemorrhages have been reported including cases or without instrumentation, as well as Cesarean-
involving a television falling on a young child section deliveries, is a relatively common cause
(Ewing-Cobbs et al. 2000). of retinal hemorrhages (Binenbaum et al. 2013a).
Retinal hemorrhages are another finding that These hemorrhages typically resolve by 4 weeks
has been linked with traumatic head injury due to of age although they may persist for longer.
physical abuse (Maguire et al. 2009; Piteau et al. These typically are benign and resolve without
2012). Retinal hemorrhages also have a differen- complication (Binenbaum et al. 2013a).
tial diagnosis. The retinal exam should be done Direct eye trauma may cause retinal hemor-
by indirect ophthalmoscopy by an experienced rhages. Traumatic head injury (without direct
ophthalmologist and the number, locations, and trauma to the eye) from impact or inertial forces
description of the hemorrhages should be pro- is also associated with retinal hemorrhages,
vided. These factors affect the differential diag- whether “accidental” or “inflicted”. The severity
nosis by pointing towards or away from various of the eye injuries is typically associated with the
possibilities. severity of the head injury (Hughes et al. 2006).
Retinal hemorrhages can be caused or contrib- Multi-layered, “too-numerous-to-count” retinal
uted to by the following: hemorrhages that extend to the periphery of the
retina have been described in inflicted head
• Ophthalmologic conditions (that usually have trauma, severe (usually fatal) crush head injury,
other associated retinopathy findings) and severe (usually fatal) accidental head trauma.
• Bleeding disorders
• Metabolic disorders (eg. glutaric aciduria History
type 1) On clinical assessment, a detailed history should
• Infections (eg. malaria) be taken. The prenatal and birth history should
• Vasculopathies and vessel abnormalities include information about any illnesses or com-
• Malignancies (eg. leukemia) plications during pregnancy, pre-natal tests, the
• Certain genetic conditions (eg. osteogenesis labour and delivery, any neonatal resuscitation or
imperfecta) complications. The growth parameters (head cir-
• Hematologic conditions (eg. severe anemia, cumference, weight, height) from birth until the
sickle cell disease, hyperviscosity syndromes) current time should be recorded. A developmen-
tal history is important to determine the child’s
Retinal hemorrhages may also be caused by current level and pattern of development and
hypertension, extra-corporeal membrane oxy- mobility as well as signs of possible underlying
genation (ECMO), and rarely, seizures, cough- neurologic issues in the past. The review of

systems can often be completed by walking bone disorders, metabolic, genetic, or other
through a typical 24 hour period beginning from childhood conditions, childhood deaths, recur-
the time the child awakens in the morning. In this rent spontaneous losses, and consanguinity.
way, the health care professional will obtain spe-
cific information about the child’s feeding, sleep- Physical Examination
ing, stooling, voiding, and behavioural patterns, A full physical examination, with careful atten-
as well as the typical activities and patterns of the tion to the neurologic exam, should be completed.
caregivers. Specific questions about the child’s Subtle bulging of the fontanelle and/or an
crying pattern and how the caregiver consoles the increase in head circumference may be the first
baby should be included. sign on assessment of an underlying head injury.
A history of recent and remote symptoms The full skin surface and the oropharynx should
should be taken that includes questions about irri- be examined for signs of injury (eg. bruises, torn
tability, difficulties with feeding, vomiting, frenulae). Vital signs and growth parameters
apneas or breathing abnormalities, seizures or should be documented. Physical features of an
abnormal movements, periods of lethargy or underlying genetic or other medical condition,
unarousability, and a change in the child’s usual relevant to the differential diagnosis, should be
feeding, sleeping, and behavioural patterns. If the looked for.
child is presenting with an acute injury or symp-
toms, the caregiver should be asked about the Medical Testing
onset and progression of changes over time. A CT scan (without contrast) is the test of choice
Often, children with traumatic head injuries when evaluating for a possible acute head injury
present with a history of a fall. Details around (Binenbaum et al. 2013b; Section on Radiology;
the circumstances of the fall are important to American Academy of Pediatrics 2009). If the
obtain in order to plan appropriate medical test- injury event occurred at least 3–5 days earlier, an
ing and care, as well as to decide on whether a MRI can be done and provides more detailed
report is warranted to child protection authori- information. MR angiogram and venogram
ties. This history should include when, where, (MRA and MRV) are helpful to assess for the
and how the fall occurred, as well as who was possibility of thromboses, arterio-venous malfor-
present at the time. A detailed description of the mations, and other vessel abnormalities. MR
fall, its height, the landing surface, the child’s spectrometry (MRS) is useful to obtain additional
position and what happened before and after the information regarding ischemia, infarction or
fall should be obtained. If the child received chronic tissue injury. However, depending on the
care or resuscitation by the family, paramedics, age of the child, an MRI may require sedation or
or others prior to presentation, this should be a general anesthetic. Head ultrasound, which can
recorded. be done on children with an open fontanelle,
The past medical history should include though less expensive and radiation-free, is not
details of the pregnancy and birth, as well as any adequate imaging when head trauma is suspected
illnesses or injuries since that time (especially (Binenbaum et al. 2013b; Section on Radiology;
bruising or oral injuries), and symptoms or signs American Academy of Pediatrics 2009).
of medical illnesses that are on the differential It should be noted that subdural, subarach-
diagnosis for head injuries. noid, and other intracranial collections cannot be
The family history is important for evaluating dated with precision based on their radiographic
the possibility of an underlying predisposition to appearance. Although most acute hemorrhages
bleeding or head injury, as well as a predisposi- will appear bright (hyperdense) on CT scan and
tion to any associated injuries (eg. fractures) that most non-acute hemorrhages will appear dark
may be present. The family history should include (hypodense), the overlap in first appearance and
questions about bleeding disorders, fractures and time of resolution is so great, that this feature

alone cannot determine the age of the collection • Complete blood count including platelet count
(Tung et al. 2006; Silvera et al. 2015). Further, • INR (international normalized ratio), aPTT
the presence of different densities does not con- (activated partial thromboplastin time),
firm that there are hemorrhages of different ages fibrinogen
(Tung et al. 2006; Silvera et al. 2015; Bradford • Factor VIII, von Willebrand testing (antigen
et al. 2013). and activity), blood group
More recently, it has been recognized that spi- • Factors IX, XI, XIII
nal imaging is also important in cases of head • Bun and creatinine
injury due to physical abuse (Dias et al. 1998). • ALT, AST, GGT, lipase or amylase
Subdural hemorrhages of the spine can be seen • Blood culture, cerebrospinal fluid sample for
and may have clinical significance. Soft tissue bacterial culture and viral testing if the child is
injuries of the cervical spine can also be seen in febrile or there is clinical suspicion of
some cases. While routine spinal imaging hasn’t meningitis
yet become the standard of care, when possible, it • Review of newborn metabolic screen
is recommended that the spine be imaged as well • Total and free carnitine, acylcarnitines, amino
as the head. The health care provider should con- acids, gas, lactate, ammonia, organic acid test-
sider doing spinal imaging when there are clini- ing on urine if metabolic testing is clinically
cal indicators of spinal injury and/or with indicated
symptomatic head injury. CT of the neck can be
done for ligamentous and soft tissue injuries, as roviding an Opinion on the Cause
P
well as bony injuries. MRI of the full spine can of Head Injuries
be done when MRI of the head is also being per- When findings of a head injury raise concerns for
formed. Imaging of the full spine should be con- physical abuse, the clinician should report their
sidered when there is symptomatic head injury, concerns to the appropriate authorities, per juris-
rib or vertebral fractures. dictional laws. The clinician should clearly
In situations of suspected head injury due to express the reasons for their concern based on the
physical abuse, it is important to consider whether history, physical, laboratory and imaging find-
other injuries may also be present. The following ings. They should also articulate the limitations
are recommended to evaluate for other injuries of the medical information to determine the pre-
(Christian et al. 2009, 2015): cise cause and circumstances of the head injury
and explain what testing or results remain out-
• Skeletal survey to be done routinely for chil- standing. The clinician should discuss the differ-
dren less than 2 years of age ential diagnosis as including both traumatic and
• Skeletal survey in select cases for children medical causes, where appropriate. In general, it
2–5 years of age takes time to obtain the medical information
• Ophthalmology assessment using indirect regarding the possible causes of the findings and
ophthalmoscopy with dilated pupils therefore the information and opinion on the pos-
• Spine imaging (CT of cervical spine when CT sible causes will evolve. Consulting with a child
used, MRI of full spine when MRI used) maltreatment pediatrician or another qualified
• Abdominal imaging (as indicated above) if specialist in the region, is recommended.
liver or pancreatic function tests or urinalysis
indicate possible trauma to the abdomen
Abdominal Trauma
Depending on the types of injuries present, the
following laboratory tests are recommended for Abdominal trauma is estimated to occur in up to
evaluation of apossible underlying medical cause 3% of cases of child physical abuse (Kleinman
or contributor (Christian et al. 2009, 2015): and Silvera 2015) and is the second leading cause

of death from abuse (Lindberg et al. 2013). position and surface are important elements of
Unlike other findings that raise concern for phys- the history. When there is no described injury
ical abuse, distinguishing abdominal injuries event, a history for any traumatic events and pos-
from medical conditions is rarely a difficulty. As sible foreign bodies (causing perforation) should
with other types of injuries, there is no abdominal be obtained.
injury that, on its own, is pathognomonic for It is important to explore possible injury
physical abuse and any abdominal injury that can events that may have occurred even several days
occur through an accidental mechanism can prior to the onset of symptoms. For abdominal
occur in physical abuse (Barnes et al. 2005). injury, the development and progression of symp-
Presenting symptoms are similar in children with toms is particularly helpful and should include
accidental and inflicted abdominal injury and in questions about abdominal pain, change in feed-
both settings, there may be a “delay in seeking ing/eating habits, irritability or lethargy, vomit-
care” as symptoms can develop slowly (Lindberg ing, fever, hematemesis, hematochezia and any
2012). However, hollow viscous injuries are preceding illness.
more commonly seen with inflicted abdominal A past medical history of gastrointestinal
injury mechanisms and combined solid organ symptoms and prior surgeries is helpful. A devel-
and hollow viscous injuries are rarely seen with opmental history, to understand the child’s level
accidental mechanisms (Trokel et al. 2006). of mobility can be used to compare to the history
While motor vehicle collisions are the most com- provided. Other historical information related to
mon cause of abdominal injuries in children, pregnancy, birth, feeding, gastrointestinal symp-
direct blows to the abdomen (as may occur with a toms, and illnesses is also important.
bike handlebar injury) can cause severe abdomi-
nal injury (Barnes et al. 2005). Falls are an Physical Examination
uncommon cause for significant abdominal A full pediatric exam is indicated, beginning with
injury (Wood et al. 2005; Lyons and Oates 1993; vital signs, growth parameters, and general
Rivara et al. 1993) and duodenal injuries in young appearance. Special attention should be paid to
children are rarely seen from accidental causes the skin surface (eg. for bruises or other signs of
(Wang et al. 2001). trauma), the mouth, and the musculoskeletal sys-
The “red flags” for possible physical abuse in tem. The abdomen should be observed for bruis-
abdominal injury are: ing or distension, bowel sounds should be
auscultated, and palpation should be done for
• Severity of injury greater than what would be tenderness or masses. The clinician should make
expected for the described injury event note of any peritoneal signs.
• Significant injury with no history of abdomi-
nal trauma Medical Testing
• Hollow viscous injury with a history of a Screening bloodwork should be done in the fol-
minor trauma lowing circumstances, when physical abuse is
• Duodenal injury in an infant, toddler or pre- considered possible (Christian et al. 2015; Barnes
school aged child et al. 2005):
• Presence of other injuries (fractures, bruising,
head injury etc.) that are unexplained, unusual • A history of abdominal injury is provided
or otherwise concerning for physical abuse • Bruising is present on or near the abdomen
• Evaluation for possible physical abuse in a
History young child is being done because of other
As with other types of injuries discussed in this physical findings (eg. bruises, fractures, head
chapter, a detailed history of the injury event is injury)
recommended. If the injury event included a fall, • The child has symptoms of an abdominal
then the height and direction of the fall, landing injury as above

Recommended screening tests include burn with a shorter exposure time to a hot liquid,
(Christian et al. 2015; Barnes et al. 2005): flame, or object and can also burn at a lower tem-
perature than can adults. All types of burns,
Complete blood count including scalds, flame, radiation, caustic, and
AST, ALT contact burns, can result from accidental and
Lipase and/or amylase inflicted means. Potential lack of appropriate
Urinalysis (for blood) supervision may also be an important element in
pediatric burns. It is estimated that severe burns
The results of the liver enzymes should be may be present in 10–12% of all cases of child
interpreted with caution, recognizing that trans- physical abuse and 10–20% of all burns are
aminases can be elevated with liver injury but related to physical abuse or neglect (D’Souza
also with damage to muscles or cardiac tissue, et al. 2009; Chestser et al. 2006; Dissanaike et al.
and in the setting of shock, hepatitis and other 2010). Burns due to neglect are felt to be nine
liver diseases. Some authors have suggested times more common than those resulting from
using an AST or ALT level of >80 IU/L as a physical abuse (Maguire et al. 2008).
threshold for performing abdominal imaging Scalds are the most common type of burns in
(Kleinman and Silvera 2015). children, especially in children less than 5 years
A CT scan of the abdomen is the test of choice of age. In general, most accidental scald (spill)
for abdominal imaging for traumatic injuries. burns involve burns to the head, face, neck and/or
This should be done with intravenous contrast chest from hot liquids other than water (often
and consideration should also be given to using coffee or tea) while most inflicted scald burns
oral contrast (Christian et al. 2015; Barnes et al. involve burns to the lower extremities from hot
2005). Ultrasound, while useful in some cases as water. Scald burns typically include areas of
an adjunctive imaging modality, does not have varying depth of burn (superficial, partial thick-
the sensitivity required to reliably diagnose ness, and full thickness) and the burn may indi-
abdominal injuries and a false negative examina- cate a flow pattern with decreasing depth of burn
tion may result (Maguire et al. 2013b). further from the site of first contact. Splash marks
If a significant abdominal injury is suspected may or may not be present. Clothing or other
to be due to an inflicted mechanism in a young objects in contact with the skin at the time of
child, further evaluation for occult injuries is rec- injury may affect the pattern and depth of the
ommended. As recommended in other sections, burn (Dissanaike et al. 2010). More viscous liq-
with suspected physical abuse in a child less than uids (eg. oil) may show a different burn pattern as
2 years of age, a skeletal survey should be per- they dissipate their heat more slowly and flow at
formed. Head imaging should also be considered a slower rate.
for younger infants. A systematic review of features differentiating
“intentional” (term used in publication) scalds
from accidental scald injuries highlighted the fol-
Burns lowing “red flags” for physical abuse (Dissanaike
et al. 2010):
Burns are a common reason for children to pres-
ent to physician offices and emergency depart- • Pattern suggesting immersion (instead of
ments. Young children are particularly susceptible spill) with relatively uniform depth of burn
to burns because of their curious nature and pro- and clear margins
pensity to explore their environment without • Burns involving the legs, buttocks and
judgement or awareness of safety concerns. In perineum or a combinations of these, espe-
addition, younger children have thinner skin that cially when symmetrical and having clear
burns more easily than the skin of older children margins
and adults (Fox et al. 2011). As a result, they can • “Stocking” or “glove” distribution

• Explanation for injury not in keeping with event, as well as the related symptoms and treat-
injury pattern (eg. history of flow/spill burn ment applied. Details, such as the child’s position
but pattern of immersion burn) and clothing worn at the time of the burn, can be
• Co-existent injuries such as bruises, lacera- helpful. If the burn involved hot water, further
tions, swellings, or fractures information should be sought about the source of
• No history or incompatible history to explain the hot water including water tank temperature
burn settings, and unexpected changes in water
temperature.
Burns that result from mechanisms other than The past medical history should include infor-
scalds are typically less severe and are commonly mation about any prior skin injuries or condi-
caused by contact with household objects but tions, as well as recent illnesses or infectious
may also be caused by flames, friction, chemi- symptoms. Similar questions should be asked in
cals, or electrical contact. “Red flags” for non- the family history. A developmental history, with
scald burns include (Maguire et al. 2004): attention to mobility and gross motor develop-
ment should be taken.
• Contact burns with a clear pattern (eg. cigarette,
iron, hairdryer) or sharply demarcated edge Physical Examination
• Burns on the limbs, back or trunk and not on A full physical examination should be conducted
the palm or fingers with documentation of the skin findings. Special
• Multiple non-scald burns attention should be paid to the child’s vital signs
• Co-existent injuries such as bruises, lacera- and volume status, and appropriate treatment mea-
tions, swellings, or fractures sures should be taken as necessary. Consultation
• No history or incompatible history to explain and referral to a burn care center may be required.
burn The clinician should note the distribution of the
burn areas (as well as areas spared) and whether
Differential Diagnosis they are contiguous or separate (eg. splash marks),
Burns can result from a variety of mechanisms the degree or depth of burn, the percentage body
that may be either accidental or inflicted. The fol- surface area covered by the burn, and whether the
lowing should be considered in the differential burn(s) have a recognizable shape or pattern. The
diagnosis: condition of the child’s clothing should also be
noted indicating whether it is burned, wet, or oth-
• Certain skin conditions (eg. guttate psoriasis, erwise altered. The remainder of the exam should
pityriasis lichenoides, epidermolysis bullosa, be done in accordance with usual practices for
chilblain) burn victims, also noting any other signs of trauma,
• Infections (eg. impetigo, staphylococcal scalded such as bruises, lacerations or limb deformities.
skin syndrome, dermatitis herpetiformis)
• Allergies Documentation
• Drug eruptions When possible, the burn should be described in
• Contact reactions (eg. phytophotodermatitis) the written record in words and using visual rep-
resentation. Clinicians can use a body diagram to
In some cases, traditional cultural or alterna- draw the approximate size and shape of the burn,
tive health practices may also cause burns (eg. indicating measurements and burn severity. With
moxibustion, cupping, maquas, garlic burns). appropriate consent, photos can be taken but this
is best done by a trained forensic photographer.
History Colour balance palettes and standardized rulers
A detailed HPI should include the mechanism, should be used. Photos must be stored in a secure
duration, timing, and events surrounding the burn fashion, linked to the child’s medical record.

Spared areas are as important as burned areas Timing of Examination

when considering overall “pattern”.
All children and adolescents presenting with a
Medical Testing reported history of sexual abuse/assault should be
Medical testing should be guided by the clinical triaged immediately to determine the urgency of
scenario. In regards to evaluation for occult inju- evaluation (Jenny et al. 2013; Palusci et al. 2006;
ries, burns should be considered similar to bruises Floyed et al. 2011; Gordo and Jaudees 1996;
or fractures such that concerns for physical abuse Hibbard 1998). Obtaining a brief summary of the
should prompt the clinician to order a skeletal abuse or assault concerns from the most appro-
survey in children less than 2 years of age and priate source; the caregiver, child/adolescent,
consider head imaging in young infants. police or a child protection worker, is integral.
When possible, information should not be col-
lected directly from the child/adolescent, prior to
Sexual Abuse and Assault a forensic interview that is typically conducted
by police, a child protection worker or trained
According to the World Health Organization, one forensic interviewer (American College of
in five women and one in thirteen men report Emergency Physicians 2013). When known, key
having been sexually abused as a child. Children pieces of information for the purposes of triaging
and adolescents who have been sexually abused/ include; when the abuse/assault occurred or the
assaulted will often arrive at a physician’s office, last contact was with the alleged offender, and the
emergency department or urgent care center for type of contact (genital-genital, oral-genital,
medical evaluation. These children are assessed genital-anal, digital-genital/anal etc.) (Christian
in settings by medical providers with varying lev- 2011; Floyed et al. 2011; Delago et al. 2008).
els of training and experience. Given the medico- Medical concerns such as acute pain, bleeding or
legal nature of the evaluation of children and discharge, as well as psychological or safety con-
adolescents with suspected and/or confirmed cerns will also influence how urgently an exami-
sexual abuse/assault, a consistent, evidence based nation is needed (Delago 2008; Melville et al.
approach to the assessment and management of 2014).
these children is critical. The goals of the medical The response to a “historical” allegation of
evaluation are to obtain a history, identify and sexual abuse differs from the management of a
document findings, provide interpretation of the more recent or acute event. Nevertheless the dis-
findings, collect forensic evidence as appropriate, closure of prior abuse/assault, no matter how
diagnose and treat medical conditions as a result remote, should be managed in a trauma-informed
of the abuse/assault, assess psychosocial issues, and systematic way. Consideration of the vic-
reassure and support the family, and ultimately tim’s safety, and that of others, is critical and
ensure the well-being of the child (Adams et al. should be addressed immediately. Familiarity
2007). It is important to remember that many with jurisdictional reporting requirements as they
children do not disclose sexual abuse until pertain to the occurrence of sexual abuse, suspi-
months or years after the abuse has occurred cion of sexual abuse, and ongoing risk of experi-
(Goodman-Brown et al. 2003). In one study, 75% encing sexual harm to a child should be
of children did not disclose sexual abuse within considered. Most jurisdictions require by law,
the first year and 18% waited more than 5 years that this type of information be reported to a local
to disclose (Elliot and Briere 1994). Sexual abuse child protection agency. The specific require-
cases can be categorized into two groups: those ments and definitions of the “mandated reporter”
requiring urgent or immediate medical care, and by practice jurisdiction should be known to the
those that require less urgent evaluation. clinician. In many communities, child and youth
advocacy centers offer a coordinated and

comprehensive response to victims of sexual comfort and privacy is key, and one should never
assault/abuse. The clinician should be familiar restrain, sedate, force or coerce a child into an
with the available resources in their community. examination. A genital examination may be dif-
The medical evaluation of non-urgent cases can ficult for a child or adolescent in the context of
be conducted in a designated outpatient setting. sexual abuse/assault and therefore support should
All aspects of the sexual abuse medical evalua- be provided. The examination should be tailored
tion are similar in the acute versus non-acute set- to the developmental stage of the child or adoles-
ting, however, timing will impact what cent and he/she should be offered the choice of a
interventions will or will not take place. Clinicians support person. Asking the child about their
should consult with a child maltreatment pedia- understanding of the reason for the visit/exami-
trician, a trained sexual assault nurse examiner, nation and providing a detailed explanation of the
or other medical expert, if in doubt as to how to procedures and what the child/adolescent may
proceed. experience, as well as accurate information about
the reasons for examination are important.
Providing information, using distraction tech-
History niques, having a support person, and allowing the
child to control some aspects of the examination
The goal of the medical history is to gather have been found to decrease distress surrounding
information necessary to guide medical the exam (Waibel-Duncan 2004).
decision-making and potential forensic evidence When examining children and adolescents it is
collection (World Health Organization 2003; important to determine their sexual maturity rat-
Finkel 2011). Rather than collecting the history ing (SMR) which is a standard system used to
directly from the child, information related to assess child/adolescent physical development.
the abuse/assault should be gathered privately SMRs utilize five stages (from prepubescent to
from the caregiver, police, or child protec- adult) based on degree of maturation of second-
tion worker (World Health Organization 2003; ary sexual characteristics during puberty (Bordini
World Health Organization 2013; American 2011). The SMR is important when considering
College of Emergency Physicians 2013; In the testing for sexually transmitted infections, pro-
case of adolescents, a medical history may be viding emergency contraception and collecting
gathered directly with caution, using open ended forensic evidence.
questions. A forensic interview is a more spe- When conducting the ano-genital examina-
cialized interview which is typically conducted tion, the examiner should consider various posi-
by a trained interviewer to determine if sexual tions which will optimize the examination with
abuse/assault has occurred, and should ideally regards to visualization and specimen collection.
be conducted prior to the examination. In addi- Examining the child/adolescent in the supine
tion to the history outlined in the above section, position with legs in a frog leg position or feet
a current and past medical history should be resting in stirrups, often provides ideal visualiza-
gathered. tion of the ano-genital structures. The prone knee
chest position can also be considered for
improved visualization, including the anal area.
Physical Examination Examination should be of the external genitalia,
with gentle traction and/or separation of the labia
A complete head to toe examination should be majora, allowing for visualization of the hymen
conducted, including the assessment of skin inju- and structures just beyond the labia.
ries that may be a result of the alleged assault. It An internal speculum examination of the
is important that certain principles be considered vagina must not be done in pre-pubertal children,
when performing a physical examination in the (World Health Organization 2003) and is rarely
context of sexual abuse/assault. Ensuring patient indicated in the context of a sexual abuse/assault

assessment. It should only be considered in the sexual contact or trauma; and findings caused by
adolescent patient when there is ongoing bleed- trauma and/or sexual contact (Adams et al. 2016).
ing (no external source), there is a need for col- If findings are considered to be those caused by
lection of cervical specimens, or a foreign body trauma and/or sexual contact they should be pho-
is suspected. Measurement of the hymenal open- tographed and immediately reviewed by a second
ing does not add value to the examination and professional with appropriate training and expe-
should not be performed (Adams 2016). A digital rience, for confirmation.
rectal examination and/or the use of an anoscope
is not recommended (Jenny 2013). An examina-
tion under anesthesia is rarely indicated in the Documentation
context of sexual abuse/assault and should only
be considered when medical signs and symp- Written documentation should include the medi-
toms, such as ongoing bleeding (no external cal history, details of the abuse/assault, the physi-
source), ongoing discharge (possible foreign cal examination findings (including the
body, or STI), or the need for surgical interven- ano-genital examination), laboratory testing,
tion are present. In these situations, consultation results and interpretation of findings. All genital
with a pediatric gynecologist is strongly and non-genital injuries or findings should be
recommended. noted for type, appearance, location and measure-
ment. It is helpful to use the face of a clock to
document the location of genital findings with 12
Interpretation of Findings o’clock representing the anterior portion of the
hymen and 6 o’clock the posterior portion when
Recent literature indicates that in most cases, pre- the child/adolescent is in the supine position
pubertal girls who are assessed related to con- (Christian 2011). Photo-documentation of the
cerns of sexual abuse, have no findings of anal or genital examination is a recommended (especially
genital injury on physical examination (Adams for examinations with abnormal findings) with
et al. 2007; Adams et al 1994; Heger et al. 2002; either a colposcope or a hand held digital cam-
Andherst et al. 2009; Heppenstall-Heger et al. era (Adams et al. 2007). Clinicians, without spe-
2003; Berenson and Grady 2002). There are cialized expertise and equipment, should ideally
many reasons for this including; no injury was not photograph the genital exam and refer to a
sustained related to the type of contact, the con- more specialized centre if needed, as appropriate
tact may have resulted in injuries that have storage and privacy parameters may not be in
healed, or tissues may have stretched without place. Diagnostic quality images allow for peer/
being injured (Adams et al. 2007). In many situa- expert review for the purposes of quality assur-
tions, formal documentation of the interpretation ance, and teaching. A detailed written description
of findings may be requested by child protection of the examination findings should always accom-
workers and/or police. To ensure that accurate pany photographs (American College of
and relevant opinions are given, an evidence Emergency Physicians 2013; Finkel et al. 1997;
based approach to the interpretation of results of Adams et al. 2015). Photographic images are con-
the ano-genital examination should be taken sidered Personal Health Information and should
(Adams et al. 2007). Guided by published, evi- be linked to the child’s medical record and stored
dence based summaries of genital examination securely. Specific consent for photography must
findings and their interpretation, the clinician be obtained from the caregiver and/or patient as
should identify the findings, and indicate into appropriate, and they should always have the right
which of the three following categories they fall: to refuse photo-documentaion. Photographs
findings documented in newborns or commonly should be taken, stored, transferred and retained
seen in non-abused children; findings with no according to the medical facility’s policies.
expert consensus on interpretation with respect to

Forensic Evidence Collection Various testing methods for sexually trans-

mitted infections exist (Black et al. 2009;
The decision to collect forensic evidence should Esernio-Jenssen and Barnes 2011; Sena et al.
be based on the case history of the abuse/assault, 2015; Hammerschlag 2010). Specimen sampling
the age and consent of the victim, the time inter- sites should be established based on the point of
val between the assault and presentation to a sexual contact as determined by the history, tim-
medical facility, and specific factors such as ing of potential exposures, and/or if symptoms
bathing, voiding, and recent change of clothing. are present. If there is no point of contact identi-
The collection of forensic evidence can be an fied, consider how high risk for STI transmission
intrusive undertaking, and therefore the clini- may be, as testing may not be warranted. If
cian should consider the likely yield of find- potential exposure was recent, consider the
ings prior to proceeding. Information from potential incubation period for the particular STI
police may be needed in order to inform how to avoid potential false-positives and/or false-
best to proceed. Forensic evidence collection is negatives. In other words, if it is an acute assault
recommended for sexual contact that may have it may not be advantageous to conduct STI test-
resulted in the exchange of biologic material in ing immediately as there maybe a time period as
the preceeding 72 h. In adolescents, some por- to when the organism may not be detected.
tions of the sexual assault evidence kit may be Delaying testing in the acute sexual assault situ-
considered for collection up to 7–12 days post- ation may assist in ensuring accurate results.
assault depending on the circumstances and However, if a child has symptoms such as vagi-
type of contact (World Health Organization nal discharge, STI testing should be conducted
2013; Adams et al. 2015; Giardet et al. 2011; immediately. Vaginal swabs are recommended
Thackery et al. 2010). versus cervical swabs in pre-pubescent children.
In the past, in pre-pubescent children, culture
has been the preferred method of testing for
esting for Sexually Transmitted
T medical-legal purposes. However, nucleic ampli-
Infections fication acid tests (NAATs) may be acceptable
and are commonly used. A study by Black et al,
Each child/adolescent should be assessed on an 2009 found that urine NAATs with process for
individual basis with regards to testing for sexu- confirmation of a positive result are adequte for
ally transmitted infections (STI). The following use a new standard of Chlamydia and Gonorrhea
situations put a child at higher risk for STIs and in children suspected of sexual abuse (Black,
are indications for testing (American College of Driebe et al. 2009). If the test is positive for an
Emergency Physicians 2013; Public Health STI, the NAAT result should be confirmed by a
Agency of Canada 2013). second set of primers, a culture, or, in some
cases, a second sample can be sent to another
• The child has symptoms or signs of an STI laboratory (Public Health Agency of Canada
(e.g. vaginal discharge or pain, genital itching 2013). Anal and pharyngeal NAATs have not
or odor, urinary symptoms, genital ulcers or been formally approved in children and it is rec-
lesions). ommended checking with local laboratories.
• The suspected assailant is known to have an Prophylaxis for gonorrhea and chlamydia
STI or to be at risk for an STI. immediately following a sexual abuse/assault is
• Another child or adult in the household is typically not recommended in pre-pubescent
known to have an STI. children (Public Health Agency of Canada.
• The prevalence of STIs in the community is 2013). However, it can be considered in some
high. cases, including adolescents, where follow-up
• There is information to suggest evidence of may be difficult to ensure. Prophylaxis should
genital, oral, or anal contact. not be provided if the samples for STI testing are

being collected, and follow up of the results is contraceptive pill is less effective in women
feasible as a positive STI result may add forensic weighing 75–80 kg and not effective in women
value to a case and ensure proper diagnosis and over 80 kg. If over 80 kg, insertion of an intra-
treatment. It is common practice for children to uterine device can be considered as an alternative
have received the Hepatitis B vaccine, however, emergency contraceptive method (Katzman et al.
if they have not, the first dose of the vaccine 2010).
should be provided at the time of assessment. If
the Hepatitis B vaccine status is unknown, the
clinician should consider checking the child’s Psychosocial Support
serology to determine Hepatitis B antibody titers.
If the patient is unvaccinated and the alleged per- Appropriate psychosocial support is integral to
petrator is known to have Hepatitis B, providing the care provided to sexual abuse/assault patients
Hepatitis B Immunoglobulin (HBIG) is recom- and their families. In the acute setting, various
mended (Public Health Agency of Canada 2013). tools such as a trauma symptom screening (Cohen
et al. 2008) and/or a suicide and/or self-harm risk
assessment (Korczak 2015) may be useful in
HIV Post Exposure Prophylaxis assessing psychosocial symptoms in a child/ado-
lescent. In addition, it is critical to offer the non-
Human Immunodeficiency Virus (HIV) Post- offending caregivers education around responding
Exposure Prophylaxis (PEP) should be offered to to and supporting their child, as this is a strong
all children and adolescents who are considered predictor of positive psychosocial prognosis in
at risk for HIV infection and who present within children (Elliott and Carnes 2001). Trauma-
72 h of a sexual assault or the last incident of focused cognitive behavioural therapy has been
sexual abuse (Sena et al. 2015). The sooner HIV shown to be the most effective form of therapy
PEP is initiated, the greater the likelihood that it when needed (Cohen et al. 2000) and therefore
will prevent transmission of the virus (American referrals should be made to an appropriate mental
College of Emergency Physicians 2013; World health professional, ideally in the family’s
Health Organization 2013; Sena et al. 2015). community.
Baseline bloodwork should be collected, and the
medication regimen and side effects discussed
with the child/adolescent and caregiver to pro- Discharge and Follow-Up
mote compliance of the HIV PEP protocol.
Please refer to guidelines from the Centre for Health care providers should ensure the patient’s
Disease Control or the American Academy of medical and mental health needs related to the
Pediatrics for the most current HIV PEP medica- assault have been addressed. It may be important
tion protocol. to arrange a follow-up appointment. Always
ensure that a plan is in place to address the
patient’s safety and well-being after leaving the
Emergency Contraception hospital.
Emergency contraception should be offered and

provided as soon as possible to all pubertal Neglect
patients who report vaginal-penile penetration
and present within 5 days of exposure (World Neglect is the most common form of child mal-
Health Organization 2013; Katzman et al. 2010). treatment around the world and the most com-
A pregnancy test must be done prior to providing mon form of maltreatment that is substantiated
emergency contraception. When applicable, by child protection agencies in Canada and the
patients should be counseled that the emergency United States (US Department of Health and

Human Services 2016; Public Health Agency of met versus inadequately met. As with other forms
Canada 2008). Authors have proposed a variety of maltreatment, the standard of “harm or risk of
of definitions for neglect which include either harm” to the child is used to assess whether
statements about omissions of care and the neglect is present. The clinician must therefore
responsibility of parents in providing children’s look at the lack or inadequacy of care in a specific
needs, an ecological perspective on the multifac- area and its impact on the child. In a medical
torial factors that lead to parenting failure and office, issues of neglect most often present as
neglect, or the effect on the child. For the clini- growth problems (eg. failure to thrive), develop-
cian, it is useful to define neglect from the child’s mental delays (eg. speech delay), poor dental
perspective as occurring when the child’s basic health, poor general hygiene and care, injuries
needs are not met, whatever the cause (Dubowitz (eg. from inadequate supervision), and behaviour
et al. 2005). This allows the clinician to remain problems.
focused on the child’s needs, distances the con- In a systematic review of features “indicative
versation from blaming the parents, and allows of neglect or emotional abuse in preschool chil-
for constructive solutions on how best to provide dren”, aggression, passivity, developmental delay,
what is needed for the child to meet their best and poor peer interaction were common. Studies
potential (Dubowitz 2009). Whatever the defini- in older children have shown that the symptoms
tion, neglect can have profound and lasting overlap with features of attention deficit hyperac-
effects on a child’s physical and mental health, as tivity disorder (ADHD), and that school-aged
well as their social and cognitive development. children with neglect present with impulsivity,
For clinical purposes, it is useful to consider inattention or hyperactivity, as well as low self-
neglect in four main categories: esteem, poor relationships and friendships, and
low academic performance. As a result, when
1. Physical neglect—the child’s physical needs children present with these features, both the
for food, clothing, housing or safety are not assessment and management of the problem
met should consider neglect. Medication management
2. Emotional neglect—the child’s need for a nur- for ADHD features in this context will not address
turing and loving environment to foster the underlying issues or provide the needed ben-
healthy psychological, emotional or social efit to children, particularly if used without other
development are not met behavioural and family interventions.
3. Medical neglect—the child’s need for neces- Clinicians are sometimes in a position where
sary medical, dental, or psychological care are they feel that a child’s medical, dental, or psycho-
not met logical care needs are not being met. This usually
4. Educational neglect—the child’s formal edu- occurs when children are not brought for care
cational needs are not met when it is needed or when children do not receive
the care that is recommended by a health profes-
The degree to which a child’s needs are met sional although it is necessary for the child’s
falls along a continuum for all children and all health or well-being (Jenny et al. 2007).
parents. Some children may benefit from all the Clinicians are referred to resources by the
material resources available but not be exposed to American Academy of Pediatrics, Canadian
aloving household that helps them to develop Paediatric Society and others for an approach to
emotionally. Other children may have warm, nur- managing this problem (Jenny et al. 2007, Baird
turing, caring parents who are unable to provide et al. 2017).
enough food for them to grow normally. Others Health care professionals are in a unique
may have their physical and emotional needs met position to speak to the needs of the child and
but not be brought for medical care when needed. the long-term negative consequences for a child
Clinicians often find it difficult to judge when to grow up without having their needs met. The
the child’s needs are adequately but not optimally clinician can play an important role by identify-

ing that a child’s needs are not being met, ruling Andherst J, Kellogg N, Jung I. Reports of repetitive
penile-genital penetration often have no definitive evi-
out medical causes for the child’s issues (eg. an
dence of penetration. Pediatrics. 2009;124(3):e403–9.
organic cause for failure to thrive, hearing loss Ateah CA, Durrant JE. Maternal use of physical pun-
for speech delay etc.), and working with the ishment in response to child misbehavior: implica-
family and community supports to assist the tions for child abuse prevention. Child Abuse Negl.
2005;29(2):169–85.
child to have their needs met more completely.
Baird B, Ward MG, Schwartz S, Thibault M, Child and
When harm or risk of harm is apparent, child Youth Maltreatment Section, Canadian Paediatric
protection authorities should also be notified as Society. Medical neglect of children and adoles-
they can assess the child and family more thor- cents: a clinical perspective. Paediatr Child Health.
Forthcoming 2017.
oughly in the home and school environment
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Update in Pediatric Critical Care
5
Lisa A. DelSignore, Traci A. Wolbrink,
and Niranjan Kissoon
Introduction Patient Monitoring
Many advances have been made in pediatric criti- Over the last decade, there has been a general
cal care medicine over the last several years. This trend towards using less invasive, or non-invasive
chapter will provide a broad overview to the most devices to monitor critically ill children as alter-
relevant advances in the following domains: natives to invasive procedures that may be associ-
patient monitoring, organ systems-based prac- ated with significant risks during insertion and
tice, educational training, global health, and qual- potential harm while in situ. Technologies that
ity improvement. Specific advances in the field of have gained prominence and acceptance in many
pediatric critical care discussed here represent pediatric intensive care units include near-
those have either demonstrated or have the poten- infrared spectroscopy (NIRS), continuous EEG
tial to demonstrate improvement in patient out- monitoring, advanced bioinformatics technolo-
comes, in addition to advances that are enablers gies, and bedside ultrasound use.
to the provision of safe, efficacious, timely and
equitable patient-centered care.
Near-Infrared Spectroscopy (NIRS)
Near-infrared spectroscopy (NIRS) monitoring

is a technique that involves placing a sensor on
L.A. DelSignore, M.D. (*)
Division of Pediatric Critical Care, Department of the patient’s skin, allowing for measurement of
Pediatrics, Floating Hospital for Children at Tufts capillary oxyhemoglobin saturation based on the
Medical Center, Tufts Medical School, 800 Washington physics of light scatter and its differential
Avenue, Box 93, 02111 Boston, MA, USA absorptive properties. Unlike pulse oximetry,
e-mail: ldelsignore@tuftsmedicalcenter.org
NIRS is not dependent on a pulsatile arterial sig-
T.A. Wolbrink, M.D., M.P.H nal, but instead reports an averaged concentra-
Division of Critical Care Medicine, Department of
Anesthesia, Perioperative and Pain Management, tion of hemoglobin saturation based on the
Boston Children’s Hospital, Harvard Medical School, absorption spectrum in the tissue region in prox-
300 Longwood Ave, Bader, 634 Boston, MA, USA imity to the cutaneous sensor. The oxyhemoglo-
N. Kissoon, M.D. bin present in the arterial system of tissues
Division of Critical Care and the Child absorbs light between wavelengths of 800 and
and Family Research Institute, Department of 850 nm. In contrast, deoxygenated hemoglobin,
Pediatrics, British Columbia’s Children’s Hospital,
University of British Columbia, Vancouver, which absorbs light at a wavelength between 650
BC, Canada and 800 nanometers (nm) predominates because


118 L.A. DelSignore et al.
of substantially larger venous capacitance and who have suffered traumatic brain injuries (TBI),
hence the NIRS reading will reflect a venous- global hypoperfused shock states, and for predic-
weighted saturation (Ghanayem et al. 2011; tion of cerebral edema in patients with diabetic
Drayna et al. 2011). ketoacidosis awaits more information (Drayna
NIRS monitoring has most commonly been et al. 2011).
used as surrogate to measure regional perfusion NIRS provides data related to regional oxim-
and oxygenation of end organs, especially the etry, rather than global oxygenation/perfusion
brain. Much of the early use of cerebral NIRS status and hence clinical decisions should not be
monitoring occurred in the perioperative setting based solely on NIRS data. Rather, NIRS data is
of children undergoing corrective repair of con- useful but should be interpreted in the context of
genital heart defects who required cardiopulmo- the clinical status and other variables indicating
nary bypass (Ghanayem et al. 2011). Normative pathophysiology. In addition, more needs to be
values have been established for various ages done to determine what constitutes a “critical
using comparative values to jugular venous bulb value” that requires immediate intervention, as
oxygen saturations, as this is a proxy for cerebral well as to define targeted patient outcome mea-
venous circulation returning to the central venous sures related to NIRS monitoring.
circulation (Drayna et al. 2011).
Monitoring NIRS trends rather than a single
value allows for interpretation of real-time phys- Capnography
iological changes, thus enabling timely thera-
peutic responses as opposed to the usual practice Recent advances have led to widespread use of
of relying on the results of laboratory or other end-tidal CO2 monitoring of mechanically venti-
diagnostic tests, which are usually delayed. lated patients. End-tidal CO2 monitoring, or time-
Downward trending NIRS values (or satura- based capnography, remains the gold standard for
tions) are often indicative of clinical conditions confirming proper placement of endotracheal
involving increased oxygen extraction, such as tubes in patients. Other recently adopted use of
hypermetabolic states, or conditions in which end-tidal CO2 monitoring include its use during
there is overall hypoperfusion or a low-flow per- active cardiopulmonary resuscitation in order to
fusion state. Abnormally elevated NIRS values guide effective resuscitation efforts, given that
(or saturations) may represent clinical condi- the presence of significant end-tidal CO2 values
tions in which there is decreased ability of the serve as a proxy for the adequacy of pulmonary
body to extract oxygen or inability of the body to blood flow as a result of high-quality chest
utilize oxygen effectively. Further research is compressions.
required to establish “critical values” that require The use of volumetric capnography to monitor
immediate diagnostic or therapeutic interven- mechanically ventilated patients is being explored
tions (Drayna et al. 2011). in critically ill patients (Blanch et al. 2006;
NIRS monitoring is most commonly used for Suarez-Sipmann et al. 2014; Cheifetz 2013).
cerebral monitoring in critically ill children, such Volumetric capnography represents the amount
as neonates who have suffered birth asphyxia and of CO2 expired as a total volume in a single
post-operative cardiac surgical patients to ensure breath. Given that volumetric capnography is not
adequate cerebral perfusion to assist in prevent- simply reflective of one specific time point dur-
ing secondary hypoxemic brain injury. Ongoing ing expiration, but instead is reflective of all
validation of cerebral NIRS monitoring in post- phases of expiration, it allows for more in depth
cardiac arrest patients with return of spontaneous real-time analysis of a patient’s physiologic sta-
circulation may provide useful information about tus and ability to achieve adequate gas exchange
management and prognosis of long-term neuro- (Blanch et al. 2006; Suarez-Sipmann et al. 2014).
developmental outcomes (Ghanayem et al. 2011). It also allows for the assessment of total dead
The use of cerebral NIRS monitoring for patients space ventilation (anatomic and physiologic) and

5 Update in Pediatric Critical Care 119
the ratio between the amount of dead space ven- form of electronic medical record, which serves
tilation and the amount of total tidal ventilation as a data storage platform of patient information
(Vd/Vt) (Cheifetz 2013). This ratio can be to assist in the clinician decision support when
trended over time in patients as a marker of ordering diagnostic procedures, medications, and
changes in pulmonary compliance, which in turn other therapeutic interventions. The use of com-
my help influence real-time ventilator parameter puterize physician order entry has been helpful in
changes in patients with severe lung disease. reducing prescribing errors (Grinspan et al.
Volumetric capnography may potentially improve 2014). Patient monitors are increasingly compat-
patient outcomes in those with acute lung injury, ible for integration with the electronic medical
may assist in safer, more effective ventilator record such that patient vital signs trends can be
weaning, and predict extubation success and incorporated directly from the monitor. Clinical-
avoid the need for reintubation (Cheifetz 2013). decision support tools can also be regularly con-
Volumetric capnography may be a surrogate figured into many electronic medical records,
monitor of pulmonary blood flow in patients with which can help prompt clinicians to review par-
stable minute ventilation who lack severe lung ticular trends or alert clinicians to changes in a
injury. As such, it may prove to be useful for patient’s clinical status or trajectory. Together
monitoring patients with pulmonary vascular dis- these advances in bioinformatics, data collection
ease like pulmonary hypertension or pulmonary and storage will help to promote safe and effec-
embolism, or as a proxy for low cardiac output tive care for critically ill patients, allowing for
states (Cheifetz 2013). access of real-time data and trends to assist in
clinical decision making.
Continuous EEG
Ultrasound
The use of continuous EEG (cEEG) monitoring
has become increasingly prevalent in pediatric Bedside ultrasound technology has improved
intensive care units especially in large academic dramatically over the last several years in terms
medical centers with the considerable personnel of higher resolution image quality, smaller, more
and resources required. The common indications portable machines, and improved usability inter-
for use aside from generalized status epilepticus faces. Pediatric critical care providers are increas-
include altered mental status and other acute neu- ingly using ultrasound equipment to assist in the
rological deficits (Sanchez et al. 2013). proper placement of central venous catheters
Continuous EEG monitoring has benefits of gath- (Srinivasan and Cornell 2011; Su et al. 2014; Lau
ering more than one time point of data, perhaps and Chamberlain 2016). Dynamic ultrasound has
allowing for more timely diagnostic and manage- superseded the traditional landmark identifica-
ment interventions and potentially the broader tion techniques and is used universally to teach
ability to standardize care for various neurologi- residents and fellows to place central lines. In
cal conditions, such as status epilepticus, that children, vascular landmarks may be difficult to
may result in improved patient outcomes. identify because of size, body habitus, and/or
overall hemodynamic status, hence, direct vessel
visualization by ultrasound during procedural
Bioinformatics placement is useful. The use of bedside ultra-
sound for central venous access and catheter
The field of bioinformatics has emerged over the placement improves safety, time to successful
last decade and continues to evolve rapidly as placement, and reduces procedural-associated
computer hardware and software, patient moni- complications (Lau and Chamberlain 2016).
toring devices, and web-based technologies Bedside ultrasound is now being used in arte-
improve. Many hospitals have adopted some rial line placement, as well as evaluation a

patient’s hemodynamic status, presence of pneu- management strategies at optimizing cerebral

mothorax, or pleural fluid assessment (Srinivasan perfusion pressure and minimizing increased
and Cornell 2011; Su et al. 2014). Bedside ultra- intracranial pressure. Overall there remains a
sound findings may corroborate suspicions based lack of strong, high quality evidence on this topic
on clinical grounds and hence allow for timely of severe pediatric traumatic brain injury, such
therapy, suggest further tests and enable serial that many of the guidelines are based of less rig-
assessment of patient status. However, its poten- orous study designs (prospective and retrospec-
tial in informing these clinical decisions with tive cohort data) (Kochanek et al. 2012).
great certainty are not fully evaluated and thus Key guidelines to highlight include that active
caution is advised. cooling to a temperature between 32 and 34°C
Standardized educational modules to certify (moderate hypothermia) should be avoided in
pediatric critical care physicians in this skill children with severe traumatic brain injury
remain in their infancy. Short, intensive, courses within the initial 24 h of admission (Kochanek
focused on the ultrasound physics, operator use et al. 2012; Bell and Kochanek 2013). However,
and interpretation are becoming more common at if there is severe intracranial hypertension asso-
national societal meetings in critical care and ciated with the traumatic brain injury, targeting
emergency care. There are emerging, intensive moderate hypothermia starting 8 h post-injury to
1–2 day “boot-camp” type of educational train- no longer than 48 h post-injury may be consid-
ing environments aimed at certification upon ered to reduce further intracranial hypertension.
completion (Conlon et al. 2015), but overall the If moderate hypothermia is initiated, the guide-
field lacks definitive criteria for what it means to lines recommend rewarming slowly to normo-
be “competent” in bedside ultrasound use and thermia; that is, at a rate no greater than 0.5°C
interpretation. per hour (Kochanek et al. 2012; Bell and
Kochanek 2013).
These updated guidelines continue to support
Organ Systems-Based Updates the use of hypertonic saline (3%) as hyperosmo-
lar therapy to reduce increased intracranial pres-
Neurology sure associated with severe traumatic brain injury
in the acute phase of illness (Kochanek et al.
raumatic Brain Injury
T 2012; Bell and Kochanek 2013). Benefits of
Severe pediatric traumatic brain injury is defined hypertonic saline use include establishing a
as a patient with a Glasgow Coma Scale euvolemic fluid balance, given that sodium is a
(GCS) ≤ 9 in the context of traumatic injury volume expander, as opposed to mannitol, which
mechanism and is associated with high morbidity while effective in treating cerebral edema also
and mortality. Much research in the last decade promotes an osmotic diuresis and hypovolemia
has focused on the understanding of the patho- which can decrease cerebral perfusion pressure.
physiology and management of severe traumatic Hypertonic saline is also less toxic to the kidneys,
brain injury with the goal of optimizing both and thus a higher serum osmolarity can be toler-
short- and long-term neurodevelopmental out- ated (360 mOsm/kg) as opposed to mannitol.
comes. In 2012, the second edition of the However, evidence against the use of mannitol in
“Guidelines for the Acute Medical Management the management of acute intracranial hyperten-
of Severe Traumatic Brain Injury in Infants, sion and severe traumatic brain injury is weak,
Children, and Adolescents” replaced that from and thus one must weigh the risks and benefits
2003 (Kochanek et al. 2012). Primary changes in based on the clinical context. Evidence support-
this edition were updates based on new evidence ing specific doses of 3% saline is also weak, but
regarding the use of hypothermia, revised cere- there is stronger evidence to support the use of
bral perfusion pressure targets by age, advances bolus doses as opposed to continuous infusions
in brain tissue monitoring, and other targeted (Kochanek et al. 2012; Bell and Kochanek 2013).

The updated guidelines additionally provide Assessment Method (Smith et al. 2016a)
weak evidence for the avoidance of steroids, (psCAM-ICU), targeted specifically at children
avoidance of use of an immune-modulating diet, 6 months to 5 years of age, and the Cornell
and avoidance of hyperventilation Assessment for Pediatric Delirium (Traube
(PaCO2 < 30 mmHg). Weak evidence supported et al. 2014) (CAPD), targeted at various ages
the modification of cerebral perfusion pressure from newborn to adolescence.
targets to consider maintaining a cerebral perfu- The pCAM-ICU and ps-CAM are variations
sion pressure of at least 40 mmHg, with a range of the same screening tool with age-specific cri-
of 40–65 mmHg representing an optimal contin- teria for assessing four main categories: acute
uum for various ages of pediatric patients change in baseline mental status, presence of
(Kochanek et al. 2012; Bell and Kochanek 2013). inattentive behaviors, overall level of alertness,
and other abnormal behaviors from baseline
Delirium including sleep-wake cycle disturbances, or the
Delirium in critically ill children is challenging presence of irritability or confusion. The pres-
to define, which in turn leads to challenges in ence of an acute change in baseline mental status
monitoring and treatment. The current gold- plus the presence of inattentive behaviors and
standard diagnosis of pediatric delirium is very either a change in level of alertness or presence of
similar to adult criteria. However, as compared to other abnormal behaviors as mentioned above are
adults, children have unique developmental, lan- highly suggestive of a diagnosis of delirium
guage, and cognitive stages that affect their (Smith et al. 2011, 2016a).
behavior and influence their ability to communi- The CAPD tool was designed to screen for all
cate and interact with healthcare providers. As types of delirium, including hyperactive, hypoac-
such, pediatric delirium is most likely under- tive, and mixed types of delirium. This screening
diagnosed and requires further study and valida- tool includes specific anchored statements for
tion of tools to use for diagnosis and monitoring what constitutes normal development at various
in order to better characterize its incidence and ages in order to assist users in rating deviation
prevalence. This is a necessary needed first step from normal developmental behaviors. The
to further investigate and characterize how patient screening questions are categorized within the
outcomes are affected by delirium and in devel- major domains of delirium encountered in the
oping standardized approaches to diagnosis and DSM-IV manual: level of consciousness, cogni-
management. tive ability, psychomotor activity, overall affect
Several validated screening tools (Smith or level of distress (Traube et al. 2014).
et al. 2011, 2016a; Traube et al. 2014) have Delirium management in the pediatric intensive
recently been published to assist in diagnosing care unit requires ongoing study for optimal and
pediatric delirium. These tools have been standardized treatment approaches. The hallmarks
adapted from existing adult-related screening of treatment remain the identification and treat-
tools and tailored to children to accommodate ment of any underlying non-psychological causes,
developmental differences. These tools are e.g. electrolyte derangements, infection, followed
based on subjective and/or objective measures by implementation of non-pharmacological strate-
that can be documented during routine nursing gies that normalize the surrounding environment,
assessment of critically ill patients. Each tool including establishing routine schedules and con-
has been validated with high sensitivity with stant re-orientation to surroundings and timing,
varying degrees of specificity for delirium. followed by use of pharmacological strategies,
Specific screening tools that have been recently especially for patients who remain agitated (Van
validated include the Pediatric Confusion Tuijl et al. 2015). Many of the specific agents used
Assessment Method (Smith et al. 2011) (pCAM- are “off-label” for pediatric patients, and thus there
ICU), targeted at critically ill children greater is not consensus across PICUs as to which agents
than 5 years old, the Preschool Confusion to utilize first.

Status Epilepticus (Abend et al. 2014). Critically ill patients with

Status epilepticus is a common pediatric neurologi- refractory status epilepticus will often require
cal emergency encountered in the PICU. Accord- intubation and mechanical ventilation for airway
ing to guidelines from the Neurocritical Care protection and require close monitoring for
Society (Abend et al. 2014), refractory status epi- hypotension.
lepticus is considered present once an appropriate
initial dose of benzodiazepine has been adminis-
tered followed by a second anti-seizure medica- Respiratory
tion, regardless of time of patient’s seizure. This
includes the presence of either clinical seizures or cute Respiratory Distress
A
electrographic seizures after initial medication Syndrome (ARDS)
administration. Acute lung injury (ALI) and Acute Respiratory
Many institutions have protocolled approaches Distress Syndrome (ARDS) remain prevalent
to the management of status epilepticus, includ- conditions that contribute significant morbidity
ing immediate assessment and stabilization of and mortality across PICUs worldwide.
airway, breathing, and circulation, followed by Defining ARDS for the pediatric population
immediate administration of a short-acting ben- continues to be a challenge. Current definitions
zodiazepine, and subsequent specified time are extrapolated from the adult literature. A
points at which the administration of additional new set of criteria for ARDS in adults, the
anti-seizure medications are indicated (Smith Berlin definition, was introduced in 2011
et al. 2016b). More focus in recent years has been (ARDS Definition Task Force 2012). The Berlin
on determining a protocolled management definition of ARDS reclassified ALI and ARDS
approach for the timely and aggressive treatment into mild, moderate and severe, with mild
of refractory status epilepticus in order to prevent ARDS being, the older American-European
ongoing morbidities and avoid permanent neuro- Consensus Committee (AECC) definition of
logical sequelae. The Neurocritical Care Society ALI. In this classification scheme, patients are
currently recommends an aggressive stepwise still classified based on the ratio between arte-
pharmacological approach that rapidly pro- rial partial pressure of oxygen (PaO2) to the
gresses to pharmacological coma (Abend et al. amount of supplemental inspired oxygen
2014). Advances in neurological monitoring, (FiO2), but also taking into account the amount
specifically continuous EEG monitoring, has of PEEP patients are receiving at the time of
allowed for timely and aggressive up-titration of calculating the P/F ratio. Similar to the AECC
pharmacological therapies at the bedside. Two definition, the lung injury insult must occur
agents most commonly used in the treatment of within 7 days of onset, be accompanied by new
refractory status epilepticus include continuous infiltrates on chest imaging, and have no contri-
midazolam infusions and pentobarbital infusions, bution from high left atrial pressures.
both initiated and up-titrated with bolus dosing in The Pediatric Acute Lung Injury and Sepsis
order to achieve rapid serum drug levels. committee group on ARDS has developed con-
Therapeutic goals of these medications target sensus recommendations (The Pediatric Acute
either clinical seizure resolution, electrographic Lung Injury Consensus Conference Group 2015)
seizure resolution, or burst suppression on cEEG, based on the adult and pediatric data for the
based on clinical setting and severity (Abend diagnosis and management of pediatric
et al. 2014). Consensus continues to lack regard- ARDS. The consensus group agreed with adult
ing the duration of these therapies for treatment recommendations that the inciting event leading
of refractory status epilepticus. Generally, these to lung injury occurs within 7 days of illness,
therapies should be continued for 24–48 h after radiographic findings consistent with new paren-
achievement of seizure resolution (or burst sup- chymal lung disease must be present, and there
pression) prior to consideration of weaning must be absence of a cardiac etiology explaining

hypoxemia (The Pediatric Acute Lung Injury There is no data to support the use of sustained
Consensus Conference Group 2015). ventilator recruitment maneuvers, i.e. using high
The PALISI guidelines also clarify that par- ventilator pressures for a brief period of time to
ticular groups of pediatric patients who have try to open atelectatic areas of lung in order to
other reasons for hypoxemia or may have some improve gas exchange (The Pediatric Acute Lung
degree of baseline hypoxemia, such as cyanotic Injury Consensus Conference Group 2015).
congenital heart disease, or chronic lung disease Thus, these maneuvers have largely fallen out of
can also develop ARDS if they fit the criteria of favor in the routine approach in treating patients
acute onset of illness, new radiographic findings, with severe ARDS. High frequency oscillatory
and lack of worsening underlying etiology as the ventilation (HFOV) remains an alternative mode
cause of hypoxemia (The Pediatric Acute Lung of ventilation for patients with severe, sustained,
Injury Consensus Conference Group 2015). hypoxemia. Use of HFOV and stepwise titration
Despite the common practice of PICU clini- of mean airway pressure requires close monitor-
cians using P/F ratios in the severity diagnosis of ing of patient vital signs and serum blood gases
ARDS, the consensus group recommends trend- given that the clinical respiratory and cardiac
ing the oxygenation index (OI) as opposed to the exam is difficult to assess in these patients.
P/F ratio to quantify the severity of illness of Other strategies that are beneficial in manag-
mechanically ventilated patients with ARDS ing patients with ARDS include adequate seda-
(The Pediatric Acute Lung Injury Consensus tion and possible use of muscle relaxation in
Conference Group 2015). The OI is defined as order to optimize gas exchange and patient toler-
[[MAP * FiO2]/PaO2], where MAP = mean air- ance of high ventilator settings, providing ade-
way pressure, FiO2 = amount of inspiratory oxy- quate nutrition, and avoiding excessive fluid
gen, and PaO2 = partial pressure of arterial intake once patients have been adequately fluid
oxygen. The suggestion to trend the OIs in resuscitated and have a stable hemodynamic pro-
mechanically ventilated patients is based on the file (The Pediatric Acute Lung Injury Consensus
fact that the amount of mean airway pressure Conference Group 2015).
required to effectively oxygenate and ventilate Although commonly used, there is minimal
the patient is more reflective of disease severity. data to support the use of inhaled nitric oxide,
General invasive mechanical ventilation prone positioning, and steroid use (The Pediatric
guidelines and therapeutic strategies for pediatric Acute Lung Injury Consensus Conference Group
ARDS continue to be extrapolated from adult 2015). Finally, in patients with severe ARDS and
data because of limited data in children. Thus, the the inability to oxygenate or ventilate effectively,
pediatric guidelines are based on weak consen- consideration of extracorporeal support should
sus. However, the general standard of care be considered.
involves avoidance of ventilator-induced trauma,
by using low tidal volume ventilation (5–7 mL/
kg) and accepting permissive hypercapnea, and Cardiology
using high-PEEP (typically >10 cmH2O) strate-
gies to avoid high peak inspiratory and plateau Cardiopulmonary Resuscitation
pressures while targeting oxygen saturations Pediatric Advanced Life Support (de Caen
between 88 and 92%. Permissive hypercapnea et al. 2015) (PALS) has undergone two recent
goals involve tolerating a serum pH range of guidelines revisions, 2010 and 2015. The
7.15–7.30, as long as the patient does not have major focus in teaching effective cardiopul-
other underlying comorbidities that would monary resuscitation continues to be the
require a higher pH (e.g. pulmonary hyperten- delivery of high-quality chest compressions,
sion, cardiac dysfunction, increased intracranial as this has been demonstrated to improve
pressure) (The Pediatric Acute Lung Injury patient survival rates. Given this fact and the
Consensus Conference Group 2015). recently updated adult guidelines, the pediat-

ric basic life support (BLS) algorithm order tures maintained between 36 and 37°C (Moler
was changed from A-B-C (airway-b reathing- et al. 2015). The AHA/PALS guidelines suggest
circulation) to C-A-B (circulation- a irway- the avoidance of fever, but more specifically
breathing) in 2010. Adults experiencing out of comment that for comatose children post-ROSC
hospital cardiac arrests typically result from a who suffered an out-of-hospital cardiac arrest,
cardiac etiology, and thus the timing and deliv- core temperature management should involve
ery of optimal chest compressions is key to the either targeting normothermia (36–37°C) for
return of spontaneous circulation and ulti- 5 days, or targeting moderate hypothermia (32–
mately survival, inciting this change in the 34°C) for 2 days, followed by normothermia for
BLS guidelines. Recognizing that many out- 3 days post-out of hospital cardiac arrest (de
of-hospital and in-hospital cardiac arrests in Caen et al. 2015; Moler et al. 2015). There is not
children are more often the result of a respira- enough evidence to provide specific guidelines
tory etiology, the pediatric resuscitation guide- for pediatric patients who suffer in-hospital car-
lines continues to emphasis the importance diac arrest with ROSC at this current time, but
of rescue breaths in addition to providing many clinicians generally avoid fever in this
timely, high- quality chest compressions (de context.
Caen et al. 2015). Other pediatric post-cardiac arrest guidelines
High-quality CPR in children entails deliver- recommend avoiding hyperoxia by targeting oxy-
ing chest compressions at a rate between 100 gen saturations of 94–99% post-ROSC. Excessive
and 120 compressions per minute, compressing oxygen administration can lead to the develop-
at a depth of at least 1/3 anterior-posterior chest ment of free radicals and further oxidative stress,
diameter, allowing full chest recoil between which can cause long-term tissue damage and
individual compressions, minimizing interrup- negatively affect end-organ function. Hypotension
tions in chest compressions, avoiding excessive should also be avoided, by maintaining blood
respirations during chest compressions, and pressure at least 5% of normal for age and height
avoiding compressor fatigue by switching com- using fluids and vasoactive agents as indicated in
pressors at least every two minute cycle of order to support optimal end-organ perfusion.
CPR. The recommended ratio of chest compres- Hypocarbia and hypercarbia should be avoided,
sions to rescue breaths for pediatric CPR has not and the current guidelines suggest setting specific
changed from prior guidelines, and remain 15:2 pCO2 targets based on patients’ underlying clini-
for a two-person resuscitation, 30:2 for a single- cal conditions prior to cardiac arrest (de Caen
person resuscitation, and continuous chest et al. 2015).
compressions with 8–10 breaths per minute
when advanced airways are present (de Caen
et al. 2015). Gastroenterology/Nutrition
ost-cardiac Arrest Management

P Nutritional Guidelines
The 2015 American Heart Association (AHA)/ Critical illness is a significant stress on the
Pediatric Advanced Life Support (PALS) updated body and as such is associated with lean mus-
the guidelines for the management of the arrest cle-mass breakdown and protein catabolism in
victim after return of spontaneous circulation the acute illness phase. Thus, optimal nutrition
(ROSC) has been achieved. These guidelines during critical illness is important to promote
incorporate the most recent findings from post- adequate healing and decrease morbidities
ROSC studies performed on targeted temperature associated with malnutrition (Mehta 2014).
management in children after out of hospital car- Standardized nutritional therapy is lacking in
diac arrest, where death and disabilities were critically ill children based on a lack of large
similar in children who were actively cooled randomized clinical trials and varying practices
between 32 and 34°C to those who had tempera- across institutions. Despite this, the American

Society for Parenteral and Enteral Nutrition nutritional needs in critically ill children. In com-
(A.S.P.E.N.) published suggested guidelines in parison, indirect calorimetry provides a window
2009 for an approach to delivering optimal into more direct measurement of the amount of
nutrition in critically ill children (Mehta et al. energy the patient is expending by directly mea-
2009). These guidelines support the use of suring the amounts of oxygen consumed and car-
enteral nutrition as the preferred mode of nutri- bon dioxide produced. This can be easily done in
ent delivery in those children with a function- mechanically ventilated patients who have a
ing gastrointestinal tract. The optimal timing closed ventilator circuit where oxygen can be
and mode of delivery (gastric versus post- measured via the inspiratory limb of the ventila-
pyloric) for enteral nutrition is not settled. tor and carbon dioxide can be measured via the
Generally, in children who were previously expiratory limb. These data can be used to calcu-
well-nourished, initiation of enteral nutrition late the respiratory quotient (R/Q), which can be
can wait until 5–7 days into the acute illness used to help define the patients’ nutritional status
(Mehta et al. 2009). However, recent literature and assist in suggesting the amount of calories
investigating the use of early enteral nutrition the patient actually needs for optimal nutrition
(within 48 h of admission) suggests that there (Sion-Sarid et al. 2013). Indirect calorimetry val-
may be a decreased mortality benefit in those ues should be followed over time, especially as
critically ill children who were previously well- the patient’s clinical condition and illness trajec-
nourished (Mikhaliov et al. 2014). While this tory change.
finding is encouraging, more research is needed
to validate this finding. Glycemic Control
Parenteral nutrition should be considered in Hyperglycemia is commonly encountered in
those patients who are unable to tolerate enteral critically ill patients as part of the body’s stress
feeds or have other contraindications to enteral response to critical illness. Much has been
feeding, such as gastrointestinal surgery. A investigated over recent years in regards to how
recent study comparing early initiation (within aggressive to control blood glucose levels in the
48 h) of parenteral nutrition as compared to late PICU in order to prevent morbidity and mortal-
initiation (after 1 week) showed no benefit to ity associated with hyperglycemia. One of the
early initiation of parenteral nutrition (Fivez major risks of tight glucose control in this set-
et al. 2016). Later initiation of parenteral nutri- ting is hypoglycemia, which can lead to sei-
tion was associated with fewer infections, zures, among other neurological morbidities,
shorter length of PICU stay and shorter length and is also associated with an increased risk of
of overall hospital stay. PICU mortality was mortality.
similar in both groups in this study (Fivez et al. The benefits of tight glucose control in chil-
2016). dren in the setting of critical illness remains
unclear, and there are ongoing studies to further
Indirect Calorimetry investigate clinical outcomes associated with
Indirect calorimetry has become increasingly tight glucose control. The strongest consensus
popular within PICUs to directly assess the statement that currently exists recommends con-
amount of calories critically ill patients require in sideration of treating persistent hyperglycemia in
an attempt to avoid both under- and over-feeding. critically ill children, as defined by serum blood
Under- and over-feeding are associated with poor glucose ≥180–200 mg/dL, with an insulin infu-
healing, increased inflammation, or difficulty sion targeting a blood glucose range of 100–
weaning from mechanical ventilation (Sion-Sarid 180 mg/dL in an attempt to avoid significant
et al. 2013). Other methods of estimating nutri- hypoglycemia (Jacobi et al. 2012). If an insulin
tional needs are based solely on mathematical infusion is initiated for tight glucose control, then
equations related to resting energy expenditure. frequent monitoring of blood glucose levels and
These formulas may over- or under-estimate patient’s clinical status is essential.

Hematology enoxaparin. It remains unclear what populations

of children should require pharmacological
Transfusion Strategies thromboprophylaxis in the critically ill setting,
The decision to transfuse critically ill children and ongoing research in this field is attempting to
based on varying degrees of anemia varies widely define current PICU practices in order to assist in
in clinical practice. Historically, targeting a forming more standardized clinical practice
hemoglobin (Hgb) level of 10 g/dL had been guidelines (Faustino et al. 2014).
common practice in order to promote optimal
oxygen delivery to ensure adequate tissue perfu-
sion and oxygen utilization. A recent study found Infectious Disease/Immunology
that a restrictive transfusion practice of transfus-
ing to a Hgb of 7 g/dL was not inferior to trans- Sepsis
fusing to a level of 10 g/dL in stable, critically ill Sepsis and septic shock remain a major cause of
children, and in fact decreased exposure to blood morbidity and mortality in children worldwide.
products and the overall number of transfusions Much emphasis in recent years has been focused
administered (Lacroix et al. 2007). Thus, the on understanding the epidemiology of sepsis, the
most recent guidelines and approach to packed molecular biology and immunology associated
red blood cell transfusions in stable, critically ill with the immune system and inflammatory cas-
children favors a more restrictive transfusion cade, defining clinical biomarkers and how the
practice in order to avoid unnecessary risks and genotypic and phenotypic variation of these bio-
complications associated with blood product markers in individuals may predispose them to
transfusions. A lower transfusion threshold for varying disease susceptibility and host responses.
critically ill children who are hemodynamically One major challenge over the last several
unstable, have evidence of acute blood loss, or decades has been lack of a unifying “diagnosis”
have significant cyanotic congenital cardiac dis- of sepsis, as it encompasses a clinical syndrome
ease, among other specific clinical contexts is as opposed to a specific single diagnostic entity.
reasonable. Therefore, the approach to finding diagnostic
Transfusion practices for other blood prod- tests or identifying specific clinical biomarkers
ucts including platelets, coagulation factors, that can assist with early diagnosis and treatment
and leukocytes tend to vary based on the clini- remains a challenge.
cal context and the decision to transfusion Several groups have developed standardized
under those circumstances requires clinician guidelines to treat septic patients with early goal-
judgment as opposed to having any specific directed therapies in order to improve morbidity
clinical values or guidelines associated with and mortality (Rivers et al. 2001; Dellinger et al.
transfusion practices. 2013; Brierley et al. 2009). A consensus of pedi-
atric sepsis investigators published the most
Thromboprophylaxis recent pediatric “Surviving Sepsis Campaign”
Prophylaxis for deep venous thrombosis and pul- guidelines in 2012 (Dellinger et al. 2013).
monary embolism in children has been a recent According to these guidelines, if there is concern
“hot topic” in the field of pediatric critical care. for sepsis and impaired perfusion, up to a total of
Thromoboembolic disease is an underestimated 60 mL/kg of fluid boluses administered in 20 mL/
complication in children and young adults, and kg aliquots should be considered within the first
decisions regarding appropriate prophylactic 15 min of clinical presentation. Monitoring for
measures in the PICU setting varies across insti- response to fluid by observing clinical changes in
tutions. It is common practice for critically ill vital signs and physical exam findings should
adults with no anticoagulation contraindications occur in real-time to aid in consideration of fluid-
to receive pharmacological thromboprophylaxis responsiveness or not. Broad-spectrum antimi-
with agents such as subcutaneous heparin or crobial therapy should also be administered

during this time as soon as possible (Dellinger common during the handover process of patient
et al. 2013; Brierley et al. 2009). care from one healthcare provider to another.
For those children who have received 60 mL/ Standardized patient handovers are essential in
kg of normal saline boluses and continue to have high reliability environments such as the pediatric
evidence of impaired perfusion, then vasoactive intensive care unit where patients are at high risk
support should be initiated, with further consider- of potential complications related to their disease
ation of the need for invasive mechanical ventila- severity and complexity of care.
tion and invasive hemodynamic monitoring via An approach to improve this area of commu-
central venous catheter placement (Dellinger nication has involved the development of a vari-
et al. 2013; Brierley et al. 2009). Placement of ety of standardized handover tools, based on
central venous access allows monitoring of goal- specific clinical settings, in order to improve
directed targets, including mixed venous oxygen patient safety and outcomes. One such tool has
saturations and central venous pressure. been the standardization of postoperative hando-
Additional therapies, such at packed red blood vers from patients in the operating room (or
cell transfusions and corticosteroids may be con- other procedural locations) and admission to the
sidered based on clinical setting and laboratory PICU. There is data to support that such a stan-
values. Refractory shock to all of the above thera- dardized handover tool has the ability to improve
pies is a consideration for extracorporeal support, handover communication and improve patient
which requires transfer to a clinical facility with outcomes by decreasing inaccuracies in informa-
the resources to do so. tion, and expediting patient care activities, such
The approach to early-goal directed therapy as timely analgesia administration without
has been called into question in resource-limited unnecessarily prolonging the handover commu-
settings after results published in 2011 from the nication (Breuer et al. 2015). The communica-
“Fluid Expansion as Supported Therapy” tion tool involves standardizing a format in what
(FEAST) trial completed in sub-Saharan Africa information is given in a systematic order while
(Maitland et al. 2011). Resource-limited settings allowing for clarifying questions on the receiv-
often have poor access to ventilators and/or vaso- ing end, and summarized by a brief verbal feed-
active medications, which must be taken into back of information received to ensure all
consideration in caring for children with sepsis information was communicated correctly
who may have fluid-refractory shock, or develop (Breuer et al. 2015). Ongoing research in this
capillary leak and edema exacerbated by fluid area continues to focus on developing and vali-
administration. The results of the FEAST trial dating these types of standardized handover
demonstrated that children with febrile illnesses tools for all environments and transfer of care
and some signs of impaired perfusion treated between varying hospital environments.
with fluid boluses on hospital admission (0.9%
saline or 5% albumin in 20–40 mL/kg aliquots)
had higher mortality rates at 48 h as compared to Pediatric Early Warning Scores
similar children who did not receive fluid boluses
(Maitland et al. 2011). Pediatric early warning scores (PEWS) have
been incorporated into routine bedside monitor-
ing of inpatient pediatric ward patients across
Quality Improvement many hospitals. Pediatric early warning scores
were developed as an objective screening tool
Standardized Handover Tools for the early detection of hospitalized patients at
high risk of cardiopulmonary decompensation in
Suboptimal communication is one of the major an attempt to improve patient safety and decrease
factors contributing to medical errors and “near- rates of out-of-PICU in-hospital cardiopulmo-
miss” events. Sub-optimal communication is nary arrests (Akre et al. 2010). PEWS classifies

information from three domains of the patients record provided a visual dashboard for all health-
clinical status: behavioral, cardiovascular, and care providers to see and track patients in their
respiratory into a composite score to determine unit, leading towards increase compliance in the
when care should be escalated (Akre et al. 2010). use of these bundles and demonstrated sustained
In general, the “higher” the score, the more decreased rates of CLABSIs (Pageler et al. 2014).
severe deviation are the patient’s vitals and clini- This specific CLABSI checklist also alerted pro-
cal status from baseline, and thus the patient is viders to the number of days in which the current
likely at higher risk of experiencing critical dete- line had been in place, as an added reminder to
rioration. Many institutions have also incorpo- review the necessity of central line access daily
rated a subjective element to the scoring system with the goal of removing the line as soon as pos-
involved adding various points for family or staff sible (Pageler et al. 2014).
concerns about the patient’s clinical status (Akre
et al. 2010).
More recent research regarding the use PEWS Education
scores has validated the use of these scores in
specific sub-specialty populations of pediatric Courses
patients, such as the cardiac (McLellan et al.
2014) and oncology (Agulnik et al. 2016) popu- Many formal courses exist for training health
lations, with or without minor modifications care providers’ knowledge, behaviors, and skills
made to the score based on the normal vital sign relevant for pediatric critical care medicine.
values found within that specific patient popula- Pediatric Advanced Life Support (PALS),
tion. Additional studies are being done to extrap- European Pediatric Advanced Life Support
olate and validate the use of PEWS in other areas (EPALS), Advanced Pediatric Life Support
throughout the hospital, including the emergency (APLS), and Pediatric Advanced Emergency
room and operating room settings. Assessment, Recognition and Stabilization
(PEARS) are examples of these types of courses
that are delivered, often to teams, and may be a
Patient Care Bundles part of required credentialing practice for health
care professionals caring for critically ill chil-
Many patient safety initiatives over the years dren. In the lower resource setting, Emergency
have encouraged the development of protocolized Triage Assessment at Treatment (ETAT) may be
patient care bundles targeted at many preventable delivered. These courses cover assessment, basic
adverse events, such as catheter-associated blood life support (including cardiopulmonary resusci-
stream infections (CLABSI), catheter-associated tation), treatment algorithms, teamwork, and
urinary tract infections (CAUTI), ventilator- communication. Over the past decade, Pediatric
associated pneumonias (VAP), among others. Fundamental Critical Care Support (PFCCS) and
Protocols for central line placement, hand Paediatric BASIC have been developed to train
hygiene practices, urinary catheter care, etc., more advanced skills including mechanical ven-
have been well validated and implemented as the tilation, and management of specific pediatric
standard of care across many PICUs. critical conditions (i.e. congenital heart disease,
Implementation of such patient care bundles has traumatic brain injury).
universally demonstrated reduction in the associ-
ated morbidity.
Furthermore, technology advances have pro- Simulation
vided a unique opportunity to incorporate check-
lists associated with these protocols into the The use of simulation for training in the pediatric
electronic medical record. The introduction of a critical care environment has undergone dramatic
CLABSI checklist within an electronic medical growth in the past decade. Simulation training

has shown improvement in knowledge, skills who took a traditional instructor-led course
and behaviors across health care professions (Kardong-Edgren et al. 2010).
(O’Leary et al. 2015) and in a variety of topics in Despite these rapidly evolving technologies,
skills training (Jeffers et al. 2016), mock scenar- much work is still needed to better understand
ios (Dugan et al. 2016), teamwork (crisis optimal e-learning practices. Current research
resource management) (Figueroa et al. 2013), efforts focus on investigating optimal e-learning
boot camps (Nishisaki et al. 2009), and just-in- design and implementation, integration of
time training (Scholtz et al. 2013). Manikin e-learning activities into an educational curricu-
fidelity and debriefing techniques differ between lum, knowledge retention following e-learning
each type of simulation. Current research efforts activities, and translation of learning into clinical
focus on understanding optimal integration of practice.
simulation activities into an education curricu-
lum, defining appropriate debriefing techniques, Conclusion
determining the frequency of simulation retrain- The topics discussed here represent a sample
ing for optimal retention, developing standard- of the most recent and impactful updates in
ized assessment strategies, and utilizing pediatric critical care that have either improved
emerging innovations, such as 3D printing, into patient outcomes, or represent encouraging
practice. advances and further areas of study that will
assist in providing safe, efficacious, timely,
and equitable patient care.
E-Learning
Acknowledgements Declared none.
E-learning is another area that has been rapidly
developing to meet demands from emerging Conflict of Interest The author(s) confirm that this
pressures in health professionals education glob- chapter contents have no conflict of interest.
ally. Advances in information technology and
sharing of educational resources has been cited
as a way to strengthen the education of health References
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Update in Development:
Section A—Infant Development 6
Madhavi Moharir and Chaya Kulkarni
I nfant Mental Health: Awareness 2002; Center on the Developing Child Harvard
Among Physicians University 2012). The formation of synapses
peaks between the third trimester of pregnancy
The early childhood period (birth to age 5) is and the second birthday. Synaptogenesis then
considered to be the most important developmen- continues throughout childhood into adoles-
tal phase throughout an individual’s life. The cence, but at a slower rate. Basic sensory circuits
human brain is the ‘master organ’ of develop- like vision, hearing and touch form first. These
ment, which undergoes its most sensitive periods serve as foundation blocks for the development
in its early years of life (Grantham-McGregor of more complex brain circuits, responsible for
et al. 2007). The development of neurons is reflective thinking, behavior and cognitive func-
mostly completed at birth, but the interconnec- tions. Synapses that are stimulated by frequent
tions between neurons i.e. the synapses—are still use during early years get hardwired, whereas
developing at an incredible rate. 700 synaptic those that are rarely used are eliminated by a pro-
connections form per second in a child’s brain in cess called ‘pruning’. Repeated pruning results in
the first few months of life, a rate that is u nrivalled a sophisticated brain architecture of intricate
throughout his or her lifespan (Zero to Three neural connections.
M. Moharir · C. Kulkarni (*)

Infant Mental Health Promotion, HSC,
Toronto, ON, Canada
e-mail: chaya.kulkarni@sickkids.ca


134 M. Moharir and C. Kulkarni
Image from: McCain, M.N., Neural pathways under construction

Mustard, J.F., & McCuaig, high Birth sensory
K. (2011). Early Years Study
limbic system
Synapse formation
3: Making Decisions, prefrontal cortex
Taking Action. Toronto:
Margaret & Wallace
McCain Family language
Foundation. p.32
low
Prenatal Early Middle Adolescence/
childhood childhood early adulthood
Neurobiology
cell differentiation
myelination puberty hormones
neuron differentiation
Vision symbols & ideas mental inferences metalinguistic

hearing mindfulness awareness
Engine abilities
touch arousal & recovery

sleep & wakefulness reading
social relationships mathematics critical thinking
talking inquiry reflective thinking
shared attention thinking strategies
considered response
memory
Growing evidence suggests that the social envi- as electrical discharges. Biochemical cascades
ronment has profound impact upon the function (changes in DNA methylation and histone modi-
of one’s genes by providing the stimulus for the fication of chromatin) ensue in response to the
variable expression of an inherited genetic code environmental cues, triggering structural and
(Denberg and Daneman 2010; McEwen 2008). chemical changes to the genes (Mellor et al. 2008;
Epigenetics—a branch of science that studies Berger 2007; Kouzarides 2007; Glaser 2000).
processes that can alter gene expression tempo- Much like operation of a light switch, some gene
rarily or permanently without changing the DNA sequences are “switched on” or activated while
sequence—can draw associations between one’s others are “switched off” or silenced. These col-
social experience and his or her gene expression lective personalized chemical signatures are
(Mellor et al. 2008, National Scientific Council called epigenomes (Mellor et al. 2008) and they
on the Developing Child 2010a, b). During any resemble the software in a computer, determin-
stage in life but particularly in early childhood, ing the dos-and-don’ts of the genetic hardware
environmental experiences act as external stimuli (structural genome). (National Scientific Council
and the sensory inputs are carried to the brain on the Developing Child 2010a, b)

6 Update in Development: Section A—Infant Development 135
Image: A
Foundations of Healthy Development Lifelong Outcomes
biodevelopmental
and Sources of Early Adversity
framework can relate
Effects OverTim
the multiple influences ative e
mul
Cu
during development to
lifelong outcomes. Environment of Health-Rated
Relationships Behaviors
SOURCE: Center on the
Gene- Educational
Developing Child at Physical,
Environment
Physiological
Achievement
Chemical, Adaptations and
Harvard University and Built Interaction Disruptions and Economic
Productivity
2010. Reprinted with Environments
permission. Copyright Nutrition
Physical and
Mental Health
2010 Center on the Bio
log s
ica od
Developing Child at l Em
bed Pe
ri
d in g D ive
u r i n g S e n s it
Harvard University
erve and Return Interaction

S and behavior. Furthermore, while all children are
Shapes Brain Circuitry born with the capacity to be resilient they are not
born resilient. Resilience, the ability to recover
Babies are born relationship-ready and in fact, from a difficult situation, is influenced by both
their development is relationship dependent. The the secure attachment relationship and a child’s
formation of a secure attachment relationship ability to regulate. Both regulation and resilience
with a primary caregiver in the first year of life therefore depend on the secure attachment being
is crucial for healthy infant development. This in place and both will develop over many years.
relationship will influence the connections made
between brain cells and the strength of connec-
tions literally driving brain architecture. Positive verview of Social Emotional
O
interactions are more likely to lead to positive con- Development
nections. Conversely poor interactions are more
likely to lead to poor connections. When infants Relationships during the first 3 years drive devel-
and toddlers experience persistent neglect and/ opment including the development of mental
or maltreatment, the absence of serve and return, health. Having an understanding of what to look
their brains look different when compared to for and what to expect developmentally in the
those children living in a responsive environment. domains of social emotional development is
The absence of serve and return relationships important for a physician. Because infants can’t
ultimately influences a child’s developmental speak and tell their experiences, for those who
trajectory. Positive serve and return relationships may be vulnerable to poor outcomes in any
support many developmental constructs that begin domain, knowing what to expect should guide the
to form early in life with the most significant one observations of a young child during every visit.
being the secure attachment. The parent’s consis- Observing both caregiving and care getting behav-
tent response to their baby’s distress is the single iors can give insight to developmental status.
most important “serve and return” interaction Below is an overview of social emotional
that influences the creation of this relationship. milestones birth to 3 years of age. These should
When in place, the secure attachment acts as an be seen as a guide. What is essential is that con-
external regulation system that the baby learns to sideration be given to:
count on when distressed. This attachment forms
the foundation for regulation and resilience across • How a child is developing compared to his
the child’s life span. A child who is responded to peers of the same age
appropriately and consistently, is more likely to • How a child is developing on a continuum of
learn how to regulate and manage their emotion development

• What developmental goals are next for a child, • Express her emotions and needs through
based on current status rather than age her cries and actions.
• What strategies can be shared with parents to Baby will find a way to let her caregivers
support the emergence of the next milestone know that she needs attention when hungry,
tired or uncomfortable, e.g., in need of a dia-
per change.
and in Hand: Growing Together
H
Everyday: Social Emotional
Milestones Overview 4–6 Months
0–3 Months With loving, nurturing early relationships baby is

beginning to understand his physical and social
Babies are born relationship ready and in their surroundings and learning to discover his world.
first 3 months of life are actively trying to make He knows who his caregivers are and who he can
sense of their world. Before they can even speak, trust to respond to his needs. This is the start of the
babies communicate with their facial expres- attachment relationship and will be dependent on
sions, voices and body language. As caregivers how well caregivers provide consistent, respon-
and babies get to know each other, babies will sive and appropriate care. As baby continues to
depend on their caregivers to recognize their cues learn about his world and to make sense of the
and respond to their needs in a sensitive, timely things around him, his caregivers need to continue
and consistent way. This is the beginning of a to provide loving and responsive relationships to
trusting relationship that will extend to the wider help guide him through those experiences.
world in later years. Babies’ relationships and By 6 months a baby will begin to:
experiences lay the foundation for their mental
health now, throughout their childhood, and well • Intentionally express his emotions.
into their adult years. He will cry or get agitated when he wants
Over the first 3 months, a baby will: attention, e.g., he may laugh and smile while
interacting with his caregivers or he may show
• Gaze at her caregiver’s face and look in the that he is excited by quickly waving his arms
direction of her caregiver’s voice. and legs around.
Baby’s caregivers should bring their faces • Recognize his primary caregivers.
close so that baby can see their features and A baby feels safest around his primary care-
expressions. Baby may not initially make eye givers and seeks a familiar presence. He
contact since her vision has not fully devel- knows who his primary caregivers are and that
oped, but she will enjoy looking up and seeing they will respond to his needs.
her caregivers’ faces. • Make eye contact.
• Smile spontaneously. Baby will begin to focus for longer periods of
By 2–3 months, a baby’s social smiles are time as his vision has developed more since
signs that she knows her caregivers. birth and he can now see things more clearly
• Recognize a familiar voice. and farther away. When a caregiver sings, bab-
For months before baby was born, her moth- bles or imitates the sounds baby makes, baby
er’s voice was what she heard most. She will will look up at his caregiver and make eye
follow that voice, turning her head in that contact. He engages by cooing and babbling
direction, and will prefer it over others. back.
Make cooing sounds when she is happy, con- • Read facial and vocal expressions and learn
tented and communicative. what different forms of interaction mean.
Be soothed when picked up and comforted When his caregivers engage with him, e.g.,
(most of the time). talking, singing, cooing or babbling, baby will

respond and make eye contact. When he hears • Show her caregivers her emotions.
his caregivers getting angry and speaking in a When baby gets scared she will want to be
voice that is louder than normal, he might near her caregivers and maybe cling to them.
become scared and cry. He will know some- When she gets mad she might make a frus-
thing is not right and may become agitated trated face. Or when she feels shy she may
and seek his caregivers’ attention. hide behind them or try to cover her face.
• Form an attachment with his primary • Begin to show affection towards her
caregivers. caregivers.
When caregivers respond to their baby’s needs Baby will want to be hugged and kissed and
especially when he is distressed, baby will in return she will hug and kiss her caregiv-
know he can trust and depend on his caregivers back. She will begin to understand the
ers. With positive, consistent care, baby will words “hug” and “kiss” and do these things
form secure attachments with his caregivers. spontaneously.
• Develop a sense of herself as a separate per-
son with her own likes and dislikes.
7–12 Months Baby is starting to have dislikes and likes
about her experiences, her toys and the people
By the age of one, baby is learning more about around her. She will let her caregivers know
her world and may even have an opinion about what she enjoys doing and being around, and
things she likes or dislikes. She is beginning to what she does not like to do.
get around by crawling, walking by holding onto
furniture or perhaps even on her own with no
support. She is curious to learn about the things 13–18 Months
around her and can now actively explore. Baby
can now understand simple language and words Baby is starting to understand more of what he
like “no,” “bye,” or “shoes.” hears and is enjoying the use of language. He
Baby will: enjoys hearing short stories and simple songs. He
will point at pictures in books and try and sing
• Begin to intentionally tell her caregivers along to songs he is familiar with. Baby enjoys
what she wants. reading the same books and hearing the same
Baby will make gestures or point at objects songs over and over; he enjoys knowing what
that she wants. She will begin to put her will happen next in the book or song. Repetition
arms out or up when she wants to be picked helps him memorize simple songs which will
up. She will begin to babble more and may help him build his vocabulary.
even say a couple of words to interact and Baby will:
communicate.
• Begin to miss her caregivers when they are • Become more confident and have a greater
not around. sense of himself.
When her caregivers leave the room baby will Baby has more likes and dislikes when it
notice, become upset and may begin to cry. comes to what he plays with, who he wants to
She misses her caregivers when they’re not play with and when he wants to interact with
there and looks for them. people.
• Begin to seek comfort from her caregivers. • Begin to take ownership of objects belong-
When baby gets upset or hurt she will want ing to him, such as toys.
and need to be comforted by her caregivers. It Baby will have a difficult time with sharing
is important to respond to baby’s distress by since his toys right now belong to him. His
comforting her. Comfort her and give her caregivers will hear him using words like
words to help her label her feelings. “no,” “mine,” etc.

• Notice his peers. she needs help. She is still dependent on them
Baby is becoming interested in what others and knows they will comfort her and respond
are doing or what they are playing with. He to her when needed.
may not join in and play with them but rather Begin to develop a sense of imagination as she
sit beside them and play on his own. He will takes on different roles and engages in pretend
watch his peers but may not initiate any interplay.
action with them. • Have more words that she uses to express
• Express his emotions to his caregivers. herself and to get what she wants.
Baby will still feel a lot of emotions, so his By the age of two, baby’s communication will
caregivers should comfort him and help him evolve from using simple two-word sentences
label his feelings. Labeling feelings will give to more complex complete sentences.
baby ownership of his emotions, and with • Parallel play starts with toddlers playing
time he will learn how to express them. next to each other.
They may not share or be doing the same
activity but they will play next to each other.
19–24 Months
Baby is growing into an independent toddler. She 25–36 Months

is mastering things on her own and seeks less help
from her caregivers. She is beginning to engage in Toddlers are confidently exploring the world, and
imaginary play. As she watches and observes her when given the chance, are socially engaged with
surroundings, she will begin to imitate the actions other children and adults. They are beginning to
of others and try to role-play. She might pick up a understand the children’s stories read to them and
broom to “houseclean,” or play “mom” with her are talking about their own personal experiences
dolls, etc. She is beginning to use simple sen- and the events they are involved in. They are also
tences with the words she knows and is beginning engaged in more complex imaginary play, from
to communicate and use language more easily. watching and imitating people around them to
She notices her peers around her and enjoys their pretending to be characters they hear about in the
company but may need help mastering her social books read to them.
play skills, like sharing and turn taking. A toddler will:
A toddler will:
• Be actively forming friendships with his
• Begin to learn about others’ feelings and peers when given the chance.
the concept of empathy. A toddler may have one specific friend that he
Baby is aware of her peers and is beginning always plays with and prefers to be around. He
to understand they have feelings just like she learns to play, engage and interact with others.
does. When someone takes a toy away from a Ensuring he has consistent play experiences is
friend or hits a friend, it hurts her and she may important for his development.
cry too. She is beginning to develop empathy • Use more language between these months.
for the people she cares for and realizes other A toddler will communicate what he wants
people also get sad. Baby is developing the and how he feels. He is starting to have con-
ability to take another person’s perspective. versations with peers and the adults he’s
• Want to make her own choices and deci- around, sharing details about himself and his
sions about how she does things. adventures. He has a grasp of language and
Baby is becoming more independent as she his speech is now more easily understood. His
masters doing things on her own. She will still use of words, complete sentences and overall
look for assistance from her caregivers when vocabulary will increase significantly.

• Begin to use words to express his feelings. communicate typical and emerging skills in
Caregivers will know when a toddler is happy, early childhood development (for more detailed
scared, sad or mad. With encouragement he information on developmental milestones visit:
will try and use words to express these feel- http://www.imhpromotion.ca/Resources/CPT-
ings, but of course, he will still use gestures, DevelopmentalMilestones.aspx). However, the
such as walking away, crying or throwing developmental milestones outlined are only
something. guidelines. Each child develops at their own
• Engage in more imaginative play. pace, with some skills emerging early, and others
Not only will a toddler imitate the people appearing later.
around him, but he will begin to use his imagi-
nation with several objects. He will enjoy pre-
tending different objects symbolize something ges and Stages Developmental
A
else—a block turns into a train or playdough Milestones
turns into a dinosaur.
• Become more aware of peers and will be Six Areas of Child Development
increasingly sympathetic toward them
when they are upset. Social Development means being able to make
A toddler will recognize others’ feelings and friends and get along with others, work as part of
might even comfort peers when he sees they a team and be a good leader. These skills are all
are upset. built on self-confidence, cooperation and trust.
• Become more engaged in social play skills. Emotional Development means the develop-
A toddler is beginning to learn how to share ment of a full range of emotions from sad to
and take turns. Cooperative play may still be happy to angry, and learning to deal with them
difficult but he is learning to play with others appropriately. This helps build self-esteem and
and enjoy their company. leads to such deeper qualities as sympathy, car-
ing, resiliency, assertiveness and empathy and the
This chapter presents a focus on social emo- ability to rise to life’s challenges.
tional development. However, a holistic view of Language Development is the ability to
the child development is essential. Often, for understand and express verbal and non-verbal
infants and toddlers who may be vulnerable for communication. This is followed by the capacity
poor development, monitoring development, not- to use words and sentences in correct grammati-
ing when milestones in any domain are not cal structure in order to communicate wishes,
reached can be critical. ideas, information and needs.
Below is a sample of what you will find. In Intellectual Development means being able
this particular resource Comfort, Play and Teach to think creatively and abstractly, to pay atten-
Ages and Stages Developmental Milestones, tion, solve problems and develop keen judgement
(created by the experts at Invest in Kids and now along with a lifelong readiness to learn.
hosted by Infant Mental Health Promotion and Gross Motor Development allows a child to
the Phoenix Centre for Children and Families) gain balance and bring large muscles under con-
a young child’s developmental milestones are trol in order to master physical activities such as
mapped out in the various domains of develop- sitting, crawling, walking, running, climbing,
ment (Social, Emotional, Language, Intellectual, jumping and generally enjoy all that his body
Gross and Fine Motor). The Milestones are allows him to do.
grouped by ages outlining typical and emerg- Fine Motor Development means mastering
ing skills, and what you can do to promote precise and accurate small muscle movements of
development in those domains. This resource the fingers and hands in order to reach, grasp and
can easily be printed to share with families to manipulate small objects.

he Amazing World of Your Baby:

T a ttention, especially when she wants to keep the
An Overview of Baby’s Development simple games you’ve created together going. At
Birth to 6 Months this point, she will start to build a healthy sense of
herself and although her emotions and moods can
Infancy is a very exciting time. You and your change quickly, she is learning how to comfort
baby are discovering each other and your baby is and soothe herself by sucking or holding onto a
discovering the world. She’s learning and doing special toy.
more and more, but she still depends on you for
everything. As you spend time with her, you will our Baby at 1 Month
Y
come to know her likes and dislikes, her style of Welcome to the first month of your baby’s life.
learning and her personality. In short, you’ll dis- Some amazing things are set to happen. For
cover a whole new person. example, you’ll notice your baby will begin to:
In her first 6 months, your baby will go from
being totally dependent on you to being able to • Stare at colourful objects.
stay alert for 2 h at a time. She will explore her • Study your face when you smile.
environment—reaching, grasping and putting • Respond positively to comfort and soothing.
things in her mouth—while she sits supported or • Cry to tell you she’s hungry or
lays on her stomach with head and chest held high. uncomfortable.
At this time, your baby will show how happy • Enjoy being talked to and respond with her
she is to be close to those she trusts. She’ll begin own special happy dance—on her back, wav-
to squeal coo, gurgle and babble to get your ing her arms and legs.
SOCIAL Skills at 1 month

Typical skills Emerging skills
• Fixes eyes on your face in response to your smile • May smile back at face or voice
• Moves body in response to your voice during • Listens to voices and coos
interaction • Recognizes parents’ voices
• Quiets down when looking at familiar faces
• Engages in eye contact
• Make eye contact with your baby • Become familiar with your face
• Smile and make happy faces • Explore your face and expressions
• Gently rock and cuddle your baby • Learn to relax and feel secure in your arms
• Hold her closely and dance slowly to music • Feel rhythm and movement in a secure hold
• Recognize the signs your baby uses to show what he is • Feel cared for and that he is getting his message
feeling across
• Pause, observe and respond appropriately to your • Become engaged in the interaction
baby’s reaction

EMOTIONAL SKILLS at 1 month

• Enjoys/needs a great deal of physical contact and • Recognizes and calms down to a familiar voice
tactile stimulation • Communicates moods through different cries
• Responds positively to comfort and satisfaction
• Primary negative response is distress or pain
• Respond quickly and sensitively to your baby’s cry or • Feel his needs are being met
discomfort • Feel secure and valued
• Tell your baby how much he is loved
• Provide soft, lullaby music • Enjoy new sounds that are as comforting as speech
• When feeding your baby, (breast or bottle) let her • Practice this skill and feel more and more confident
grasp your finger with her ability to grasp
• Feed your baby whenever he is hungry • Trust that his needs will be met
INTELLECTUAL SKILLS at 1 month

• Cries when hungry or uncomfortable • Turns toward familiar sounds and voices
• May make throaty sounds like ‘ooooh’ or ‘aaaah’ • Can distinguish men from women, and mother
• Enjoys being talked to and responds to voices/sounds from other women’s voices
• Pays close attention to faces of those closest to him • Can distinguish everyday speech from non-speech
• Responds to loud or sudden noises with a sudden start sounds
(early signs of a developing response system) • Able to read and respond to positive and negative
• Will focus on high contrast patterns and faces; prefers expressions as well as subtle differences in
these to bright or big objects parent’s voice
• Able to co-ordinates eyes and track objects, e.g.,
follows toy from side to centre of his body but
only if it is in his line of vision
• Respond to your baby’s cry with a song, a soothing • Feel his needs are being responded to
voice and a hug • Feel a sense of security in your response to his
• Respond when your baby is startled by noise needs
• Hold your baby and let her see your face as much as • Study and learn your facial features
possible • Responds to the sound and pitch of her parents’
• Say rhymes, sing songs or speak softly voices, i.e., may quiet down, gurgle, coo, etc.

INTELLECTUAL SKILLS at 1 month

• Tell your baby about all the caregiving routines you are • Learn to associate a positive tone with nurturing
going through activities
GROSS MOTOR at 1 month

• Lifts his head when held at your shoulder; his head • Fits his form to yours when held; grasps, clasps
sags, flops forward or backwards when not supported people
• All arm, leg and hand movements are still reflexive, • Lifts head temporarily when lying on stomach
they move with little control; when lying on back, tonic • Holds head in line with back when pulled to
neck reflex characterized by bobbing head (fencer’s sitting position
position) still predominates; arms and legs are thrust in
play
• When on tummy, turns head to clear nose from bed;
lifts head briefly
• Rolls partway onto side from back
• Gently touch your baby during feeding, changing and • Help you learn what type of touch he likes
bath time • Learn that his caregivers want to make him feel
• Massage your baby’s arms, legs and tummy comfortable
• Support your baby’s head against your shoulder as you • Get to see more of her environment
walk her around the house • Strengthen her neck muscles as she lifts her head
• Give your baby some tummy time to see her world
• Tell him what body parts you are washing during bath • Start to eventually learn the words for parts of his
time body
• Use his name when you come towards him • Start to learn his name and your voice
FINE MOTOR at 1 month

• Stares at colourful objects 8–14 in. away • Holds object for a few moments without any intent
• Follows person with eyes while lying on back or purpose
• Generally keeps hands closed in a fist or slightly • Coordinates eyes better to track moving objects
open • Becomes fascinated by her own hands
• When fingers are pried open (usual position is a fist),
grasps handle of spoon or rattle, but drops it quickly

FINE MOTOR at 1 month

• Take your baby’s hands and gently rub them on your • Watch, feel and learn about your face
face • Look and follow your face with his eyes
• Move your face slowly from side to side in front of
your baby’s face
• Suspend a colourful toy over the crib • Practice looking at things when on her back
• With baby lying on her back, alternate the position • Look at objects using both sides of her head; also
of her head and feet in the crib prevents “flathead” condition
• Give your baby a rattle to hold • Learn to hold it briefly
our Baby at 2 Months

Y • Follow objects and people with his eyes.
As your baby enters his second month, he will • Smile when others talk to him and smile at
gain new skills right before your eyes. At this stage him.
you will notice that your baby is beginning to: • Show excitement or delight with small throaty
sounds.
• Turn his head to both sides. • Recognize familiar voices and people.
SOCIAL SKILLS at 2 months

• Smiles in social contact with others besides his • Stays awake longer if people interact with him
mother • Shows excitement when she sees familiar people and
• Listens to voices and coos things
• Studies faces alertly and directly, then gets excited; • Becomes more expressive with her face, body/muscle
is more oriented to her surroundings; moves arms tone and voice
and legs and ‘talks’ in response to what she sees
• Visually follows a moving person
• Recognizes and becomes quiet for a familiar,
gentle voice or face
• Talk to your baby during diapering and feeding • Become familiar with the voices of those who care for
routines her most often
• Sing to your baby • Take comfort in songs and sounds she knows


• Use a mix of high and low pitched voices • Be more interested in interacting with you
• Exaggerate a big smile or wide eyes • Love to look at your face
• Engage in face-to-face conversations about any • Become engaged in dialogue as well as be entertained
topic, for example, plans for the day, pictures
hanging on the wall, etc.
EMOTIONAL SKILLS at 2 months

• Communicates moods of distress with different • Fits her form to yours and relaxes body when held
cries and excitement and delight with small throaty • Makes appropriate facial expressions in response to
sounds emotions, for example, fear, joy, anger
• Can quiet himself by sucking his fingers, a pacifier,
etc.
• Expresses contentment when touched and cuddled
• Able to express discontent, e.g., fusses at loud
noises
• Displays different emotions as seen with peaks of
irritability and crying
• Show awareness of your baby’s cues that tell you • Feel secure and understood
how he likes to be handled and touched
• Respond to baby’s cues consistently and
appropriately
• Respond to your baby’s choice to stop an • Communicate to you more often knowing that you
interaction understand his cues
• Copy the faces your baby makes
• Create routines • Begin to understand that her feelings are important

• Respond to your baby’s signals in the same way and valued
every time • Respond with her own smiles to copy you and others
• Learn to anticipate what comes next
• Feel secure

INTELLECTUAL SKILLS at 2 months

• Gurgles, coos and squeals • Repeats actions for his own sake
• Shows responsiveness to touch and to oral and visual • Holds onto objects briefly as his voluntary grasp
stimulation replaces reflex grasp
• Stares at surroundings or attractive large, moving • Begins to look at his hands as objects for
objects from several feet; moving or contoured objects examination
hold his attention longer Starts to associate people with behaviour, for
• Clearly discriminates voices, people, tastes, proximity example, mother and feeding
and object size • Begins to sense that hands and feet are extensions
• Recognizes a few objects, for example, a bottle or of himself with limits and opportunities
rattle
• Look at your baby, smile at her, and offer soothing • Respond to eye contact and the sound of your
words familiar voice with her own coos and smiles
• Answer your baby’s happy noises • Begin to know she can count on you to respond
• Sing simple songs or do short finger plays with • Show you what gives him pleasure and indicate
repeating sounds what he wants more of, for example, by kicking
• Play a game of taking turns by copying sounds your arms/legs
baby makes • Begin to understand that conversation is a
partnership and his sounds are equally valued
• Talk to your baby during daily routines • Begin to understand the words and tone of voice
• Repeat favourite rhymes and songs that go with regular routines
• Learn to recognize certain words and actions
GROSS MOTOR at 2 months

• Movements are more deliberate, for example, turns • Can hold head up at 45° angle for a few minutes
head to both sides when lying down • Arms and legs cycle more smoothly
• Moves arms and legs and ‘bicycles’ with legs when • Arms move more symmetrically to reach for a toy
excited
• Lifts head temporarily when lying on stomach
• When sitting, keeps head erect; head may bob as she
tries this out
• Rolls from side to back
• Muscle reflex is developing, e.g., body startles
involuntarily
• Blow on your baby’s tummy • Enjoy the sensation as he works his abdominal
• Prop your baby on his side using a rolled up towel muscles
behind his back • Enjoy looking at the world from a different angle


• Push gently against the bottom of your baby’s feet • Kick and stretch in this resistance game
• Lie on your back and slowly and gently raise and • Enjoy looking at your face from a new vantage point
lower your baby off your chest in a horizontal
position
• Lay on the floor with your baby on your thighs; then • Learn to anticipate receiving the kiss at a set interval
curl up to kiss her of time
FINE MOTOR at 2 months

• Keeps hands closed in a tight fist most of the time • Grasps at things become voluntary
• Follows objects with eyes, for example, a mobile is a • May swipe at objects
source of pleasure
• Fascinated by own hands; watches them and turns
them over momentarily
• Holds objects briefly
• Help your baby grasp your pinky finger while • Begin to move fingers out of the fist position
making eye contact, talking or singing • Begin to open his fist to explore things; will also
• Open your baby’s hand and help him explore your begin to feel safe and confident to explore further
face, moving his hand over your eyes, nose and
mouth
• Move a colourful toy slowly from left to right in • Learn to coordinate both of her eyes to follow an
front of your baby’s eyes object
• Place your thumbs in baby’s palms and when she • Enjoy the physical sensations of exercising both
grasps them, open her arms wide; bring her arms sides of her body
together and cross them over her chest, slowly and
gently, using rhythmic movements and a song
• Hold your face close to your baby’s and let her try to • Begin to try to reach out or swipe at your nose and
reach for your nose other things, such as earrings
• Open your baby’s fist and rub her hand over different • Begin to experience touch on different parts of her
textures hand


Y • Stop sucking so that he can hear sounds.
Your baby will start to demonstrate more predict- • Use his voice in response to adult talk and
able skills. He will start to: smiles.
• Coo with open (‘aaaah’) and closed (‘eee’)
• Hold his head up with more control. vowel sounds.
• Play with his hands by clasping them and • Study objects for a long time, even turning
bringing them to his mouth. them upside down to get another view.

• Smiles immediately and spontaneously • Knows difference between family members and
• Responds in excitement with total body and strangers
vocalizes to familiar people or things • Cries less often as he finds other ways to communicate
• Enjoys socializing and playing with other people; and as parents’ ability to understand his needs improve
watches speaker’s eyes and mouth
• Stops sucking to hear sounds around him; then
looks around and sucks at the same time
• Turns head to follow moving objects, voices, or
music
• Vocalizes in response to adult talk and smiles
• Return your baby’s smiles • Respond with smiles with other family members
• Spend close, personal time with your baby every • Enjoy relating to adults who love her
day
• Mimic and exaggerate your baby’s facial • Try to imitate your facial expressions
expressions • Enjoy sharing time with you
• Get down on the floor next to your baby to talk,
read a book or sing to her
• Give your baby time to react and then respond to • Learn about the basics of taking turns in conversation
her • Watch and listen to the objects as he moves
• Suspend objects that make a noise

• Shows appropriate facial expressions in response to such • Starts to laugh
emotions as anger, fear, joy • Starts to show anger when he cannot get
• Reflects feelings of happiness with chortles or squeals; what he desires
frustration with whimpers; and hunger with smacking lips
• Begins to show sadness
• Responds to familiar people; may stop or start crying
according to who holds him
• Can distinguish and express discomfort


• Respond to your baby with positive encouragement during • Develop a positive sense of self
interactions, for example, say “Good reaching,” when he • Begin to quiet down on his own after an
reaches out for something upset
• Provide soft toys, blankets and other “soothers”
• Know your baby’s signals when she has had enough • Learn to trust that you will not push her
• Build bits of exciting physical activity into your baby’s day beyond the limits of what she enjoys
• Learn how to get excited and then calm
herself down
• Be consistent with routines and responses • Feel secure as he learns to predict what
• Be aware of toys and objects that comfort your baby and comes
make them available whenever he is distressed • Understand that his feelings count
LANGUAGE SKILLS at 3 months

• Coos with both open vowel sounds (i.e., ‘aaah’); and • Begins to babble and amuse self with new noises
closed vowels (i.e., ‘eee’) • Begins to imitate sounds
• Responds to speech stimulation by gurgling, cooing,
and squealing
• Expresses himself regardless of what else is going
on around him
• Distinguishes speech from sounds you make
• Expresses different cries for different needs
• Tell your baby what you are doing as well as what • Enjoy listening to your voice and come to expect
she is feeling and hearing during all routines certain routines
• Imitate the sounds your baby makes to start a game • Chat and experiment with different sounds then start
of taking turns to take turns
• Repeat favourite rhymes and songs • Learn to recognize certain words and actions


• Begins to become aware of himself as a person by • Repeats actions for his own sake
looking, examining and feeling what he can do with • May associate a specific action with a result; very
his own toes, feet, fingers and mouth as well as objects preliminary indications of understanding cause
• Begins to show memory, for example, waits for an and effect relationships
expected reward, e.g., sitting in a highchair and • Retains an object in hand voluntarily
anticipating mealtime • Manipulates a large ring or rattle
• Recognizes familiar objects and people, even at a
distance
• Enjoys repetitive games and repeating a newly learned
activity
• Tries to prolong a pleasing image or action by
continuing to look, listen or grasp
• Call your baby’s name when she is not looking • Learn to locate sounds
• Play simple tickling games • Learn that certain actions have specific results, for
example, tickling means fun and laughing
• Hit a toy that makes a noise while your baby is • Begin to sense a connection between what his
looking fingers and hands can do with objects
• Place a toy close enough for your baby’s kicks to hit it • Discover that he can cause something to move and
and make a sound make a noise

• Keeps head in mid-position while on her back, and • Swipes with arms
moves her arm and leg on one side in unison, then the • Tonic neck reflex (characterized by bobbing head)
arm and leg of the other side begins to disappear
• Raises head and chest when on tummy • When pulled to stand, presses feet against surface
• Holds head up with more control and stands briefly
• Sits with support on a lap • Lifts head and supports chest on extended forearms
• Briefly bears weight on legs by pushing down with • Splashes and kicks with hands and feet when in the
legs when placed on a hard surface bathtub
• Shift your baby to different positions, for example, on • Be less likely to get bored with his immediate
tummy or back, or on your lap surroundings


• Tilt your baby from side to side on your lap while • Learns to balance and strengthen muscles needed
singing a song for sitting
• Bounce your baby gently on your knees to different • Learn to control her head in this action game
rhymes or short songs
• Place baby on his tummy and lay down on the floor in • Practice holding up his head and chest to see your
front of him face

• Plays with hands by bringing them together and • Begins to swipe for dangling objects, but may be
clasping them far off target
• Hands/fingers stay open more as grasp reflex fades • Looks from one object to another
• Bring hands to mouth • Watches and touches fingers of both hands as they
• Reaches for objects with both arms, starting at sides move toward midline and meet; early stages of
and closing in front of body; often contacts object with eye-hand coordination
closed fists
• Allow your baby to suck on his fingers/thumb • Learn to use his own body to soothe or calm
• Carry your baby around from room to room or outside himself
to familiarize him with his surroundings • Become familiar with his surroundings; learn to
look at and follow different objects
• Clap your baby’s hands together to play “Pat-a-cake” • Learn what her hands can do in a fun way
• Give your baby different textures to touch e.g., furry, • Learn that materials have different sensations when
hard, squishy touched
• Hold dangling objects in front of your baby’s eyes to • Learn how to use his eyes and hands together in
encourage him to reach out and touch them order to obtain objects within reach


Y • Laugh out loud when tickled or during social
As your baby’s fourth month begins, you will see games.
some truly awesome changes. This is when your • Show anticipation and excitement by breath-
baby begins to: ing heavily.
• Turn his head to find out where a sound comes
• Lift her head and chest when she’s on her from.
tummy, and extend her arms.
• Try to grasp objects with fingers and palm
now that her hands are open.

• Gazes into your eyes during feeding or diapering • May prefer one toy over others
• Uses her voice to initiate socializing; coughs or • Interested in and smiles at her mirror image
clicks tongue
• Responds to and enjoys your touch
• Makes social gestures such as waving or kicking
when she sees a familiar person, for example, she
will signal “pick me up”
• Enjoys social games and play and will laugh out
loud when tickled or when playing peek-a-boo with
a scarf
• Smiles and vocalizes to an actual face rather than to
an image
• Sing and talk to your baby as much as possible • Take comfort in the songs and sounds she knows
• Let her spend special time with siblings every day • Build relationships with key family members
• Sing action songs such as “Head & Shoulders” or • Get to know the tune and movements and come to
“The Wheels on the Bus” expect certain actions
• Use different voice tones for songs • Become familiar with different pitches of sound
• Call your baby’s name when she is not looking • Eventually respond to his name
• Talk about what you hear, for example, “the phone is • Learn to listen and become familiar with household
ringing”, or “there’s daddy’s car” sounds


• Fusses or cries to gain attention from familiar adults, • Expresses anger when he cannot get desired effect
or when attention or toy is taken away from him • May differentiate between mother’s image and his
• Yawns and arches back or turns away when he has own in the mirror; turns to see mother’s “real” face
had enough interaction or there is too much noise • Follows someone with eyes and continues to look at
• Shows anticipation and excitement by breathing the door when that person leaves the room
heavily
• Shows he’s not sure (stops cooing and smiling) or
he’s afraid (fusses) if a new person moves toward
him; turns his head into shoulder of parent when a
new person approaches
• Stops crying when he hears your voice or
caregiver’s, he attempts to soothe himself
• Are responsive to your baby’s feelings • Feel that her emotions are understood
• Find out the best ways to soothe your baby’s upset or • Feel loved and secure
distress
• Play games like “peek-a-boo” or “Mummy’s coming • Learn that you leave but you come back
to get you” • Become familiar with her own name
• Use your baby’s name often as you talk to her
• Call out to your baby when he starts to fuss • Learn to calm down to the sound of your voice
• Respect your baby’s hesitancy with new people by • Feel a sense of security even in frightening situations
being close or holding him

• Babbles strings of syllable-like sounds • Attempts to make consonant sounds
• Experiments with sounds using variation in pitch and
tone
• Communicates pain, fear, and loneliness through
crying; joy or interest by cooing sounds
• Uses his own special kind of cry when hungry
• Makes babbling sounds when looking at toys or
people
• Listens to music or a music box
• Babble back to sounds she makes • Feel the sounds she makes are as important as yours


• Shake simple noise makers (small bottles or yogurt • Respond to sound with eye movements and head
pots with a toy inside) in front and to both sides of turning
your baby’s head
• Introduce a new finger play each week • Watch and listen to words and actions

• Starts to explore things by bringing them to his • Finds an object that is partially hidden
mouth • May transfer a toy from one hand to the other
• Turns head toward sound to find out where it comes • Swipes at objects with open hand of one arm but
from often misses
• Uses entire body (arching, kicking, stretching) to • Begins to figure out appropriate responses to other
reach towards a toy that intrigues him people’s actions
• Has mental model for human face; knows mother or
father and may resent strangers
• Becomes aware of his own fingers and how they
feel different from another’s
• Are predictable in your actions • Begin to respond to routines and patterns of

behaviour
• Offer objects with different textures to explore • Experience and eventually learn to distinguish
different textures, e.g., hard, soft, bumpy, etc.
• Make a small photo album of the family • Learn to recognize familiar faces in the family


• Lifts head and chest when on her stomach and • Rolls from stomach to back
supports herself on forearms or on outstretched arms • Uses protective extension i.e., stretches arms and
• Turns head in all directions to follow a toy when legs downward
lying on stomach
• Brings both hands to chest and keeps head in midline
when lying on back
• Holds head steady when supported in a sitting
position; may prefer sitting to lying down
• Thrusts legs and feet against bottom of crib over and
over
• Rolls from side to side on stomach
• Change your baby’s position throughout the day, for • Enjoy a variety of physical positions and be less
example, from your shoulder to your lap, from his bored
back to his tummy • Feel respected and valued
• Observe your baby’s positions to learn what he likes
and dislikes
• Place colourful toys in front of and to your baby’s • Be encouraged to push chest up, lean on her
sides when she is on her tummy forearms and turn her head so she can get a better
• Bend your baby’s knees up to her chest and her toes look
up to her chin in time to a rhythmic song • Feel the physical sensation of her legs and toes as
they are exercised
• Put the same toy in front of your baby, changing • Learn to explore a toy in different ways given his
your baby’s position or location, and also changing own or the toy’s physical position
the position of the toy • Experience the sensation of flipping between two
• Cross one leg over the other and roll your bay over major positions of his body
from back to side or tummy

• Relaxes with hands mostly open, not in fists as • Claps hands
before • Can bring hands together though hands may meet
• Reaches for objects when supported in sitting below, beyond or in front of object
position, and then brings them to mouth • Waves a rattle placed in his hand
• Uses mitten grasp, i.e., fingers close on open palm
with thumb sticking out
• Glances from one object to another and looks at toys
placed nearby
• Tries to swipe at objects, but still inaccurate; may
look from object to hand, and back to object; often
misses, but can grab it sometimes


• Let your baby play with your fingers while breast- or • Enjoy the intimacy of touch at such times
bottle-feeding • Be able to focus and explore without feeling rushed
• Show your baby one toy at a time
• Hold toys out for your baby to grab • Practice the skill of looking, reaching and touching
• Sit on the floor with your baby on his back, between many times
your legs; as you sing, gently pull your baby up to a • Strengthen his arm, back and abdominal muscles in
sitting position this face-to-face game
• Label each toy your baby holds and plays with • Learn the names for objects over time
• Praise your baby’s successes with descriptive • Begin to learn what she is good at
phrases, for example, “Great reaching”

Y • Make sounds and interrupt conversations
The fifth month of life sets the stage for more when he wants attention.
interactive developmental growth. You will notice • Display an awareness and wariness with
your baby starting to: strangers.
• Babble double consonants such as baba, dada,
• Sit, if supported, to view her world. mama.
• Start to connect eyes and fingers. Cooperate in
reaching and grasping toys.

• Makes sounds and interrupts conversations when he • Observes adult’s facial expressions intently
wants attention • Bangs playfully on mirror image
• Smiles and vocalizes to her mirror image • Learns how to tease
• Distinguishes familiar and unfamiliar adults
• Shows anticipation, waves and raises arms to be
picked up
• Tries to get close to someone near crib
• Frolics happily when played with; plays with rattle,
pats bottle or breast
• Smile at others when you are out and encourage your • Learn that the world is generally a friendly place
baby to smile too • Learn that he can use his voice to get your attention
• Respond to the sounds your baby makes


• Sit or hold your baby in front of a mirror and make • Love to look at your face and her own
faces • Begin to talk back to her image and yours
• Talk to your baby during mirror play
• Hold out your hands and ask your baby if he wants • Begin to learn the meaning of social gestures
to be lifted up—remember that he won’t answer, but • Learn about and become more familiar with the
if his hands go up you know you’re right! people in her world
• Create a book of pictures for your baby with familiar
people

• Displays awareness and wariness of strangers • Smiles, laughs, squeals when happy; grunts when
• Expresses anger when can’t get desired effect angry
• Clings to parent when held • Is content to play by himself for a while with a few
• Shows fear, anger and disgust toys either in the crib or playpen
• Pushes away when he doesn’t like what you’re doing • Shows strong dislikes and likes about food
to him, for example, wiping his nose
• Describe the different emotions your baby shows • Begin to learn about different emotions
during the day • Feel safe and secure with you when others are
• Reassure your baby when he clings to you or acts around
fearful around strangers
• Use feeding, bathing and changing as a time to play, • Respond to your emotions
adding gentle tickles and finger plays • Seek more of your attention
• Sing action songs such as “If You’re Happy and You • Begin to become familiar with different emotions
Know It” to demonstrate different emotions
• Read a book showing pictures of people with • Learn about different expressions
different faces; look at each page leisurely and • Learn that people show different emotions
describe the emotions in each picture
• Talk about the different expressions you and your
baby see on other people


• Watches your mouth, listens to your voice, then • Touches your hand to restart activity
experiments with her own sounds • Responds to her own name
• Tries to imitate sing-song quality of voice
(inflections)
• Babbles double consonants (baba, dada, mama)
• Makes “raspberry” sound—tongue out and blowing
• Looks up when she hears her own name
• Use her name in songs, “Where is Priya, where is • Begin to respond more and more to her name
Priya, Where are you….There you are, There you
are and how do you do?”
• Use different or funny voices when telling stories • Notice different voice inflections
• Repeat the same songs and finger plays • Begin to imitate the sounds as she hears

• Experiments with the concept of cause and effect, • Reaches for a second object with purpose
e.g., Cries more deliberately; waits to see if anyone • Works toward a desired, but out of reach, object
is coming and then cries again
• Turns head deliberately to sound or to follow
vanishing object, e.g., leans over to look for
something if dropped
• Wants to touch, hold, turn, shake and taste
everything
• Remembers her own actions in the immediate past
• Tries to maintain interesting changes he can make in
his environment through repetitive actions
• Respond to the range of emotions she shows to get • Begin to learn she is a separate person from you
your attention • Feel safe knowing you will respond to her needs
• Let your child experience different textures by touch, • Begin to learn about different textures and which ones
smell, or taste he likes and dislikes
• Move out from behind to either side of your baby to • Learn that even when he can’t see you, you still exist
encourage him to find you in different places


• Give your baby toys that require her to work for a • Learn that her actions can affect things—the start of
particular action, e.g., a noise-maker cause and effect

• Brings feet to mouth and sucks on toes • Rolls over from back to stomach
• Moves by either rocking, rolling or pivoting around • Starts to learn to sit unsupported leaning on arms in
in a circle on his stomach front of him
• Sits supported for long periods (30 min) with a firm
back
• When held in standing position, stamps feet and
jumps up and down, bearing almost all weight on
legs shoulders
• Rolls from stomach to back; on tummy, pushes on
hands and draws up knees
• Create safe spaces with pillows • Learn to explore his new-found abilities safely
• Kiss your baby on each cheek and on his neck, arms, • Move various parts of his body as they are kissed,
legs, feet and learn where they are
• Hold your baby in a standing position on your lap • Enjoy practicing weight bearing with his legs
• Create games with songs that move your baby’s • Practice shifting from lying, to sitting, to standing
limbs and torso with your assistance
• Lie your baby over a tubular pillow with her arms • Strengthen her back, hips and arms in preparation
extended; let her reach for a toy while you rock her for crawling
gently back and forth • Be encouraged to reach for and burst the bubbles,
• Place baby in your lap; blow bubbles within easy much to her delight
reach of her arms or legs

• Eyes and fingers co-operate in grasping and • Transfers objects from hand to hand
manipulation and can reach target with good aim • Bangs objects on table
• Drops and picks up objects • Grasps and holds two objects at once
• Grasps object with partial thumb and forefinger
• Holds bottle with one or two hands
• Grabs or waves object with either hand


• Provide familiar soft toys in play spaces that are easy • Be more confident about grasping things
to reach and grasp • Develop the fine motor skill of picking up and letting
• Practice passing objects back and forth go, gaining more and more confidence with each
attempt
• Help him play finger games and sing songs that use • Feel more confident about what his fingers can and
finger play can’t do
• Offer your baby a number of different toys to hold • Develop the ability to grasp things of differing
and explore shapes and sizes
• Use an old plastic container or the top of a table as a • Learn that hands are not just for holding things—
drum they can help you make noise
• Make a noise maker for your baby to hold, play with • Have fun learning to pass things from one hand to
and pass from hand to hand another with confidence

Y • Use hands to bang and splash objects.
Approaching the half-year mark, your baby is • Prefer to play with people, especially games
becoming an active member of the family. At this like ‘peek-a-boo.’
stage he will: • Vocalize both pleasure and displeasure.
• Study objects for a long time, even turning
• Roll from stomach to back and over again. them upside down to get another view.

• Prefers play with people, especially co-operative • Is able to copy some facial expressions
games—“peek-a-boo”, “come and get me”, “go and • Starts to cooperate in games with others, e.g., ball
find” games, building blocks, etc.
• Tries to imitate some facial expressions
• Smiles at and enjoys patting mirror image;
differentiates self from mirror image
• Distinguishes adults from children; smiles at and
reaches out to pat children who are new to him
• Demonstrates delightful openness and friendliness
• Call out to your baby in a fun voice from another room • Begin to call out to you or get your attention when
• Read to your baby at any time she hears your voice
• Enjoy the quiet one-on-one time


• Follow your baby’s lead instead of deciding what to • Like to interact and connect with you and others
play • Begin to understand that things don’t disappear
• Play peek-a-boo with your baby when they are out of sight
• Arrange time for your baby to be with other babies with • Become comfortable with other babies
you present all the time • Feel secure with new faces in the room
• Sit with your baby in front of a mirror and point to her • Begin to see himself as separate from you
saying her name; then point to yourself saying
“mommy” or “daddy”

• Vocalizes pleasure and displeasure, i.e., squeals with • Distinguishes self as separate from parent
delight and grunts with anger • Demonstrates stranger anxiety
• Responds sometimes to the emotional tones of • Expresses nervousness or anxiety when separated
parents’ voices from parent
• Begins to quiet down on his own after getting upset • Shows attachment to special toy or object and uses it
• Displays strong likes/dislikes about food to provide comfort in the absence of someone
• Can be content to play in crib/playpen for a while familiar, e.g., may have a special toy that always
with one or two toys goes to bed with him
• Begins to communicate discomfort with strangers
• Watch to see which behaviour helps your baby • Realize what comforts him
soothe himself and encourage it • Learn to cope with his emotions
• Respond to your baby’s squeals of delight with • Use his blanket or toy to feel safe and secure
happy sounds of your own especially when you are unable to provide comfort
• Use daily routines like feeding and bathing as a time • Feel loved because you are responding to him
to play; add tickles, peek-a-boo or finger plays • Squeal some more to engage you in a conversation
• Recognize baby’s reluctance to play with strangers • Feel reassured about what to expect at these times
and not force him to do what doesn’t want to do • Respond to your emotions
• Seek your attention more
• Learn that you recognize and respect her feelings
• When you have to go out, leave your baby with the • Learn that others he is familiar with can also comfort
same person him
• Create a routine for times when you have to be away • Look to the people he knows for support and
from your baby comfort


• Makes some vowel-consonant sounds using such • Waves in response to “bye-bye”
consonants as f, v, th, s, sh, sz, m and n • Listens to own voice sounds and those of others
• Has a ‘conversation’ by babbling with family
members
• Begins to understand some words by tone of voice,
intonations and a look on your face
• Turns when he hears his name to show
understanding
• Encourage your baby to repeat an action by laughing • Love the sense of approval and will repeat an action
and clapping that pleases you
• Babble with baby! When he “talks” to you, answer • Start to learn that the noises he makes have meaning
with what you think he may be saying
• Use words that incorporate the sounds that your • Start to learn that different sounds can go together to
baby can make make other sounds

• Looks at and studies things for a long time; turns • Enjoys peek-a-boo more as she understands things
objects upside down to get another view of them are still there when they are out of sight
(example, lifts cup by handles) • Realizes he can move things, e.g., slides toy or
• Looks for family members or pet when the name is object across surface
called. • Demonstrates early problem solving, e.g., holds one
• Picks things up, shakes them, listens to sounds they block, reaches for a second; looks at third block
make when dropped; senses the relationship between trying to figure out how to grab it
her hands and objects • Rotates objects to find their functional side
• Follows path of fast moving object with eyes
• Provide a variety of containers for your baby during • Obtain sensory pleasure and relaxation from water
bath time play while practicing motor control and problem
solving
• Show your baby a favourite toy and partially hide it • Discover how objects disappear and reappear
under a scarf • Practice searching for hidden objects
• Completely hide an object under a container while
your baby is watching


• Give your baby cause and effect toys; choose toys • Learn that she can make things happen
that make noise or change when squeezed, shaken or • See and hear the results of her actions
rolled • Explore how objects move in space
• Give your baby balls to roll and blocks to stack and • Learn that he can make things happen, for example,
knock over when he knocks over a tower of blocks it makes a
noise

• Rolls from back to stomach, stomach to back • Uses protective extension, i.e., arms extended out
• Sits by himself with support either leaning forward front or to the side
on arms or propped up against a pillow; sits well in a • Holds weight on one hand when on stomach
chair • Goes from sitting to lying on tummy
• Pulls himself up from lying on his back when you • Creeps forward on tummy
grasp his hands
• Bears large amount of weight on legs and bounces
when held in standing position
• On tummy, lifts and extends legs high; may get up
on hands and knees in crouch position, to move
forward or backward or rock back and forth
• Give your baby lots of praise for each effort to roll • Feel good about your positive reaction and try to do
over or get onto her knees it again
• Lie on your back with baby next to you in the same • Feel safe and secure in attempting to roll over by
position; reach over and holding your baby’s hand, herself
gently encourage her to roll over; imitate the action
yourself and praise her efforts
• Sit your baby on the floor propped by pillows • Begin to see the world from a different view
• Prop your baby in a sitting position; face your baby • Begin to feel confident about sitting with you so
and sing simple songs like “Row, row, row your close by
boat”
• Lay your baby on a soft area on the floor • Begin to see that he can move in new and exciting
encouraging him to roll over by placing a favourite ways
toy nearby • Enjoy the physical sensation of toes being wiggled
• Play “This Piggy Went to Market” on each foot with and anticipate the tickling at the end
exaggerated facial expressions


• Reaches for objects with one hand; picks things up • Drinks from a sippy cup with help
with a raking motion; still usually holds things in the • Attempts to feed self
palm of her hand (example, holds a block skilfully)
• Uses hands to grasp, bang and splash, for example,
hold bottle, bang spoon on table
• Rotates wrist to turn objects as way of exploring
• Puts hand on breast or bottle while drinking and may
pat gently; pats and pulls at hair, glasses and face
• Follows a moving object with her eyes
• Transfer objects from one hand to the other while still
bringing hands or toy to mouth
• Offer different kinds of water toys your child can • Enjoy practicing eye-hand coordination skills
reach for, handle and put in his mouth while splashing in the tub
• Fill a large plastic container with household objects • Learn how to grasp an item and move it in space
(not small enough to fit into baby’s mouth); show her
how to take things out and put them back in
• During meal times let your baby hold an use a sippy • Learn that he can do things just like you
cup or utensil • Develop the grasp needed to hold smaller objects
• Suspend a large nerf ball in a mesh bag within such as spoons
reaching distance and show your baby how to hit the • Learn to make objects move by using either her
ball with either hands or feet hands or feet
he Amazing World of Your Baby:

T can make them do. Although she shows signs of
An Overview of Baby’s Development independence, such as trying to feed herself, the
at 7–18 Months security of your presence is still vital to help her
discover her world with confidence. She learns
Infancy is a very exciting time. You and your by doing things over and over and likes it when
baby are discovering each other and your baby is you repeat familiar songs, finger plays, stories
discovering the world. She’s learning and doing and games. She will also respond to her name by
more and more, but she still depends on you for turning and looking when you call, and will bab-
everything. As you spend time with her, you will ble sounds that are her words for certain things.
come to know her likes and dislikes, her style of The last part of infancy is a time when great
learning and her personality. In short, you’ll dis- strides are made in motor skills like walking,
cover a whole new person. climbing, stooping, even dancing. Her dexterity
By the end of the first year your baby will be is amazing. She’ll stack a few blocks, play with
an active learner, increasingly using her gross shape-form puzzles, and even scribble with a
and fine motor skills. As her coordination large crayon. She is truly becoming a social crea-
improves, her curiosity will prompt her to find ture and loves to be the centre of attention. And
out what different objects can do, and what she though she enjoys being with other children, she

is not ready to share or play with them. This is • Move either by crawling, bum shuffling, or
also the time your child will start putting sounds pivoting on the tummy
together to make words, point with her index fin- • Use her first and second fingers with her
ger to let you know what she wants and begin to thumb—even feed herself a cracker.
respond to simple requests such as “Come” or • Copy actions he sees others do, such as wav-
“Go get…”. She is ready to move to the next ing bye-bye
stage—toddlerhood. • Clearly attach herself to familiar caregivers
and want to stay close
our Baby at 7–9 Months
Y • Show intention when exploring objects to
The second half of the first year shows some understand what they do or sounds they make
remarkable new abilities. At this stage you will
notice your baby will begin to:
SOCIAL SKILLS – 7–9 months

• Plays social games such as peek-a-boo, pat-a-cake, • Demonstrates sense of control of his environment,
so-big, bye-bye and ball games e.g., extends toy to show you, but won’t give it to
• Holds hands over eyes, trying to get someone to play you
peek-a-boo • Learns to protect self and possessions
• Shows desire to be included in social interaction by • Tests parental reactions during feeding and bedtime
showing off to adults; performs for home audience • Able to concentrate other people’s actions, e.g., likes
and repeats act if applauded to watch people scribbling on paper
• Resists pressure to do something he doesn’t want to • Shows persistence and may refuse to allow himself
do, for example, no longer automatically accepts to be distracted
feeding and will push spoon away
• Copies actions he sees others do
• Intentionally points to things he wants
• Shouts for attention; breaks into the conversation
with his voice signalling emphasis and emotion
• Sing a song about looking for your baby, for • Begin to develop a sense of himself separate from
example, “Where is Marco, where is Marco, where you
are you? There you are, there you are and how do • Feel secure knowing that this hide-and-seek game
you do?” always ends with you being reunited
• Use a soothing voice and a hug and explain how to • Be reassured that you are there to help with his
take turns if your baby gets upset playing with others emotions when others are around
• Play time for your baby to be with other babies • Enjoy spending time with other babies
• Follow your baby’s lead instead of always deciding • Try to communicate to them using sounds or
what game to play gestures
• Enjoy the sense that she has control over her actions
and wishes


• Go slowly with your baby; don’t force him to go tom • Understand he can warm up to a stranger and
someone she doesn’t know or isn’t sure of approach others on his terms, e.g., he may bring out
• Play, and invite others to play, peek-a-boo with your lots of toys so the attention is on the other person
baby and not on him
• Understand that you and others are still there even
when you can’t be seen
EMOTIONAL SKILLS – 7–9 months

• Feels strongly about what she does or does not want • Shows clear like or dislike for certain people, objects
to do or places
• Laughs because she has discovered she can laugh • May be more sensitive to other children and will cry
whenever she wants if they cry
• Looks worried when she hears a loud noise, such as • Begins to evaluate people’s moods and motives
a balloon popping or the vacuum running or when
someone speaks in a very stern voice
• Displays fear of separation, i.e., is clearly attached to
familiar caregivers, follows and wants to stay close
to them
• Expresses fright, i.e., is frightened by new
experiences, new people and will fuss or cry if you
look or behave differently
• Watch to see what behaviour helps your baby soothe • Realize what comforts him
himself, and encourage it • Learn to cope with his emotions in his own way, for
• Make sure you or someone familiar always responds example, using a special blanket or toy to feel safe
to your baby’s “calls” for help and attention and secure if you are unable to provide comfort
• Learn that she can depend on you
• Learn that others can provide emotional support too
• Play some exciting, physical games that energize • Learn how to become excited, and to calm down
your baby, without making him anxious again
• Play one-to-one games like showing baby his eyes, • Trust that you and others won’t push him beyond his
nose and mouth in a mirror limits
• Enjoy spending time with you
• Show his feelings by making faces and body
movements


• Tell your baby about the routine, for example, “I • Feel safe, secure and respected as an individual
need to change your diaper; let’s take a toy for you • Begin to learn what’s happening next; this helps
to play with while we do this” control her emotional reactions
• Create routines for all regular activities, like
changing, bedtime, feeding or playtime
LANGUAGE SKILLS – 7–9 months

• Says several sounds like ma, mu, da, di, and ba all in • Shows understanding of words through appropriate
one breath as well as multi-syllabic babbling, e.g., behaviour or gesture
da-da-da or ga-ga-ga • Labels an object in imitation of its sound, example,
• Recognizes some words; shows excitement when she train—choo-choo or dog—woof
hears “bottle” or some other familiar word; looks • Has adult intonation when babbling
toward mommy when asked, “Where’s Mommy?” • Listens selectively to familiar words and begins to
• Can do simple things when asked, for example, recognize some
“Show me the ball” or “Wave bye-bye” • Knows what ‘no-no’ means
• Turns to listen when she hears familiar sounds like
the telephone or her name
• Uses special words meaningfully, example, dada and
mama as specific names
• Copy your baby’s actions, e.g., clap if he claps • Feel his actions are important
• Want to try other actions to get you to do the same
thing
• Start to take turns
• Use baby’s name in familiar songs for example, • Recognize her name and feel pleasure hearing it in a
“Farmer Brown” becomes “Farmer Shiv” song
• Try to imitate you singing the song
• Practice using her name
• Respond to your baby’s babbling sounds by making • Know that you are interested in what he says
the same kinds of noises • Feel encouraged to babble on

INTELLECTUAL SKILLS – 7–9 months

• Recognizes size of objects by reaching for small • Shows problem solving by using another object to
object with finger and thumb and large object with get the one she wants, e.g., pulling a string
both hands horizontally to pull toy closer or holds onto two
• Distinguishes near and far objects and space objects and reaches for a third
• When exploring objects, demonstrates understanding • Realizes size differences between objects
of what they do or what sounds they make, e.g., she • Begins experimenting with familiar behaviours, e.g.,
bangs a block on the floor, shakes a noise maker imitating people when they’re out of sight and
harder, purposefully pushes buttons on toy, or hits a earshot; will imitate a new gesture
rubber toy to make it squeak • Starts to combine known bits of behaviour in new
• Searches for an object when it is taken away but only ways
in the place where it first appeared • May associate picture of baby with herself, and
• Continues to experiment with things she can do with make a sound of recognition
one side of her body, then the other
• Understands meaning of ‘in’ and ‘out’, demonstrated
by dropping several large beads in a cup or bowl,
dumping them out, and repeating the game over and
over
• Help him calm down when he is upset • Be better able to soothe and calm himself over time
• Play a game in which you and your baby copy each • Learn how to watch and copy an action
other’s simple actions like clapping, shaking a toy, or • Learn that she can make an adult follow her lead
blowing a kiss
• Give your baby different objects to play with in the • Enjoy the relaxing feel of the water while learning
bath, e.g., different sized containers about volume, quantity and other mathematical
concepts
GROSS MOTOR – 7–9 months

• Balances himself while sitting; sits alone steadily for • Makes stepping movements
longer periods without holding on; sits and bounces • Stands holding on to your hands; held standing, puts
on his buttocks one foot in front of the other
• Pushes up on hands and knees and rocks back and • Uses protective extension of arms to keep from
forth; sits up by pushing up from crawl position with falling backwards
arms at side • Lowers himself to sitting from standing, holding on
• Crawls with an object in one or both hands; may to supports
also move by “bum” shuffling or turning in circles • Crawls up stairs
on stomach • Takes side step holding on to furniture (called
• Helps out when you pull him to stand; sometimes cruising)
pulls himself up using furniture; stands firmly on his
legs when held in standing position


• Play on the floor and put some distance between you • Start to explore her environment more actively
and your baby; encourage her to move toward you • Know that she can reach you even when there is
• Holding your baby’s hands, go for a walk some space between you
• Get down to his level and play hide-and-seek in a • Gain confidence in her legs and know she is safe
safe, small area of the house trying something new because you’re right there
• Put objects a bit out of reach but don’t frustrate him • Begin to feel more independent while feeling loved,
safe and secure as he always finds you
• Be encouraged to exert new independence and
reward herself by getting object without help
• Sit your baby on the floor near steady, firm furniture • Learn to pull herself up to standing position
so she can pull herself up onto her feet (make sure • Learn to use her body in a new way
corners of furniture are protected) • Know she is safe because you are right there
• Safely support your baby under the arms to help her
to climb up a few steps
FINE MOTOR – 7–9 months

• Grasp is more refined; progresses from holding • Removes pegs from pegboard
things in palm to using thumb, first and second • Is able to throw objects
fingers • Builds tower of two blocks
• Rakes at tiny objects and picks up shoe laces, cereal • With index finger, pokes fingers into holes or
or crumbs with thumb and forefinger anything that looks interesting
• Drops objects unintentionally and then looks for • Takes objects out of container purposefully
them • Releases objects voluntarily
• Feeds self some finger foods such as a cookie or
cracker
• Picks up, holds and manipulates an object, in each
hand simultaneously; bangs objects together at
centre of his body
• Explores objects by grabbing, shaking, sliding and
banging
• Provide finger foods for snacks and meals • Begin to feel independent as he starts to feed himself
• Roll the ball back and forth on the floor with your • Learn how two people can enjoy a turn-taking game
baby in sitting position


• Create noise makers using plastic bottles that your • Learn that her actions cause things to happen
baby can grasp and shake (see Activity Centre) • Learn to control finger movements
• Use finger plays with your baby such as the “Finger
Family” (see Activity Centre, songs)
• Give your child a container and objects to pick up • Further develop his ability to grasp and release
and place into the container objects
• Give your child blocks to stack up and knock over • Explore how objects can be moved in space
• Experience the effects on her motor skills
our Baby at 10–12 Months

Y • Repeat sounds or gestures if laughed at.
The last months of your baby’s first year are a • Display affection with hugs, kisses and pats.
time full of wonderful new accomplishments. • Understand simple sentences and requests like
Now your baby will start to: ‘Where’s your shoe?’
• Realize that things are still there, even when
• Walk while holding onto furniture. they are out of sight.
• Pinch fingers neatly to pick up the smallest
items.

• Knows when parent approves or disapproves of • “Dances” to music
behaviour • Shows familiarity with rituals and routines of the
• Tries to help when being dressed, for example, by day; knows what comes next
putting arms out for sleeves or feet for shoes • Experiments with ways to get attention; enjoys
• Loves to shake head and say ‘no’ even when he being centre of attention
means ‘yes’ • Responds to requests, e.g., generally gives up toys
• Imitates adult movements and movements and play on request
of other children
• Repeats sounds or gestures if laughed at
• Distinguishes self from others
• Describe feelings; put words to your baby’s • Feel you are responding to his feelings
expressions, for example, when your baby is crying, • Begin to recognize some of the words used to
say “Ling is feeling sad,” and respond appropriately describe feelings
• Create a routine for daily events and talk about it • Feel comforted by your response
before it starts and as it is happening, example, “It • Feel safe and secure because he knows what’s
will be bath time soon,” then let him help to get happening next
things ready


• Look at family photos and talk about what the • Start to put names with people’s faces
people in the pictures are doing • Try to say some of the names
• Provide a safe place where your baby can crawl and • Communicate his interest in objects around him by
explore gazing, reaching or pointing
• Talk to your baby about upcoming events, for • Learn about what is happening and how that affects
example, mommy’s or daddy’s return to work from her
parental leave

• Is able to seek comfort when upset, i.e., reaches up • Negativism increases; refuses eating a meal, new
to be held foods; resists napping; may have tantrums
• Expresses many emotions and recognizes them in • Displays independent behaviour; resists adult control
others, e.g., sad, happy, mad, scared, hurt, discomfort • Communicates specific preferences for certain
• Feels guilty when he does something wrong people and toys, e.g., crying, laughing
• Will communicate his need to be in constant sight • Able to communicate discomfort when fearful or
and hearing of an adult stressed; may express new fears and insecurity with
• Displays affection in hugs, kisses, pats and smiles situations he was fine with before
• Turn everyday routines into playful moments by • Feel loved

adding tickles, giggles and fun interactions • Look forward to daily routines because she enjoys
• Ask your baby for hugs and kisses fun times with you
• Feel very loved
• Be encouraged to respond to happy actions
• Provide opportunities to play with other babies • Enjoy the company of other babies
• Try out ways to communicate and engage with other
babies
• Look at magazines or books with pictures of people • Begin to label emotions

expressing different emotions; talk about how that • Enjoy looking at books
person is feeling; be sure to use common emotions
such as happy, sad and mad


• Understands simple sentences, questions and • Responds to simple verbal requests
requests, for example, ‘Give the book to me,’ ‘Find • Uses expressive vocabulary, 2–8 words, like ‘no’,
your ball’, ‘Where’s your shoe?’ ‘baby’, ‘bye-bye’, ‘hi’ and words that imitate sounds
• Learns words and appropriate gestures like saying of objects, i.e., bow wow
‘no’ and shaking his head, saying ‘bye-bye’ and • Uses a single word to express a whole thought
waving, also exclamations such as ‘oh-oh!’ • May not talk as much while mastering walking
• Starts to anticipate when a surprise happens in a
song
• Take turns making sounds with you
• Sing familiar songs as often as possible • Attempt to imitate the words or actions
• Encourage your baby to make music and dance with • Love making noise, hearing rhythm and moving her
shakers, pots and pans body in time to music
• Label everything in your baby’s world • Learn the names of common objects

• Searches for object if he knows it is hidden, e.g., lifts • Enjoys looking at pictures in books
inverted cup, looks in box for toy or unwraps toy • Points to correct parts of the body when asked
• Tries out new actions for same goal; modifies old where they are
ones through trial and error • Knows that smaller objects fit in larger ones
• Associates actions and sounds with things for • Searches for hidden object, whether he remembers it
example, meows for kitten, points up when he sees a was hidden or he hasn’t seen it hidden
bird • Able to match shapes, e.g., places a cylindrical
• Is aware of his own actions and some of their object in a matching hole in a container
implications; compares same action done with both • Repeats an action that gets a reaction, such as
sides of his body knocking over blocks
• Develops stronger memory skills
• Use encouraging words such as “good for you” • Develop feelings of self-confidence, independence
and a sense of power and satisfaction
• Play a game in which you and your baby take turns • Learn to watch and copy an action
doing simple actions, e.g., clapping, blowing a kiss • Learn that she can make an adult follow her lead


• Provide a variety of interesting objects and boxes or • Explore the objects and begin to have an
containers for baby to explore, e.g., cereal boxes, understanding of functions and dimensions (size and
yogurt containers, sponges, etc. shape)
• Attach a toy by an elastic to your baby’s highchair • Begin to look for the object when he throws it off
the tray; learn he can get it back by pulling on the
string

• Turns in a circle when sitting—twists to pick up • Walks with one hand held
objects • Squats down, stoops, bends over, then gets up
• Stands by flexing knees, pushing off from squat • Crawls up and down stairs
• Walks while holding on to furniture • Walks alone 2 or 3 steps
• Walks when you hold both hands • Plops down when moves from standing to sitting
• Crawls up stairs position
• Crawls on the floor expertly
• Provide lots of encouragement when baby tries to • Be motivated to keep on trying

stand holding onto furniture • Feel more confident about taking steps and feel
• Go for walks in the park or yard and give your baby secure with this new way of moving
the chance to practice walking with your support
• Roll a ball back and forth between you and your • Learn to coordinate eye and hand movements for
baby bigger actions such as pushing, pulling, throwing
• While playing on the floor, place some of his • Learn to move confidently in different directions
favourite toys around him far enough away so he has from the sitting position while reaching for objects
to reach to get them; praise him when he is of interest
successful
• Supporting your baby from behind or by holding her • Learn to crawl up steps with a sense of security
hand, practice going up a few steps knowing you are there if she falls
• Once your baby can pull himself up holding onto • Feel your physical and emotional support as he
furniture, encourage him to hold on with one hand; practices standing freely and learns that if he falls he
urge him to let go once he’s comfortable; position can get right back up
yourself close by in case he falls


• Uses neat pincer grasp (tips of index finger and • Uses both hands freely—may show preference for
thumb) to pick up small items one
• Puts objects in and takes them out of container • Pulls off socks, hats
• Points, pokes, touches and pries with extended index • Holds crayons, makes marks
finger • Builds tower using two cubes
• Places one block on top of another without balancing • Points with index finger
• Voluntarily releases objects to another person on • Feeds self with spoon and drinks from a cup
request
• Holds spoon but needs help with its use
• Place finger foods on your baby’s plate or tray and • Feel more confident and encouraged to use her
show her how to pick them up fingers to pick up the food
• In a safe place on the floor, use soft building blocks • Learn about what is involved in stacking objects
to make a tower; show her how to pick up one block • Feel confident about how to pick up and let go of
and place it on top of another objects
• Create a safe space in the kitchen with lots of • Enjoy putting things inside of one another and
different sized plastic containers and bowls seeing how they fit
• Together with your baby, sing songs and fingerplay • Learn to move his fingers with greater control
that encourage him to move his fingers • Feel loved and secured playing with you
• Introduce your baby to cause and effect toys that • Learn that she can control things in her environment
require her to do something to hear noise or see
action
our Child Between 13 and 18 Months

Y • Turn pages of a book.
Your baby’s second year of life brings new skills • Show a sense of humour.
for a different perspective on the world around • Identify herself in the mirror or photograph.
her. At this stage your baby will begin to: • Realize that things are still there, even when
they are out of sight.
• Push and pull toys while walking.
SOCIAL SKILLS 13–18 months

• Points to show you something • Names pictures in a book
• Understands far more words than can speak, e.g., • Imitates animal sounds
can point to at least three different body parts when • Uses own name to refer to self
asked, “Where’s your mouth?” • Follows simple directions without gestures, e.g.,
• Uses “no” correctly, often with a shake of the head “Come, show me, go get, etc.”
• Uses five or more words to express needs, desires or
expressions such as “all gone”
• Tries to sing songs


• Use your child’s relaxed bath time to name parts of • Learn to point to different parts of the body by name
her body
• When dressing your child, hold up his socks and say, • Practice matching words to the different parts of his
“Socks go on your feet. Show me your feet.” Repeat body as well as developing a positive sense of self
using other clothes and body parts and body image
• Count things together in books and find the same • Match real objects with those that she sees as
objects in your home two-dimensional in print

• Is more confident, exploring and trying new things, • Shows jealousy when attention is given to other
taking risks when a trusted adult is present or has family members
provided reassurance • Shows frustration easily
• Shows particular interest in a music tape, special • Displays a sense of ownership over toys and people
picture books or fish in a tank
• Identifies self in mirror or photograph; becomes
more of an individual
• Hugs and kisses parents and other very familiar
people and pets
• Enjoys being the centre of attention
• Encourage your child to safely explore his • Explore his environment in a self-directed way
surroundings, e.g., cupboards • Develop a sense of competence and feeling that he
• Give your child many opportunities to feel can influence others
successful, e.g., play a game that he has initiated or
allow him to take off his shoes
• Use stories, songs or toys (teddies) to explore • Express emotion in response to what she sees or
feelings hears
• Provide opportunities for your child to play on her • Learn to be self-reliant for small periods of time
own


• Teach your child simple words to express his • Learn to connect words to how he feels
feelings, e.g., “I’m sad, I’m tired” • Become better prepared to deal with any changes
• Inform him when a routine will be different and and lessen his anxiety
what will be happening
LANGUAGE SKILLS 13–18 months

• Begins to show sense of humour • May be able to cooperate at times but may not
• Plays best on her own; doesn’t want to share toys, respond quickly or will do the opposite of the
shouting, “Mine, mine” or fights with another child request
over who gets to use a specific toy • Plays alongside and parallel to another child
• Enjoys imitating adult task, example, dusting, • Tries to dress/undress himself, e.g., pull up pants,
sweeping floors, setting the table, raking lawn, etc. undo Velcro shoe fasteners
• Strongly resists limits you set
• Looks at you when you are talking or playing
together
• Have good-bye routines when you and family • Be comforted by these routines which mean that
members leave each other people always come back
• Give your child the opportunity to partake in some • Enjoy imitating an adult task while feeling a sense of
daily chores, e.g. emptying the laundry basket, independence
putting food in cupboards
• Provide regular opportunities for your child to play • Begin to learn the give and take that comes with
with other children her age being in a social group
• Introduce make-believe toys such as dolls with • Enjoy recreating familiar actions she has
accompanying props, e.g., small bottle, blanket, experienced herself
cradle or stroller
• Share a toy with your child, taking turns with it • Begin to learn what’s expected when he plays with
• Use “Yes” and “No” to clearly set limits and explain others
why; always respond warmly • Begin to understand what actions are acceptable or
not acceptable


• Realizes things exist when they are out of sight • Groups similar things, such as socks, shoes
• Shows understanding of some colours and shapes, • Engages in imaginative play during daily routines
e.g., matches circles and squares on a form board such as feeding, putting to bed or bathing dolls
• Identifies pictures when requested, e.g., “Show me” • Uses playdough and paints
or “Where’s the ___?”
• Gains new understanding of the world around him
while exploring the environment by looking for
something to fit in holes; mix, fill, pile and dump
sand at the sand table; stack, knock over or restack a
set of boxes, blocks
• Shows increased memory skills
• Read board books and look at pictures with your • Learn to point to different parts of the body by name
child
• Watch your child’s cues to learn the things he likes • Take the lead in playing or doing things she enjoys
to play with
• Offer a toy with wheels that can be pulled by a • Begin to understand cause and effect
string; encourage her to watch what happens when
she pulls the string

• Walks alone • Walks down stairs holding rail—both feet on step
• Crawls or walks upstairs one step at a time holding • Tries to kick a ball
onto banister or hand • Likes to ride toys
• Pushes and pulls toys while walking • Likes to run, but falls and bumps into things
• Squats to pick up toy without falling • Walks backward
• Climbs on things by himself, for example, chairs,
sofas, tables or out of cribs, high chairs, strollers
• Stay close and supervise your child in the park • Feel safe while exploring and testing out new motor
• Safety proof the house skills
• Feel confident playing and exploring at home


• Take your child to the park or playground often • Take every opportunity to practice walking,
• Play favourite music/songs and encourage her to climbing, jumping and running skills
move to the music • Have fun swaying legs, body, arms and head to
different rhythms
• Arrange an obstacle course in a room so she can • Learn how to move her body through space
crawl through a box, under a chair, over a big pillow, • Feel the difference in weight; learn how to hold each
etc. one (one hand or two), to throw or roll the balls
• Offer your child balls of different sizes

• Releases object to other person on request or gesture • Feeds self with spoon and fork
• Picks up and eats finger foods, e.g., raisin, cheerio, • Throws ball forward
cracker, etc. • Begins to unlatch, unscrew, open and take apart
• Turns container upside down to get an item out • Squeezes, pokes, and pats playdough
• Puts pegs into a pegboard • Copies simple lines drawn on paper
• Turns pages of a book
• Stacks three or more blocks
• Scribbles with a big crayon
• Give your child the opportunity to feed himself • Practice independent, self-help skills and be proud of
finger foods at meal times newly emerging abilities
• Spend time reading picture books with your child • Use small muscles in his fingers to turn the pages
and set the pace of your time together
• Offer your child plastic bowls she can either stack or • Practice independent, self-help skills and be proud of
put one inside the other newly emerging abilities
• Provide big crayons and lots of paper • Use small muscles in his fingers to turn the pages
and set the pace of your time together
• Provide pots and lids to encourage finding matching • Enjoy making noise with the pots and lids while
sets beginning to appreciate different sizes of objects
• Help your child to solve a simple jigsaw puzzle with • Explore how things fit together using his new fine
one or two large pieces motor abilities

he Remarkable World of Your

T tasks such as large puzzles, taking lids off jars,
Toddler: An Overview of Your using a fork, pulling off shoes and socks and
Toddler’s Development at building bigger and better block towers. Language
19–24 Months is exploding at this time, even though his favou-
rite word is “No!” When he talks, you should be
The toddler stage is a hugely exciting time, as able to understand him about half the time. And
parents begin to get a real sense of their child’s more and more, he will express his feelings,
personality, especially with their toddler learn- interests and needs in words.
ing to do so many things. Your child will try to
be independent but will still be a bit scared of it our Toddler Between 19
Y
all. At this stage, it’s common for him to cling to and 24 Months
you 1 min, afraid you will leave, and then want Your toddler is entering a new and exciting stage
nothing to do with you the next. These sudden of life. In this first stage, he will start to:
shifts of emotions, tantrums and bouts of help-
lessness are all part of his becoming his own • Kick a ball.
person. • Take off shoes, socks and hats.
By 24 months, many toddlers play on their • Show ownership or possession of objects.
own, use their new motor skills to run, kick balls, • Show fear, but is able to be settled down.
jump and climb. They also can tackle fine motor • Use two word sentences such as ‘More juice.’

• Enjoys playing alone for a few minutes, e.g., • Distinguishes herself as a separate person, contrasts
building blocks, drawing, looking at books herself with others
• Shows ownership or possession of objects and • Begins to be toilet trained
cannot share easily • Puts on simple clothing without help
• Says ‘no’ and likes to do things without help
• Helps with simple household chores
• Use everyday routines (e.g., walks, meal times) as a • Learn the words to use when talking about feelings
time to talk about family and friends • Feel comforted and supported to see there are ways
• Follow your child’s lead rather than direct the play; to deal with her emotions
suggest things, but let your child decide what she
wants to do
• Look at photos of family events so your child can • Begin to associate certain emotions with behaviours
find himself and identify family members • Begin to see what can make others sad, happy, angry,
• Set up a water play activity with another playmate; etc.
give them dolls, sponges, and towels


• Prepare your child ahead of time for new social • Know he can rely on you to help him cope with his
events, e.g., “At playgroup we will sing songs and emotions
listen to stories” • Begin to develop some strategies to deal with his
• Let your child help with chores, e.g., wiping spills, emotions
putting clothes in drawers

• Beginning to develop a range of emotions; is subject • Uses words such as “NO” a lot
to mood swings and tantrums; shows some • Shares a piece of food
aggressive tendencies, e.g., biting and hitting • Familiar with routines and the order of the day; is
• Shows concern for others unhappy about any changes in routine and likes to do
• Shows fears, but can be settled down things the same way each day
• Is pulled between the need to show independence • Develops a sense of comfort or fear with different
and still being dependent for certain things experiences and objects, e.g., fear of the dark
• Still cautious around unfamiliar adults i.e. allows
self to be drawn into play with a new adult as long as
a familiar person is nearby
• Recognize and name your child’s emotions, e.g., • Learn the words to use when talking about feelings
“Your crying tells me you are sad” • Feel comforted and supported to see there are ways
• Suggest ways to deal with her feelings, e.g., “When to deal with her emotions
you feel angry, come and get a grown-up for help”
• Sing songs that use emotion words, e.g., “If you’re • Begin to associate certain emotions with behaviours
happy and you know it, clap your hands” • Begin to see what can make other sad, happy, angry,
• Read stories that explore different emotions and etc.
discuss them simply from the character’s perspective
• Notice when your child is frustrated and step in to • Know he can rely on you to help him cope with his
help him deal with his emotions emotions
• Offer your child different choices to help him cope • Begin to develop some strategies to deal with his
with his feelings emotions


• Uses two word sentences, e.g., “more juice” or • Sings simple songs with correct words and actions
“want cookie” • Is more articulate; many more words are understood
• Asks for help using words or actions by others outside the family
• Jabbers in run-on flow of words while talking to • Starts to use plurals
stuffed animals or self • Uses past tense
• Names some pictures in a book Imitates spontaneously or repeats new words
• Imitates new words and phrases, e.g., “Go bye-bye”
and “Mommy’s car”
• Read books to your child that reflect her reality, e.g., • Begin to recognize common events and situations in
starting child care, going to the doctor, playing with printed materials
another child
• Count fingers, toes, eyes, ears, mouth and nose • Develop a strong sense of physical self, and learn
during bath or play time numbers and words for body parts
• Point out familiar sounds when walking or playing • Begin to distinguish different sounds and learn the
outside, e.g., car horns, dogs barking or fire truck names for them
sirens

• Understands how familiar objects are used, e.g., • Explores one-to-one correspondence
spoon for eating, cup for drinking, ball for throwing, • Has a sense of more than one
hammer for banging, etc. • Has intense curiosity to investigate any new person,
• Understands the passing of time and the meaning of object or sound
“not now” and “when we go home” • Understands two-part requests, e.g., “Go to the shelf
• Recognizes and names familiar people in photos and bring over the blocks”
• Busy mastering existing skills which leads to the
emergence of new ones
• Shows increased memory for details and routines,
e.g., says “hot” when reaching for a coffee cup;
holds up seat belt in car seat to indicate it needs to be
secured; remembers where objects go
• Follow your child’s lead in play, allowing her to be • Begin to develop a sense of control about what she
the director of the activities does and feel that you value her efforts


• Count fingers, toes, eyes, ears, mouth and nose • Develop a strong sense of physical self
during bath or play time • Explore relationships of size in objects as well as the
• Provide different size containers for water and sand concept of empty and full
play
• Offer experiences that allow him to use his skills but • Feel confident enough to try to overcome the
challenge him a bit, e.g., if he can stack three blocks, challenge
add a fourth

• Takes lids off jars • Opens doors by turning knobs
• Fits cups and boxes inside each other (nesting) • Imitates horizontal or circular strokes with a crayon
• Takes off shoes, hat and socks • Snips with scissors
• Strings large beads, using one hand to slide the bead • Folds paper in half
while the other hand holds the string
• Raises and drinks from a cup then replaces it on
table
• Allow your child to undress as much as she is • Feel independent while practicing eye-hand
capable of coordination
• Provide lots of containers during bath time • Enjoy the sensory pleasure of pouring water in and
out of containers repeatedly
• Provide large beads or buttons with a shoelace or • Practice the fine motor coordination sequence
string for beading required for inserting, threading and pulling
• Offer simple from boards or shape sorters (no more • Use his eyes and hands to practice distinguishing
than three shapes) differences of shapes, such as circles, squares and
triangles
• Help your child make pictures using stickers; talk to • Practice the two step process of peeling/lifting the
her about what she is doing sticker off and placing it somewhere on the paper
• Invite your child to open and close few plastic • Use fine motor skills to put on lids
containers in your kitchen • Display very preliminary use of trial and error to find
solutions


• Rides on small wheeled toys • Walks on tip-toes
• Carries a large toy while walking • Throws and retrieves objects
• Kicks a ball • Jumps in place with both feet
• Squats while playing • Catches a large ball
• Walks backwards or sideways pulling a toy
• Backs into chair to sit down
• Provide child-sized furniture • Feel more in control if he can sit in a small chair and
• Provide child-sized versions of adult things, e.g., at a small table to do his activities
soccer ball • Feel like he can do really important things with his
body
• Provide your child with toys that allow her to push • Practice climbing on and off ride toys and learn to
and pedal with her feet coordinate her eyes, feet and hands
• Pretend you are at the zoo and ask your child to • Practice and refine new motor abilities
move like animals, e.g., hop like a frog, squat like a
bird, jump like a rabbit
• Describe your child’s movements and actions as he • Learn to label his own actions and begin to
climbs the stairs, jumps over an object or crawls understand words related to position (i.e. up/down,
under a chair over/under, through)
• Play different kinds of music for your child to dance • Respond creatively by inventing his own movements
to (e.g., march, rock ‘n’ roll, waltz) and physically interpret the mood and speed of
music
he Remarkable World of Your

T lessness are all part of his becoming his own
Toddler: An Overview of Your person.
Toddler’s Development at In the final phase of toddlerhood, your child’s
25–36 Months mental abilities show dramatic growth. He explores
the more abstract concepts of shapes, colours, size
The toddler stage is a hugely exciting time, as and quantity by playing with puzzles, paints, water
parents begin to get a real sense of their child’s and sand, and, of course, books. He may be able to
personality, especially with their toddler learn- match objects, sort clothing, count and tell the dif-
ing to do so many things. Your child will try to ference between “one” and “many.” Although he is
be independent but will still be a bit scared of it more sociable now and enjoys playing with other
all. At this stage, it’s common for him to cling to children, he is still not great at sharing or cooper-
you 1 min, afraid you will leave, and then want ating. These days, your toddler is spending a lot
nothing to do with you the next. These sudden of his time building confidence and self-esteem,
shifts of emotions, tantrums and bouts of help- ready to enter the world of the preschooler.

our Toddler Between 25

Y • Scribble, clutching the crayon in her whole
and 30 Months hand.
As she starts into her third year, you will notice • Show she can be attached to a cuddly or favou-
some dramatic achievements. For example, your rite toy.
toddler will start to: • Express feelings through language and pre-
tend play.
• Walk upstairs and downstairs alone, with both • Better understand the similarities and differ-
feet on one step. ences of shapes and sizes

• Establishes self as separate from parents, saying, • Helps put things away
“No! Me do it!” • Approaches new person after you have talked to
• Displays shyness around strangers and in outside them
situations • Begins to show more readiness for co-operative play
• Likes to play near other children but not yet able to • Is more able to wait patiently for needs to be met by
play co-operatively others
• May pull hair, hit or bite other children when • Knows own gender, and that of others
frustrated
• Becomes aware of gender differences
• Praise everyday experiences and encourage positive • Know you notice her and develop a feeling of self
behaviour worth
• Provide safe opportunities to assert independence • Know she is a separate person but that you are there
• Read stories to your toddler about ways people care to help her if needed
about each other • Begin to understand the actions that go with caring
and how to get along with others
• Provide opportunities to go to the park and play in • Feel a sense of belonging in a group
the sand with other children • Begin to develop social skills and become more able
• Invite one peer over to play for a short time to play with others one on one
• Encourage your toddler to play with his dolls and • Begin to practice caring for the needs of another
pour them drinks
• Share a quiet activity together, such as reading a • Feel valued because you made time for her
book • Begin to learn positive ways to interact with other
• When conflicts occur, explain how her behaviour children and to problem-solve
makes the other person feel • Develop important social skills while doing a
• Encourage taking turns adding ingredients when soothing and enjoyable activity
making playdough together


• Moves back and forth between wanting • Separates more easily from parents
independence and needing security of parents • Responds to other children’s feelings and begins to
• Can still be attached to a cuddly or favourite toy show empathy
• Demands his own way much of the time • May develop sudden fears
• Needs an ordered, predictable routine (e.g., when • Displays frustration and tantrums if he is not
saying good-bye to parent in the morning) understood
• Expresses feelings through language and pretend • Becomes less upset by limits and discipline
play (e.g., roaring like an angry lion)
• Model coping with emotions, such as talking • Feel comfortable expressing his feelings
through frustrating problems with your toddler, • Be more likely to recognize emotions in other
using words like, “This makes me feel sad/happy” children and adults
• Move your toddler to a quieter place when he is • Learn strategies for dealing with emotions
having difficulty coping with his emotions • Learn more acceptable coping skills
• Provide the chance for pretend play with dolls and • Express different emotions through toys
teddies in order to experiment with emotions • Begin to understand that he is a separate person from
• Give your toddler many opportunities to “do it you
myself;” offer times to practice getting dressed or • Develop the ability to understand another person’s
helping with household tasks emotions and what might have caused them
• Read books that illustrate how children or animals
experience a range of emotions like jealousy, anger,
affection
• Encourage your toddler to understand how others • Begin to develop empathy and sympathy
may feel in situations • Begin to be aware of the feelings others may have
• Help her understand how her behaviour may have an • Begin to understand how other children might feel in
impact on others certain situations
• Watch education programs on television and point • Enjoy being with you and talking about an imaginary
out the kinds of emotions characters are feeling character

• Uses “self-centred” pronouns like ‘I’, ‘me’, ‘mine’, • Is able to use words that describe things, e.g., big,
‘you’ dirty, wet, hot
• Puts together simple, two-word sentences • Participates more in conversations and stories
• Answers simple questions like, “What’s your • Is able to provide more information about self (e.g.,
name?”, and performs simple tasks when asked to name, gender, age) and understands two-step
• Enjoys looking at books and talking about the directions
pictures • Can recite a few simple nursery rhymes
• Sings parts of songs • Using plurals in a general way (e.g., foots not feet)


• Provide opportunities for your toddler to talk about • Know that you are interested in what he has to say
things that he finds interesting and will want to converse with you
• Let your toddler fill in the blanks while singing a • Enjoy singing important words on her own
song
• Keep expanding language by adding more new • Develop confidence in the use of many words and
words and descriptions about events in your toddler’s feel secure enough to try new words
day

• Engages in simple pretend play with others • Sorts groups of objects into sets
• Matches shapes, pictures, some colours • Completes simple puzzles
• Can better understand the similarities and differences • Combines toys and games in more complex ways
of shapes and sizes (e.g., uses playdough in dramatic play
• Becomes aware of verbal sequence of numbers • Begins to understand the concept of future time, e.g.,
• Shows increased attention span, staying with ‘soon’, ‘in a long time’, but not past, e.g.,
activities longer ‘yesterday’
• Begins to understand one-to-one actions, e.g., one
plate per person
• Incorporate numbers and counting into daily • Begin to understand that numbers are a part of his
routines, such as tidying up toys or putting away tin everyday environment
cans • Observe how dry ingredients change in texture
• Make playdough with your toddler through the process of cooking
• Incorporate counting into child-initiated activities, • Begin to recognize and correctly repeat numbers;
such as block building, for example, “Let’s count may only count to 4 with confidence
how many blocks you used in your tower” • Enjoy working with you to solve problems
• Provide different sized jars and lids and, together,
find out which ones match


• Offer experiences for your toddler to sort objects, for • Experiment with sorting, such as the big blocks in
example, all the puzzles in this box, crayons in this one pile, little blocks in another
tin • Compare the different sizes and shapes of objects he
• Play with playdough using different tools, cookie creates
cutters, rollers and so on

• Scribbles, holding the crayon in whole hand • Begins to use thumb and fingertips when holding
• Imitates drawing vertical and horizontal lines crayon
• Builds a tower of five or more blocks • Imitates drawing a cross, copies a circle
• Strings beads, picking them up with thumb and • Folds paper
forefinger • Uses small scissors to snip paper
• Removes lids from jars, rotating wrist • Removes clothing already unbuttoned; pulls up
zipper
• Praise your toddler’s drawing efforts and describe • Know your are interested in his creations and feel
the markings you see encouraged to draw more
• Provide your toddler with chances to practice • Develop confidence in his ability to dress himself
dressing skills, helping with buttons and zippers • Enjoy the soothing feeling as he squeezes, pinches,
• Make playdough with your toddler and create rolls, pats and shapes the dough
different shapes together
• Make necklaces together using beads, cut up straws, • Strengthen her ability to pick things up using thumb
bits of paper with holes punched in them and forefingers (pincer grasp)
• Supply your toddler with costumes for pretend play • Practice dressing skills as she engages in an
including hats, shoes, coats, pants imaginative activity
• Provide many art materials including markers, • Become more able to control these materials as she
crayons, paint and chalk scribbles and copies lines and shapes
• Provide your child with tongs and various items to • Practice the grasp he will be using to cut with
sort onto different plates scissors
• Provide puzzles of different sizes and colours, and • Learn to use his grasping skills, problem-solve and
different numbers of pieces complete tasks he started
• Invite your toddler to help with simple cooking jobs • See how his growing skills can be used to help other
like ripping lettuce or stirring with a spoon people


• Walks backward and sideways • Walks on narrow balance beam
• Walks upstairs and downstairs alone, both feet on • Walks upstairs and downstairs, alternating feet,
one step holding the handrail
• Runs without falling • Runs, avoiding obstacles
• Jumps in place, both feet off the floor • Jumps forward
• Climbs on a riding toy and makes it go using both • Pedals a tricycle
feet at the same time
• Join in pretend play and move with your toddler, • Know that you enjoy playing with her and will be
jumping like mother and baby frogs, slithering like able to practice different actions by using his
daddy and baby snakes imagination
• Praise your toddler’s efforts when she runs at the • Develop confidence in her ability to test her physical
park or goes down the slide abilities
• Do knee bounces like “To Market, To Market” • Enjoy being cuddled while you bounce and giggle
together
• Play different music and encourage your toddler to • Make comparisons between each movement and
explore different movements like jumping, rolling, learn to match them to different music styles, speeds
stretching, marching and walking • Be able to practice coordinating arm movements and
• Set up some plastic bottles for bowling pins so your aiming a ball
toddler can knock them down with a ball • Be able to explore different movements like flying,
• Play “Sleeping bunnies,” substituting different galloping and stomping
actions and creatures like birds, horses and elephants
• Play simple movement games where your toddler • Learn several concepts through movement like stop/
can stop and go, change directions, move quickly or go, fast/slow, backward/forward, up/down
slowly • Be able to label his body parts and learn that
• Sing songs like “If you’re happy and you know it,” shoulders shrug, feet stomp, hands clap, knees bend
naming body parts and doing different actions and hips twist
• Demonstrate different movements like marching, • Feel encouraged to explore new physical skills by
bending, stretching and following your example
our Toddler Between 31

Y • Remove lids from jars, rotating her wrist.
and 36 Months • Enjoy playing near other children, but he is
The last half of your child’s third year is full of not yet able to play co-operatively.
exciting developmental gains. At this stage you • Enjoy looking at books and talking about the
will notice your toddler beginning to: pictures.
• Match shapes, pictures, and some colours.
• Run without falling.


• Expresses affection openly • Imitates adult behaviours, for example, shopping in
• Uses social conventions like ‘please’, ‘thank you’ make-believe grocery store; creates an imaginary
and greetings friend to talk to
• Plays alongside others comfortably • Is comfortable around new adults
• Is more able to play co-operatively and take turns • Helps other children to do things
• Plays make-believe games • Develops pro-social skills like turn-taking, sharing,
using words to resolve conflicts
• Introduce your toddler to familiar neighbours and • Learn to recognize people and feel safe with them
community workers • Learn how to show affection appropriately
• Demonstrate affection with hugs and loving words • Know his behaviour was appropriate and be
• Acknowledge his positive behaviours, for example, motivated to repeat it
“The way you shared was so polite”
• Provide many dramatic play props like food • Recreate her experiences in pretend play situations
containers, play money, a basket (e.g., shopping)
• Invite two of your child’s friends over for a cooking • Be able to practice his social skills as she shares art
or craft activity materials or takes turns adding ingredients
• Encourage your child to wash plastic dolls by • Practice caregiving and nurturing skills with others
providing a small basin of water and cloths
• Plan shopping excursions with your toddler, • Model these actions in his pretend play
including list-making, looking at flyers • Learn about language skills and imagination
• Provide puppets and dolls for dramatic play • Practice waiting his turn while developing his
• Play simple turn-taking games like “I Spy With My observation skills
Little Eye”

• Objects to major changes in routines • Explains feelings when asked about them
• Recognizes and responds to other children’s feelings • Is more able to understand the feelings of other
• Becomes more comfortable with new people children, and talk about them
• Wants independence but may fear new experiences • Gets excited about activities she may have done,
• Desires approval and needs praise e.g., baking cookies
• May stamp feet when frustrated
• May request certain stories to help resolve fears,
e.g., of monsters
• Try to maintain regular routines and let your toddler • Feel a sense of security and predictability
know when a change is coming • Become more self-assured and feel more encouraged
• Praise your child’s emerging abilities and to try things
independent efforts • Learn to understand his own feelings and respond
• Acknowledge his feelings and talk about them appropriately to those of others


• Sing the song “If you’re happy and you know it, clap • Learn to label different emotions and explore how
your hands,” substituting different feelings and people express their feelings
actions (grumpy/stamp feet) • Begin to think about what causes people to have
• Find people pictures showing different emotions; different feelings and recognize words that match
talk about the person’s feelings and why they might emotions
feel that way • Become more comfortable being away from her
• Encourage your child to do small excursions with parents
other familiar caregivers, e.g., going to the park
• Read books with your child about different feelings • Have a chance to ask about emotions and learn about
• Create a picture chart of his day (e.g., showing his own
breakfast time, nap time) • Have a comforting reminder of his routine and learn
• Do his favourite activities with him about the sequence of events
• Feel proud to demonstrate his abilities

• Uses “self-centred” pronouns like ‘I’, ‘me’, ‘mine’, • Is able to use words that describe things, e.g., big,
‘you’ dirty, wet, hot
• Puts together simple, two-word sentences • Participates more in conversations and stories
• Answers simple questions like, “What’s your • Is able to provide more information about self (e.g.,
name?”, and performs simple tasks when asked to name, gender, age) and understands two-step
• Enjoys looking at books and talking about the directions
pictures • Can recite a few simple nursery rhymes
• Sings parts of songs • Using plurals in a general way (e.g., foots not feet)
• Provide opportunities for your toddler to talk about • Know that you are interested in what he has to say
things that he finds interesting and will want to converse with you
• Let your toddler fill in the blanks while singing a • Enjoy singing important words on her own
song
day


• Develops size comparisons, using language like • Separates small objects from large ones
‘bigger’, ‘smaller’, ‘really little’ • Understands different forms of measurement for
• Tries to dramatize thoughts and ideas (e.g., pretends weight, height and length
to be a dinosaur) • Makes a plan before taking action (e.g., searches for
• Counts three objects needed felt board pieces)
• Matches similar pictures and objects, sorts different • Notices changes in nature (e.g., when a seed he
ones planted sprouts)
• Enjoys creative movement • Uses words associated with an understanding of time
(e.g. sleep time)
• Pretends to be community helpers
• Use laundry routines as an opportunity to describe • Learn number concepts and counting in a playful
and sort family members’ clothing way
• Introduce the concept of first, second, third in simple • Begin to recognize that numbers are used in different
games, asking, “Who is first? Who comes second?” ways
• Provide simple puzzles with three to six pieces • Gain confidence in his ability to put things together
day

• Holds pencil in writing position • Experiments with pencils, crayons and markers,
• Imitates drawing a cross, circles, dots, small lines, using an adult-like grasp
swirls • Draws squiggles and says that’s her name
• Cuts paper with scissors, but may not be able to cut • Participates in songs and finger plays
along straight lines • Plays with different manipulative toys, e.g.,
• Turns pages of book one at a time connecting straws and snap blocks
• Turns rotating handles, doorknobs • Puts on and takes off clothes
• Do simple finger plays like “This Little Piggy” with • Enjoy having his fingers played with as he pretends
your child they are “piggies”
• Compliment your child’s drawing skills, and • Feel proud of his abilities and creations and want to
comment on how “grown up” he is make more and show them off
• Read your child’s favourite book to him and put him • Learn to love looking at books because of the time
in charge of turning the pages spent reading with you


• Provide different things to write and draw with (e.g., • Be encouraged to use different things to colour with
pencils, markers, crayons, chalk) and express herself
• Supply your child with board books to read to her • Use page turning skills as she develops her early
dolls and teddy bears literacy skills
• Help your child cut out small pieces of paper to use • Learn that cutting paper helps with other projects she
as tickets for a puppet show is doing
• Provide different kinds of dress up clothes with • Practice self-help skills at his own pace through
snaps, buttons, zippers creative play
• Make greeting cards with your child, and together, • Use skills like cutting, folding and drawing to
print special messages express his ideas and feelings
• Role model reading and writing in front of your • See reading and writing as useful and want to do
child them too

• Participates in group activities that include running, • Walks on balance beam a few steps, going forward
galloping, crawling, rolling over and twirling around and backward
• Walks on balance beam, alternating feet a few steps • Rides tricycle, steering well and using pedals
• Runs, avoiding obstacles • Kicks ball with increasing accuracy
• Climbs up the ladder of a slide or other play • Throws ball overhand with fairly accurate aim
equipment • Participates in circle games involving many players,
• Pedals a tricycle such as ‘The Hokey Pokey’
• Encourage your child as she attempts more • Develop confidence in her physical abilities and be
challenging skills open to trying new activities
• Count out loud how many stairs she manages • Know you are noticing her and gain self-confidence
independently and offer praise • Feel successful every time she hits the target or gets
• Set up a big target for your child to throw a ball at or the ball in
a big box to kick a ball into
• Participate in physical activities with your toddler by • Enjoy the interaction and know that it is fun to
playing tag or rolling down a hill exercise because of your example
• Play music and provide him with colourful scarves • Explore the different actions he can do with his body
to move and dance with and be inspired by the music
• Demonstrate movements like galloping and twirling • Learn different possibilities for movement by
by playing “Follow the Leader” observing and trying them out


• Show your child pictures of different animals, e.g., • Demonstrate her understanding of how animals
birds, turtles, fish, and say, “Show me how you move move through her own creative movement
like a fish!” • Practice Learn to take her time and be cautious when
• Talk about safety rules and explain how to use playing at the park
playground equipment carefully • Begin to understand concepts like going over and
• Create a simple obstacle course with blocks and around, in and out
hoops
he Busy World of Your Preschooler:

T Four-year olds are more even-tempered and
An Overview of Your Preschooler’s cooperative with parents though they still stand
Development at 36–48 Months up for what they want. A 4-year old is full of
energy and loves testing her body with climbing,
Your preschooler is a pretty capable person by jumping, skipping and even pedalling a tricycle.
now. In her third year, your child shows more She can now focus for longer periods on activities
self-esteem, confidence, optimism and enjoy- like cutting and pasting, drawing and creating
ment of daily activities. She is becoming her interesting projects. Her imagination is develop-
own person and standing up for what she wants. ing with make-believe play and she enjoys play-
She is quite an accomplished negotiator and ing out situations that are familiar in her life.
tries to make things go her way. Your child will
have endless questions about how things work our Preschooler Between 36
Y
and why things happen. Language development and 48 Months
is still on the fast track and most 3-year olds will Your child has a very active time ahead of her. At
have a vocabulary of over 700 words. Three- this stage your preschooler will:
year olds are better at understanding and fol-
lowing simple rules and controlling their • Climb, slide and swing on playground
impulses. Toilet training is usually completed equipment.
(with the exception of night time for some). She • Handle child’s scissors and cut out simple
is quite adept on the playground, climbing up designs.
and sliding down equipment, and has good con- • Enjoy playing with other children and social-
trol over her fine motor skills. At the end of the ize well.
third year she may have started using safe scis- • Become less self-centred and more able to
sors, copying letters and even printing some let- understand feelings and point of view of others.
ters of her name. • Start to count objects.

• Enjoys playing with other children and socializes • Participates in interactive games like ‘London
well Bridge’ and ‘Farmer in the Dell’
• More able to take turns, share, co-operate • Enjoys games with rules
• Greets familiar adults and says ‘please’ and ‘thank • Complies with requests from parents more often
you’ • Seeks adult approval
• Imitates mom or dad in play • Enjoys dramatic play with others
• Likes to talk and carry on conversations


• Give your preschooler a special responsibility, like • Feel that she has a special and important role in the
watering the garden family
• Be available to your preschooler and ready to talk to • Know that you are interested in her activities and
her when needed feel secure
• Tell your child what she does well • Be encouraged to take on more activities
independently
• Provide opportunities for your child to play with • Develop his ability to share and take turns
other preschoolers • Enjoy playing with you and begin to understand
• Spend time playing simple games that require games with rules
turn-taking, e.g., simple card games like Go Fish • Begin to practice turn-taking, even in everyday
• Praise turn-taking during everyday routines, e.g., events
waiting for his turn to take a bath
• Ask your preschooler about her day, e.g., “What was • Want to talk to you more often about her experiences
one special thing you did?” • Have a better understanding of routines, rules and
• Explain to your preschooler reasons behind your limits
requests • Learn positive ways to interact with others and use
• Model using words like ‘please’ and ‘thank you’ these appropriately

• Experiences a broad range of feelings, e.g., jealousy, • Continually grows in independence and self-esteem
excitement, fear, happiness, anger • Expands pretend play into rich, connected themes
• Expresses needs with words, e.g., “I’m tired” • Is more even tempered and co-operative with parents
• Is more able to express anger verbally rather than • Shows empathy, e.g., for a friend who is upset
physically • May show attachment to one playmate
• Is becoming less egocentric and more able to
understand feelings and point of view of others
• Is less upset by limits and discipline
• Model coping with emotions • Learn acceptable ways to cope

• Help your preschooler deal with tantrums by talking • Feel supported when experiencing negative emotions
to her about what makes her feel better when she is • Begin to develop the ability to empathize with others
angry or sad
• Explore books that talk about emotions


• Arrange special play dates with his friends • Feel supported in his social needs
• Provide opportunities for him to make choices about • Develop a sense of mastery and positive self-esteem
play activities in areas he likes
• Help him set small goals he can achieve during play • Develop the ability to complete a task or activity
or other activities
• Engage in activities that make your preschooler • Feel respected when you engage in her favourite
happy, e.g., reading books, doing puzzles activity
• Provide her with some tasks that require some • Learn to persevere on a task for a period of time
concentration • Develop confidence in her ability to be responsible
• Give her some responsibility during daily routines,
e.g., choosing her clothes and getting dressed

• Enjoys books, simple songs, nursery rhymes, • Asks and answers ‘who, what, where, why, when,
nonsense words and stories how’ questions
• Uses a vocabulary of about 900 words • Can follow a three-part command
• Uses sentences with five words • Recognizes some letters and words
• Uses plurals and pronouns, e.g., ‘I, you and me’ • Uses regular past tense forms, but may add ‘ed’ to
• Understands position words, such as ‘in’, ‘out’, some words (e.g., eat-ed)
‘behind’, ‘in front of’ • Understands “It’s time to”
• Read your preschooler his favourite books before • Use words and sentences he has memorized to
bed participate actively in the experience
• Talk to your preschooler about events or people that • Start to categorize and sort the emotions and
make him feel happy, sad, or angry responses of others
• Have your preschooler “show and tell” their • Enhance the descriptive vocabulary to describe their
favourite people, places and things surroundings
• Sing the alphabet song • Learn the letters and order of the alphabet
• “I SPY” alphabets (e.g. “I spy the letter A”) • Learn to recognize letters of the alphabet
• Ask your preschooler to tell you about the stories • Begin to understand how writing can represent her
that go with the pictures she has drawn thoughts and ideas


• Enjoys dramatic play and role playing; play is • Sorts and classifies objects by characteristics
becoming more realistic, e.g., school, fire station, • Understands ideas like opposites
shop • Understands different forms of measurement, such
• Classifies objects by purpose, e.g., ‘to play with’, ‘to as weight, height and length
wear’ • Attaches words to numbers, for example, when you
• Understands the order of daily routines say the word ‘three’, it means three things
• Sorts objects by colour and size • Understands time intervals better, e.g., today,
• Counts objects tomorrow, yesterday
• Introduce the concepts of sorting and classifying in • Begin to understand that similar items can be sorted
daily routines, e.g., “Your socks go in this drawer into groups
and your shirts in the other”
• Play guessing games that encourage her to think • Use her memory instead of relying on concrete
about functional relationships, e.g., “What do you objects
draw with?” • Begin to understand that measurement can take
• Put measuring cups and spoons in the bath tub so different forms, e.g., “We can measure how tall you
your preschooler can practice measuring are and how much a cup of water is”
• Provide hard and soft craft materials such as • Begin to understand the concept of opposites
feathers, cotton balls, strings, popsicle sticks and
beads; have your preschooler create a picture and
talk about the different textures and why some are
soft or hard
• Use coloured beads or buttons in play as an • Begin to recognize patterns and shapes, understand
opportunity to explore different patterns, shapes and how sequences are made up of patterns
sequences • Understand how quantity, numbers and measurement
• Include your preschooler in cooking activities and all relate
use these to explore measurement

• Builds a tower of using blocks • Carries liquid in a cup, with some spillage
• Handles scissors and cuts out simple designs • Puts on shoes, but not yet able to tie laces
• Holds pencil with thumb and forefinger in adult-like • Prints some capital letters
grasp • Dresses and undresses without assistance
• Draws a house, and people with two to four body • Cuts out and pastes simple shapes
parts
• Can button large buttons


• Encourage your child to draw pictures of his home • Feel secure and understand his special role in the
and all the people who live in it family
• Praise your child’s increasing ability to dress and • Feel capable and motivated to practice these skills
undress independently with less and less help
• Give your child the opportunity to help with bringing • Gain pride in his growing ability to carry things and
cups and dishes to the table to be responsible for a task
• Provide your preschooler with a box of mixed beads • Engage her small motor skills in sorting different
or buttons that she can sort by colour or shape in an materials according to their characteristics
egg carton • Strengthen her pincer grasp (thumb and forefinger)
• Give her a broad selection of arts and crafts materials while creating drawings and collages
for drawing, cutting and pasting • Practice skills necessary for dressing herself through
• Provide dolls with clothing that have buttons, dramatic play
zippers, snaps, laces
• Use peg boards, connecting blocks and other • Physically create patterns and shapes and learn to
building materials to explore different patterns, label and identify them
shapes and sequences • Enhance decision-making and categorize pictures as
• Give your child different magazines and small people, animals, food, vehicles while improving her
scissors to cut out his favourite pictures for making a cutting skills
collage • Understand that his hands can represent thoughts and
• Provide your child with small building blocks or ideas through constructing and drawing
drawing materials that use small motor skills

• Runs several steps with alternating arm movements • Catches a large ball with arms extended
• Catches, bounces and throws a ball easily • Gallops, runs, walks and tip toes as part of a group
• Climbs, slides and swings on playground equipment activity
• Gets up from squatting position without any help • Jumps off the ground with a two-footed jump
• Gallops, runs, walks, wiggles, and tip-toes with other • Turns somersaults
classmates • Stands on one foot with momentary balance
• Praise your child’s developing skills e.g., “You are • Become more confident in her abilities and want to
so good at catching the ball” repeat the activity
• Put on your child’s favourite music and explore • Love spending time with you and enjoy being able to
different movements together show you how many ways she can move
• Be available to help your child try more challenging • Feel secure and develop the confidence to try more
skills, e.g., using the slide independently challenging activities on her own


• Encourage your child to move like different animals, • Practice a variety of physical actions while using his
e.g., jump like a frog, swim like a fish, wiggle like a imagination
worm, gallop like a horse • Develop literacy skills as he creates movements for
• Turn nursery rhymes into movement activities, role playing
prompting him to do the actions, e.g., jumping over a • Practice social skills like turn-taking while he plays
candlestick or over the moon! a fun, movement game
• Invite your child’s peers over and teach them a
simple game like ‘London Bridge’
• Explore yoga stretches with your child, e.g., cat, • Learn to move her body in ways that are both
dog, rabbit, snake, candle and rag doll relaxing and imaginative as she pretends to be
• Set up a simple obstacle course using hoops, a table, different animals and things
cones, balance board, etc. • Develop an understanding of concepts like over,
• Play simple games like ‘Simon Says,’ and suggest under, around, up and down as she navigates the
different actions for your child to try, e.g., “Simon obstacles
says jump three times! Simon says do one • Develop listening and counting skills while she
somersault!” demonstrates her growing physical capabilities
he Busy World of Your Preschooler:

T speak almost like an adult, using correct gram-
An Overview of Your Preschooler’s mar 90% of the time. She uses language to
Development at 48–60 Months describe objects, events and sort out the past,
present and future. By the end of the year, your
Your preschooler is a pretty capable person by 5-year old knows “left” from “right”, can identify
now. Four-year olds are more even-tempered and colours, shapes and sizes and can copy patterns
cooperative with parents though they still stand and sequences. She is ready to conquer new
up for what they want. A 4-year old is full of worlds—like school!
energy and loves testing her body with climbing,
jumping, skipping and even pedalling a tricycle. our Preschooler Between 48
Y
She can now focus for longer periods on activities and 60 Months
like cutting and pasting, drawing and creating The fifth year of your child’s life signals the end
interesting projects. Her imagination is develop- of early childhood. As she prepares to enter a new
ing with make-believe play and she enjoys play- world of school and friends, she will begin to:
ing out situations that are familiar in her life.
By the fifth year, your child is embracing life • Start running, then stop and change direction
fully. She is learning to cope with frustration and smoothly.
to understand rules. With the emergence of a con- • Draw a person with head, arms, legs and trunk.
science, she adopts rules, accepting them as her • Begin to grasp the concept of sharing.
own. She is much better at taking turns and play- • Use pretend play to gain control of frustrating
ing cooperatively, as well as planning and prob- and frightening experiences.
lem solving with others. Now your child can • Tell long stories about her own experiences.


• Plays games with simple rules • Explains rules of a game/activity to others
• Shows attachment to one playmate • Plays cooperatively in a group of 2–3 children
• Shows interest in gender differences, and may undress • Apologizes for actions he didn’t mean to do
with other children • Shows an understanding of right and wrong
• Enjoys dramatic play with other children • Listens while others are speaking
• Begins to grasp the concept of sharing
• Provide opportunities for your child to create her own • Start to create her own stories
stories, either by drawing them or by telling them to • Feel proud of what’s she’s done, and have a strong
others sense of her strengths and abilities
• Tell her how proud you are of her abilities whenever
you catch her doing something well
• Encourage more sophisticated pretend play by • Engage more in problem solving, making
providing props, e.g., restaurant, grocery store, doctor’s decisions and conversation
visit • Strengthen social skills while playing with peers
• Provide many opportunities for social interactions with
other preschoolers
• Encourage your child not to give up on games or tasks • Learn to persist at a task, especially when others
when he plays with others are counting on him
• Create the opportunity for your child to play with • Feel a sense of leadership
younger children

• Uses pretend play to gain control of frustrating and • Shows a desire to fit into home routines
frightening experiences • Shows ability to reflect on himself and his actions
• Experiences positive self-esteem, feels good about e.g., “What I said wasn’t nice”
himself and takes pride in his accomplishments • Experiences and understands positive and
• Complies with requests from parents more often negative feelings about another person
• Concentrates and works alone for up to 20–30 min • Is able to distinguish fantasy from reality
• Keeps going on a difficult task for longer periods • Starts to show more interest in taking care of
himself alone, e.g. cleaning room, bathroom
needs, bathing
• Monitor and put a name to things that may cause your • Experience lower stress levels and feel your
child’s experiences to be negative parental support
• Give your child the chance to develop his strengths and • Learn to feel capable in different areas, e.g.,
talents sports, music, drawing


• Provide crayons, paper and markers and encourage • Use her creativity to express emotions and talk
your child to draw and talk about her pictures and about feelings in relation to events
events • Identify and talk about feelings in an imaginative
• Create a stage where your child can act out situations way
and emotions by herself or using puppets
• Show and coach your child on how to handle emotions • Learn how to express anger and frustration safely
and feelings • Learn that wanting to try out new things is ok and
• Support your child when he wants to try new things or can bring success
take risks in social situations

• Plays with words in silly rhymes • Asks “how”, “why” questions and listens closely to
• Loves to recite and chant jingles and rhymes explanations
• Talks about imaginary situations • Uses ‘yesterday’ and ‘tomorrow’ correctly,
• Uses new and unfamiliar words incorporating past, present and future tenses of verbs
• Tells long stories about own past experiences • Says most speech sounds accurately but may have
• Uses an average vocabulary of 1500 words difficulty with some sounds e.g. “th” and “s”
• Shows interest in written words and letters, e.g., reads
own name and some words
• Encourage your child to talk by asking open-ended • Enjoy special shared time while using his imagination
questions, e.g., “How come…?” or “Why do you and building his vocabulary and comprehension skills
think…?”
• Give your child simple problems to solve, e.g., • Learn to identify things that are the same and
“how many different ways can you make a sound different
with your body (fingers, feet, mouth, etc.)”
• Point out words that he sees around him every day, • Begin to understand how writing can represent her
e.g., Stop sign, labels on milk or cereal boxes, thoughts and ideas
“Keep dogs on leash”


• Understands how to sort and classify objects by • Understands concepts of texture, weight, position
characteristics and space
• Enjoys games that require matching items • Understands different forms of measurement for
• Recognizes and identifies bigger, biggest, smaller and weight, height and length
smallest • Plans and builds with simple tools
• Identifies and names different colours
• Replicates patterns, sequences and order
• Understands the order of numbers
• Tell your child stories without pictures • Practice reasoning skills as he thinks about the
relationship between cause and effect
• Create a matching card game based on your child’s • Use his creativity to think things out and stretch his
interests, e.g., vehicles, dinosaurs, etc imagination
• Use household objects/food to do simple addition and • Begin to understand concepts of “more” and “less”
subtraction, e.g., “If you have three apples and eat one, and explore basic math
how many are left?”
FINE MOTOR SKILLS – 48–60 months

• Draws person with features including head, arms, legs • Carries a cup without spilling what’s in it
and trunk • Cuts on a line or cuts out simple shapes along an
• Cuts and pastes using art materials outline with scissors
• Paints with a large brush on large paper • Strings small beads to make a necklace
• Manipulates clay, playdough • Prints recognizable numbers, letters and words,
• Draws lines, simple shapes and a few letters including her own name
• Dresses and undresses with little help
• Give your child sensory materials to play with like • Enjoy the pleasurable feelings of the materials
sand or water along with different sized containers, while learning about volume
sieves and utensils • Learn about the sense of smell and how colours are
• Make play dough for your child, scented with spices made while manipulating the dough to make shapes
(vanilla, mint) and food colouring
• Make pencils, crayons and chalk available often • Get used to colouring, drawing pictures or
• Offer a variety of arts and crafts materials for your exploring letters and numbers
child to make anything she wishes, e.g., boxes, glue, • Use her imagination and fine motor skills to make
ribbons, tubes, yarn, scissors, tape, etc. her own creations

FINE MOTOR SKILLS – 48–60 months

• Use peg boards, connecting blocks and other building • Physically create patterns and shapes and learn to
materials to explore different patterns, shapes and label and identify them
sequences • Enhance decision-making and categorize pictures
• Give your child different magazines and safe scissors as people, animals, food, vehicles while improving
to cut out his favourite pictures for making a collage her cutting skills
• Provide your child with small building blocks or • Understand that his hands can represent thoughts
drawing materials that use small motor skills and ideas through constructing and drawing

• Rides a tricycle without bumping into things • Walks up and down stairs, alternating feet without
• Bounces, throws and catches a large ball support
• Starts, stops and changes direction smoothly when • Jumps down from half metre high
running • Skips for a distance
• Climbs playground equipment without any difficulty • Kicks a soccer ball
• Jumps forwards and backwards for short distances • Hops on one foot
• Support your child’s exploration and curiosity about • Use her motor skills to discover new concepts of
her physical environment physical characteristics of things
• Supervise play and safety, i.e., helmets for bike riding, • Enjoy mastering skills without worry of injury
care when throwing balls to others, etc.
• Take your child on a “bike hike” around the park or • Enjoy exploring his area and learning about places
neighbourhood and people
• Arrange for playmates to come over to play outdoor • Practice motor coordination skills while learning
games, e.g., hide and seek, tag games with rules
• Teach safety rules for walking or riding on streets, • Slowly learn how to manage safety; full mental
e.g., always stop at the curb before crossing the street; capacity for these rules is absent before age 10
never ride on the road, etc. • Learn how to cope with disappointments as well as
• Teach your child that when playing certain games, successes
someone wins and someone loses; help your child
understand how to win and lose graciously
term and also impacting both physical and men-

So What Derails Early Development? tal health outcomes. For this reason, at the very
least, when consulting with families where there
As mentioned earlier, adversity early in life can is adversity (poverty, parental mental health chal-
derail development ultimately influencing devel- lenges, substance use etc.), monitoring overall
opmental trajectory in the short term and long development can alert a physician to potential

developmental challenges which, when The stress response involves activation of the
recognized and responded to early can be mini- hypothalamic-pituitary-adrenocortical axis and
mized or overcome. It is important to understand the sympathetic-adrenomedullary system,
that the absence of serve and return or the pro- which results in increased levels of stress hor-
longed and frequent activation of the stress mones mainly cortisol and adrenaline (Danese
response system can have a devastating impact and McEwen 2012, McEwen 2008, Glaser
on a child’s outcomes across the lifespan. 2000). While transient increases in these stress
hormones are protective and even essential for
oxic Stress Derails Healthy
T survival (positive stress), excessively high lev-
Development els for prolonged periods can be quite harmful
Hans Seyle, a physician in Prague in the early and toxic (McEwen 2005, 1998, 2008, McEwen
1900s, was the first to use the term “stress” in a and Seeman 1999) and can lead to a chronic
biological context, defining it as “the non-specific “wear and tear” effect on multiple organ sys-
response of the body to any demand placed upon tems including the brain (McEwen 2005, 1998,
it”. Seyle further suggested that factors which McEwen and Seeman 1999). Chronic exposure
alter or disrupt the body’s state of equilibrium or to stressful experiences particularly affects the
homeostasis lead to stress. Researchers such as size as well as the neuronal architecture of the
Shonkoff et al have extensively studied the amygdala, hippocampus and the pre-frontal cor-
adverse effects of stress influencing the mental tex leading to functional differences and deteri-
and cognitive function of young children not only oration in learning, memory, and aspects of
in their life span but also their offspring and executive functioning (Danese and McEwen
future generations (Shonkoff et al. 2012a, b). 2012, Glaser 2000, McEwen 2008, McEwen
The neural circuits for dealing with stress are and Gianaros 2010). Stress can cause physio-
particularly malleable (or “plastic”) during the logic disruptions that result in higher levels of
fetal and early childhood periods. During such stress-related chronic diseases. (Glaser 2000,
sensitive developmental periods, the brain archi- Juster et al. 2010, McEwen 2008, Danese and
tecture is particularly vulnerable to stress. McEwen 2012).
Positive
–
Brief increases in heart rate,
Hypothalamus – mild elevations in stress hormone levels.
Negative
CRH Feedback Tolerable
Serious, temporary stress responses,
Corticotropin buffered by supportive relationships.
Releasing Anterior
Toxic
Hormone Pituitary
Prolonged activation of stress response systems
ACTH
in the absence of protective relationships.
Adrenocorticotropic
Adrenal Image: National Scientific Council on the Developing
Hormone
Cortex Child, 2012 Toxic Stress: The Facts
HPA Axis
CORT
Image: Basic hypothalamic–pituitary–adrenal axis sum-

mary (corticotropin-releasing hormone=CRH, adreno-
corticotropic hormone=ACTH). Original work from
Jessica Malisch and Theodore Garland Feb. 25, 2004

When infants and toddlers experience positive Child 2010a, b). These early stresses in a child’s
or tolerable stress that is buffered by a supportive environment prime the neurobiological stress
relationship the child learns how to cope with system to respond to lower threshold stimuli
stress—resulting in what is referred to as a secure that are normally not stressful, thereby increas-
attachment. However, when the child’s stress ing the risk of stress-related physical and men-
response system is activated for a prolonged tal illnesses (National Scientific Council on the
period without a supportive buffering relation- Developing Child 2005, 2008). Maladaptive
ship, this can become toxic stress which leads to infant social behavior may reflect exposures to
the development of maladaptive coping strategies traumatic and uncompensated adverse childhood
(Toxic Stress: The Facts). encounters including the absence of a responsive
Significant mental health problems can and relationship.
do occur in young children. In some cases, these When an infant has multiple aforementioned
problems can have serious consequences for early risk factors compounded in his or her environ-
learning, social competence, and lifelong health. ment, the chances of this child being identified
with developmental deficit skyrockets. The fact
I nfants Most at Risk that 90–100% of all toddlers with seven adverse
Any child lacking a supportive relationship childhood experience risk factors have impaired
to buffer the impact of a stressful and/or trau- development is simply astonishing (Barth et al.
matic experience is vulnerable to a toxic stress 2007).
response. At greater risk are those infants who
are not living in a secure and stable home with ow Can This Information Change
H
a parent or caregiver who is consistently caring, the Practice of Clinicians
supportive and responsive, are most vulnerable and Practitioners
to experiencing the toxic stress response and Through research, we better understand the
consequently less than optimal brain develop- behaviors of infants and toddlers that can be indic-
ment. These may be children with parents who ative of poor social emotional development. Those
suffer from substance abuse, poor mental health, in the health and social services areas need a
experience poverty, experience violence or have working knowledge of early development to
themselves been victims of abuse and/or neglect understand normal behavior vs. abnormal behav-
and therefore may not understand the significance ior. These professionals then need to understand
of their relationship with their baby and the need the specific behaviors that may be indicative of
to respond to their baby consistently in a nurtur- vulnerability or a delay in development. There
ing and caring manner. In a recent review of the was a time when child welfare focused primarily
data in Ontario, it was determined that the major- on safety. Access to food and shelter, absence of
ity of cases referred for investigation involving broken bones or physical ailments meant a child
infants, the main concern was parenting. In the was fine. Today, we know that in the case of
United States, an estimated 1 in 7 children has infants and toddlers we must look beyond the
experienced some form of neglect, physical or obvious signs and observe behaviors and interac-
emotional abuse (National Scientific Council on tions with primary caregivers more closely. The
the Developing Child 2010a, b). Those living in absence of “normal” interactions should be a rea-
low income families are on average exposed to son to observe more, ask questions and conduct
less and lower-quality parental responsiveness developmental screening that includes a focus on
in conjunction to more frequent conflictive and social emotional development. Today’s clinician
punitive parenting behavior (Evans 2004, Dodge has access to easy to use screening tools that look
et al. 1994, McLoyd 1998). Furthermore, half at overall development and social emotional
of these children have witnessed violence, or development as early as 3 months. Those systems
are indirectly victims of violence themselves caring for infants and toddlers can make some
(National Scientific Council on the Developing immediate changes.

1. Early screening for all children but at the very 649–65. https://doi.org/10.1111/j.1467-8624.1994.
tb00774.x.
least those who are in vulnerable situations. In Evans GW. The environment of childhood poverty. Am
a recent pilot that screened children under 5 Psychol. 2004;59(2):77–92.
being served by child welfare using the Ages Glaser D. Child abuse and neglect and the brain—a
and Stages Questionnaire 3, it was found that review. J Child Psychol Psychiatry. 2000;41:97–116.
https://doi.org/10.1111/1469-7610.00551.
60% of children already had an established Grantham-McGregor S, Cheung YB, Cueto S, Glewwe P,
delay in one or more areas that had not been Richter L, Strupp B, International Child Development
identified by any of the professionals involved. Steering Group. Developmental potential in the first
Those same children were also screened using 5 years for children in developing countries. Lancet.
2007;369:60–70.
the Ages and Stages Questionnaire Social Juster RP, BS ME, Lupien SJ. Allostatic load biomarkers
Emotional. Of those screened over 50% of chronic stress and impact on health and cognition.
(Kulkarni et al. 2015). Based on the results, Neurosci Biobehav Rev. 2010;35(1):2–16.
the caregivers of those showing delays were Kouzarides T. Chromatin modifications and their func-
tion. Cell. 2007;128(4):693–705.
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to respond to the child’s needs. Health and Family Law Initiative (FLI). Imprint The
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tions such as the Nurse Family Partnership Hospital for Sick Children, Toronto. Issue 64, Summer
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(Olds et al. 2013). McEwen BS. Protective and damaging effects of stress
3. Integration of the new research on brain devel- mediators. N Engl J Med. 1998;338(3):171–9.
opment, epigentics and toxic stress response McEwen BS. Stressed or stressed out: what is the differ-
into undergraduate graduate training pro- ence? J Psychiatry Neurosci. 2005;30(5):315–8.
McEwen BS. Central effects of stress hormones in health
grams in the areas of health sciences, social and disease: understanding the protective and dam-
work and education. aging effects of stress and stress mediators. Eur J
Pharmacol. 2008;583(2–3):174–85. Epub 30 Jan 2008.
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Update in Development: Section
B—Autism Spectrum Disorder 7
R.G. Smith and D. Samdup
Recently, a patient of mine who happens to be a Finally, there is a 16-year-old young lady,
very bright 10-year-old young man with an who first spoke at age 6-years, who can now tell
Autism Spectrum Disorder came into my office me the day of my birth seconds after I tell her
and sat down. Without asking me anything about my birthdate, then she tells me “Man you are
my day, or what type of summer I was having he old!”
stated: “So Dr. Smith what can I teach you today? Such is the nature of some of my days in my
I know, tell me all the countries of the world in Autism Clinic!
alphabetical order AND their capitals?” When I
started to say that I could not do that, he quickly
retorted: “Aren’t doctors supposed to be bright?” hat Is an Autism Spectrum
W
And he quickly reeled off to me every country Disorder?
and its capital (IN ALPHABETICAL ORDER),
some of which I had never heard of! He then pro- The autism spectrum disorders (ASD’s) are a het-
ceeded to ask me if I knew the distance of Mars erogeneous set of neurodevelopmental syndromes
from Earth! This very bright young man has one characterized by deficits in social communica-
friend at school, who is also on the Autism tion and social interaction and the presence of
Spectrum. He is often seen walking around at restricted, repetitive behaviors. Social commu-
recess reenacting video games or speaking nication deficits include impairments in aspects
Japanese to himself, which he learned from of joint attention and social reciprocity, as well
watching Yu-Gi-Oh on the internet! as challenges in the use of verbal and nonverbal
Then there is an 8-year-old nonverbal boy communicative behaviors for social interaction.
with ASD who can spin anything in my office Restricted, repetitive behaviors, interests, or
(including chairs), but struggles in school and is activities are manifested by stereotyped, repeti-
highly disruptive because of this fixation and his tive speech, motor movement, or use of objects;
tendency to run out of the classroom. inflexible adherence to routines; restricted inter-
ests; and hyper- and/or hypo-sensitivity to sen-
sory input (American Speech-Language Hearing
R.G. Smith (*) • D. Samdup Association 2015). This results in the inability
KidsInclusive Centre for Child and Youth
to engage in and benefit from many of the basic
Development, Hotel Dieu Hospital, 166 Brock St.,
Kingston, ON K7L 5G2, Canada activities of life including but not restricted to
conversing, learning, and engaging in meaning-
Queen’s University, 99 University Ave.,
Kingston, ON K7L 3N6, Canada ful and mutually beneficial relationships (Joseph
e-mail: gs3@queensu.ca et al. 2014).


208 R.G. Smith and D. Samdup
The purpose of this update is to provide a disorder, especially what used to be called
review of current literature pertaining to some pervasive developmental disorder, not otherwise
of the more useful and practical innovations in specified (PDD-NOS) (Kullage et al. 2014;
the field, based on recent publications as well Smith et al. 2015).
as some consensus. We have also taken the lib- Whether a true increase in autism spectrum
erty of inserting some practical key points in the disorders has resulted in the increase in ASD
update. These are intended to facilitate acquisi- prevalence, or the latter is due to changes in com-
tion of salient historical points, as well as demys- munity awareness, and identification patterns, is
tifying presentation of the diagnosis to parents still not clear (Rice et al. 2012). However, these
and caregivers. authors state that “disentangling the many poten-
We will begin by giving a general overview tial reasons for ASD prevalence increases has
and then select a few important and possibly con- been challenging. Understanding the relative
troversial topics to discuss. Throughout the chap- contribution of multiple factors such as varia-
ter, we will attempt to make things easy to tion in study methods, changes in diagnostic and
understand, practical and as much as possible, community identification, and potential changes
evidence-based. in risk factors is an important priority for the
ADDM network and for the CDC.” Fombonne
(2003a, 2005) states that “surveys conducted
Prevalence Update in the 1960s and 1970s only dealt with autism
disorder (as opposed to ASD) and with a rather
Prevalence is the actual number of cases alive, narrow definition of autism… and not account-
with the disease either during a certain period of ing for autism occurring in subjects who are not
time (period prevalence) or at a particular date in “mentally retarded” (intellectually disabled). The
time (point prevalence). Incidence is the rate of closest estimate of ASD prevalence available
new (or newly diagnosed) cases of the disease. It in the late 1970s was 20 per 10,000 in a survey
is generally reported as the number of new cases from the United Kingdom that was limited to
occurring within a period of time (e.g., per the severely impaired children with ASD”. He
month, per year, etc.). Thus incidence gives further stated that “rates of autism disorder in
information about the RISK of acquiring a dis- recent surveys have consistently been more than
ease, while prevalence gives an indication of 10 per 10,000 whereas previous prevalence esti-
how widespread a disease actually is. The preva- mates ranged from 4 to 5 in 10,000” (Fombonne
lence data for autism spectrum disorders appears 2002). Therefore, he felt that from the available
to be a rapidly moving target. Current estimates evidence it could be concluded that recent rates
range from 1 in 45 to 1 in 68 from the Centers for for both ASD and autistic disorder are 3–4 times
Diseases Control and Prevention-CDC (2014) higher than 30 years ago! Fombonne (2003b)
(Zablotsky et al. 2015). Despite this, certain concludes that the combination of the broadened
aspects of the demographic characteristics have definition (especially at the less severe end of the
remained stable over time. For example, the spectrum), possibly differences in methods for
male-to-female ratio appears to be quite stable case finding, changes in referral patterns, avail-
with a mean ratio of about 4 to 5:1, ranging from ability of services, public and professional aware-
approximately 1.5:1 to 16:1 depending on the ness, diagnostic concepts and practices, could
cognitive level being looked at. Boys are far all contribute to the apparent or real increase in
more represented in the “higher functioning” prevalence.
group. However, both sexes are found through- As stated above, current data from the CDC,
out the intellectual spectrum. It is suspected that suggested that about 1 in 68 children have been
with the somewhat stricter criteria for diagnosis identified with autism spectrum disorder (ASD)
of autism spectrum disorders in the DSM 5, according to estimates from CDC’s Autism and
there may be a slight reduction in the frequency Developmental Disabilities Monitoring (ADDM)
of diagnosis of some types of autism spectrum Network. There was a sex differentiation with

7 Update in Development: Section B—Autism Spectrum Disorder 209
approximately 1 in 42 boys being affected, sadly, many of us have seen parents who opted
and 1 in 189 girls living in the ADDM net- not to immunize their second child after the first
work communities being identified with an was diagnosed with the regressive form of ASD,
ASD. Worldwide, the prevalence seems to more only to have the second child subsequently be
closely approximate 1 in 100 (The Morbidity and diagnosed. With increasing reports of outbreaks
Mortality Weekly Report 2014). The annual cost of measles in particular in various parts of the
financially and otherwise to families and govern- United States (CDC data; Centres for Disease
ments clearly is intimidating at the least! Control and Prevention 2016), this raises new
concerns about the health and well-being of these
children. Measles can be a devastating disease
What Causes Autism? causing serious pneumonias and other respiratory
morbidities, but is also known to potentially
With the rapidly escalating prevalence of autism cause a profound and progressive (but thankfully
spectrum disorders, researchers worldwide are rare) neurological disorder called subacute scle-
attempting to identify potential genetic and epi- rosing panencephalitis (SSPE). Accumulating
genetic factors that may play a role in causing data from various different sources, including
this disorder. genetic, neuropathological, electrophysiological,
Despite significant research documenting no and even infant eye gaze preference studies, have
link between the measles-mumps-rubella (MMR) suggested that the developmental pathways for
vaccine and autism development, there persists a autism are created much earlier than clinical
belief among parents that there is indeed a causal symptoms are manifest—informing both the tim-
relationship, especially with regards to the regres- ing and the types of environmental exposures on
sive form. This has resulted in lower immuniza- which research should focus (Pierce et al. 2016).
tion rates in many countries. Xiang and colleagues utilizing the large
Wakefield et al. (1998) in the Lancet, initially Kaiser-Permanente database, found that early
claimed an association between the autistic diag- onset (<26 weeks gestation) gestational diabetes
nosis and the presence of lymphoid hyperplasia increased the risk of ASD diagnosis (Xiang et al.
and measles antibodies, in a since retracted pub- 2015). Numerous studies have identified ante-
lication which led to an unwarranted hype about natal maternal stress as a possible “epigenetic”
the possible causal relationship between the mea- factor in autism spectrum disorders (Talge et al.
sles vaccine and the development of regressive 2007; Babenko et al. 2015; Grossi et al. 2016;
autism. Crawford 2015; Matelski L, Van de Water J 2016;
The recent publication in JAMA (Jain et al. Walder et al. 2014; Kinney et al. 2008). Severe
2015), where they looked at 95,727 children with maternal stress in pregnancy has been associated
older siblings, 994 (1.04%) were diagnosed with with lower cognitive and language abilities in
ASD, and 1929 (2.02%) had an older sibling with childhood (Buss et al. 2010). King et al. (2012)
ASD. Of those with older siblings with ASD, reviewed the impact of natural disasters on neuro-
6.9% had ASD versus 0.9% who had unaffected developmental disorders including autism using
siblings. These children were all privately insured the Québec ice storm and Louisiana hurricane
in the United States of America. They concluded studies which revealed not only a “stress severity
that there was no association between MMR vac- impact” but also a timing (gestation) impact. It
cine receipt and ASD even among children appears that 5–6 months gestation is a particu-
already at higher risk for ASD! Taylor et al. larly vulnerable period especially based on the
(1999) in 1999 published similar findings in the Louisiana study (King et al. 2012). Beversdorf
Lancet, as did Madsen et al. (2002). Doja and et al. (2005) suggested that pathological changes
Roberts (2006) did a literature review, and a in the cerebellum in autism are thought to corre-
Cochrane review (Demicheli et al. 2012) was spond to an event before 30–32 weeks gestation.
published in 2012 on the subject, all of which In a retrospective study of 434 mothers of children
found no support for any link. Anecdotally, and with autism compared to 191 surveys to mothers

of children with Down syndrome, the researchers A Further Word About Risk-Factors
found a higher incidence of prenatal stressors in
autism at 21–32 weeks gestation, with a peak at A number of factors have been identified as
25–28 weeks. Autoimmune disorders have also potential risk factors for ASD:
been associated with ASD (Sweeten et al. 2003;
Molloy et al. 2006). • Increased parental age (fathers ≥50 years;
A relatively new (and somewhat controversial) mothers 40–49 years AND <20 years; there
area of interest involves the so-called “gut dysbi- was a joint effect of maternal and paternal age
osis” phenomenon. GI symptoms are frequently with increasing risk of ASD for couples with
reported in ASD and include constipation, diar- increasing differences in parental ages) (Lord
rhea, food allergies/intolerance and abdominal and Bishop 2015).
pain. Rosenfeld (2015) reviewed the research re • Both short and long inter-pregnancy intervals
microbiome disturbances and autism spectrum (IPIs) have recently been found to be associ-
disorders and the so-called “microbiome- gut- ated with an increased risk of autism spectrum
brain axis”, and concluded that it was still prema- disorders (Sandin et al. 2016). Compared with
ture to render definitive conclusions and establish children born to women with IPIs of
causation but recommended further research. De ≥36 months, children born to women with
Angelis et al. (2015) found altered fecal micro- IPIs of <12 months had a significantly
biota and metabolomes in children with autistic increased risk of any ASD (pooled adjusted
disorder and PDD-NOS compared to healthy odds ratio [OR] 1.90, 95% confidence interval
controls. Mayer et al. (2015) suggest a possible [CI] 1.16–3.09). This was less significant for
benefit of probiotic treatment in rodent models long IPIs (Sandin et al. 2016).
of autism. Clearly further studies are required
before this can be recommended in humans. In
a review O’Mahony et al. (2015), they reviewed Genetics
the evidence on the role gut microbes could
play in childhood disease generation, includ- Autism spectrum disorder (ASD) is clearly a
ing autism. They concluded that “it must be highly heritable condition (Agudelo et al. 2016).
appreciated that there are complex relationships A number of authors (Packer 2016; Sandin et al.
between host genetics, microbial interactions, 2014) summarize by stating that a range of epide-
and environmental factors that determine the risk miologic studies have supported the notion that
of disease development. However, key develop- ASD is multifactorial, with strong contributions
mental windows exist in the prenatal and postna- from additive genetic and non-shared environ-
tal periods that allow the microbiota to influence mental risk factors. A very important recent find-
essential modulatory systems and vice versa”. ing was that de novo copy number variants
Potential areas for intervention or prevention (CNVs) are strongly associated with ASD risk
were suggested. The higher prevalence of ASD in (Sebat et al. 2007). To date at least 65 autism risk
extremely premature infants adds further intrigue genes have been identified with several others
to the stress related hypothesis as well as the gut showing strong potential (Packer 2016). It
dysbiosis theories (Groer et al. 2015). It may be appears as if the future task of identifying the
that for probiotics to have a role in prevention, relationship between genotype and phenotype
they must be used EARLY in life, especially in could be quite complex and challenging. Listing
high-risk infants (e.g., premature infants, and sib- genes already identified as being significant is
lings of children with ASD, or perhaps even preg- beyond the scope of this update. We strongly
nant mothers). Thus far, however, there is NO recommend the excellent review by Packer

evidence of proven preventative or therapeutic (2016) for this purpose. A recent study published
benefit from probiotics use in other than pos- in Nature Medicine (Yuen et al. 2015) and look-
sibly GI related issues. ing at quartet families with autism spectrum

disorder (two or more affected siblings with group appeared to share impairment in both flex-
ASD) revealed that some 69.4% of the affected ibility and planning with the ASD group, while
siblings carry different ASD-relevant mutations. it shared the response inhibition deficit with the
These siblings with discordant mutations seemed ADHD group. Conversely, deficit in attention,
to demonstrate more clinical variability than working memory, preparatory processes, fluency,
those who shared a risk variant. The authors con- and concept formation did not appear to be dis-
cluded that there appears to be substantial genetic tinctive in discriminating from ASD, ADHD, or
heterogeneity in ASD, necessitating the use of ASD + ADHD group. Miodovnik et al. (2015),
whole-genome sequencing (WGS) to delineate found that approximately 20% of children (who)
all the susceptibility variants in research and clin- had initially been diagnosed with ADHD before
ical diagnostics. ASD were diagnosed with ASD ∼3 years (95%
It is also very clear that a number of genetic confidence interval 2.3–3.5) after children in
syndromes have a higher than normal associa- whom ADHD was diagnosed at the same time or
tion with the development of autism spectrum after ASD. The children with ADHD diagnosed
disorder. These include DiGeorge syndrome first were nearly 30 times more likely to receive
(~20%), 22Q duplication, Angelman, Trisomy their ASD diagnosis after age 6 (95% confidence
21 (~8%), Fragile X (25–40%), 15q11–13 dele- interval 11.2–77.8). The delay in ASD diagnosis
tion, Tuberous Sclerosis (60%), Cornelia de was consistent across childhood and independent
Lange and others. Recent reports suggest an of ASD severity.
association between autism spectrum disorders The recurrence risk after one child is diag-
and fetal alcohol spectrum disorders (Varadinova nosed with ASD approximates 20% (19–27%)
and Boyadjieva 2015; Evrard 2010). In clinical (Schaefer 2016; Zwaigenbaum et al. 2012).
practice many of us working with this population
certainly see features of ASD in many children
with FASD. A “New” Finding
ADHD and ASD share environmental and bio-
logical risk factors. Individuals with both disor- • Although the literature is quantitatively lim-
ders are more severely impaired than those with ited, some recent publications suggest a possi-
only one. There is strong evidence for genetic ble association between gender identity
overlap between ADHD and ASD, demonstrat- disorder (GID), or gender dysphoria (GD) and
ing that rather than being an artifact of diagnosis, ASD. Skagerberg et al. (2015), looked for an
comorbidity is rooted in shared genetic risk fac- association between GD and autistic features
tors (Antshel et al. 2013; Visser et al. 2016). A using the Social Responsiveness Scale (SRS).
substantial minority of youth with ADHD dem- Approximately 46% fell within the normal
onstrate traits of autism spectrum disorder (15– range on the SRS, and of those 2.8% had an
25%), and interestingly, ADHD is one of the most ASD diagnosis. 27.1% fell within the mild/
common comorbidities in children with ASD moderate range and of those 15.6% had an
(40–70%). Van der Meer et al. (2012) question ASD diagnosis and 6.7% and ASD query.
whether autism spectrum disorder and ADHD rep- Twenty-seven percentage also fell within the
resent different manifestations of one overarching severe range and of those 24.4% at an ASD
disorder. A large number of copy number variants diagnosis and 26.7% in ASD query.
and chromosome abnormalities confer risks for VanderLaan et al. (2015) identified that high
ADHD and ASD (please refer to Van der Meer birth weight was associated with both high
et al. (2012) for more details about this impor- gender nonconformity and autistic traits
tant and interesting phenomenon). In another among GD children. Pasterski et al. (2014)
great review by Craig et al. (2016) they reviewed found less consistent data in adults with gen-
the similarities and differences in executive dys- der dysphoria. Schalkwyk et al. (2015) sug-
function in these disorders. The ASD + ADHD gested that perhaps a more complex approach

that attempts to understand gender in in the high risk range (8–20) were considered
developmental terms is potentially more
at sufficiently high risk to be referred directly
salient for both research and clinical purposes. for diagnostic assessment without the follow-
They also suggest that the current understand- up interview. The revised scoring increased the
ing about the unique social development of overall rate of ASD detection (67 versus 45 per
individuals with ASD, may impact the process 10,000 (Robins et al. 2014). The communica-
of gender identity formation and thus under- tion and symbolic behaviour scales infant toddler
line the need for such an approach. In our checklist CSBS-ITC, is a broad band screener
clinic, we have recently had 4 patients self- to detect infants/toddlers (6–24 months) with
identify as “transgender” or gender dysphoria. communication delays including ASD from the
general population. Positive and negative predic-
tive value support the validity of the CSBS-ITC
Assessment/Evaluation for children 9–24 months but not 6–9 months
(Wetherby et al. 2008).
Autism spectrum disorder can be diagnosed reli-
ably by age 2 by an experienced professional
(Lord et al. 2006). For many children <3 years, Historical Pearls
early intervention can improve outcomes, includ- In trying to elicit a history consistent with
ing core deficits of ASD (social attention), e.g., an ASD diagnosis, it is sometimes difficult
language and symptoms severity (Dawson et al. to be sure how to interpret the responses to
2010; Kasari et al. 2010). our questions. Do parents REALLY under-
Primary care providers have the opportunity stand what we are asking? Here are some
to conduct developmental surveillance during ways to simplify this process:
well-child visits and monitor for early signs of
delays including autism spectrum disorder at • Does your child play WITH or AMONG
each visits. other kids?
Diagnosing a child with ASD takes two steps: (1) • Is your child a “creature of habit?”
Developmental screening and (2) Comprehensive • Is your child a “stickler” for rules?
diagnostic evaluation. The American Academy • Does your child like to “run” the show?
of Pediatrics (AAP) recommends screening all
children for ASD at 18–24 months of age. The The above are questions that many par-
modified toddler checklist for autism M-CHAT ents of kids with ASD can relate to. I am
is a modified screening tool which can be used amazed at the different reaction I get when
for children 16–30 months old during the well- I ask, “Does your child play with other
child visits. This is a 23 item parent questionnaire kids?” vs. “Does your child play WITH or
with the structured follow-up interview to clarify AMONG other kids?”
items endorsed by parents. Recently Robins et al. A similar question would include “HOW
(2014), validated a newer version of this instru- does your child play with other kids?”
ment, the modified checklist for autism in tod- [Sidebars are great for calling out
dlers, revised with follow-up M-CHAT-R/F. The important points from your text or adding
questionnaire was reduced to 20 items with additional info for quick reference, such as
three risk ranges. Children in the low risk range a schedule.
(0–2) did not require follow-up interview unless They are typically placed on the left,
<24 months of age, where a repeat screening after right, top or bottom of the page. But you
the second birthday is required. Children in the can easily drag them to any position you
medium risk range (3–7) required the follow-up prefer.
interview to clarify the risk of ASD, if at least When you’re ready to add your content,
two items remain positive, then preference for just click here and start typing.]
diagnostic evaluation was indicated. Children

Children with positive ASD screens and Examination of the child should document
c linician concern should be referred for further growth parameters especially head circumfer-
diagnostic assessment. Evaluation of ASD should ence since children with ASD may have accelera-
include a comprehensive assessment by a team tion of head growth followed by stabilization
that has expertise in diagnosis and management. (Courchesne et al. 2003). Look for dysmorphic
Since this is not always feasible, depending on features, neurocutaneous lesions and medical/
the location or wait list, the diagnosis can be eval- genetic disorders that may co-exist with ASD e.g.
uated/confirmed by another pediatric specialist Fragile X, tuberous sclerosis etc. (See also sec-
(psychologist, psychiatrist, neurologist, develop- tion “Genetic Disorders”.)
mental pediatrician, general pediatrician) with Consider if the child has other co-existing or
expertise in ASD in collaboration with other team co-morbid conditions e.g. intellectual disability,
members (speech and language therapist, occu- language delays, developmental coordination
pational therapist, teachers, etc). disorder, ADHD, anxiety, etc., and carry out
Assessment includes a detailed neurodevel- appropriate assessments for identification.
opmental history: current concerns, prenatal,
perinatal, developmental history, medical, social
and three generation family history (including Investigations
mental-health history). Information and function-
ing in multiple settings e.g. home, school, after All children with ASD should have an audio-
school programs and community by using rating logical exam and lead screening (if there is his-
scales, structured interviews and observations. For tory of pica, or live in a high-risk area). EEG is
the parent interview, the ADI-R, though lengthy, not recommended routinely except when there
has been established as a useful diagnostic tool is suspicion of subclinical seizures or clinical
in the assessment of ASD (Lord et al. 1994). seizures and/or history of developmental regres-
Clinicians may decide to use other questionnaires sion. There is no evidence to support the role of
if ADI-R is not feasible. The social communi- clinical neuroimaging in the diagnostic evalua-
cation questionnaire SCQ is the screening tool tion of autism (Filipek et al. 2000). It should be
based on the ADI-R that can be used for children performed based on clinical suspicion of exist-
with a mental age over 2 years (Rutter and Barley ing alternative diagnosis e.g. Tuberous sclerosis,
2003). Social Responsiveness Scale, second edi- or presence of microcephaly or extreme (≥4 SD)
tion (SRS-2) is designed to identify social impair- macrocephaly, or focal seizures (Anagnostou
ment that is seen in ASD and to differentiate it et al. 2014). If a metabolic etiology is suspected
from social difficulties that occur in other disor- magnetic resonance spectroscopy should be con-
ders. It can be completed for children as young as sidered with standard neuroimaging. Metabolic
30 months to adulthood and takes about 15 min testing should be guided by clinical indicators
to complete (Constantino 2012). A useful tool for (seizures, neuro- regression, extrapyramidal
the evaluation of autism is the Autism Diagnostic signs, severe intellectual disability, failure to
Observation Schedule 2nd Edition (ADOS-2), thrive, etc.). Suspicion of a particular genetic
which is a semi structured, standardized assess- disorder helps in the selection of the specific
ment of communication, social interaction, play genetic investigation since many recognizable
and restricted and repetitive behaviours. Module syndromes have documented association with
1–4 provide cut off scores for ASD and can be ASD (e.g. Fragile X, Angelman syndrome,
used in children as young as 31 months. The etc.—see earlier) Chromosomal microarray
toddler module (12–30 months) of the ADOS (CMA) is a first-tier test in place of karyo-
provides ranges of concern reflecting the extent type and the diagnostic yield is nearly 30% in
to which a child demonstrates behaviors associ- complex ASD (congenital anomalies, micro-
ated with ASD (Lord and Rutter 2012). cephaly, seizures, dysmorphic features). Other

testing should include DNA testing for Fragile the paper by Zwaigenbaum et al. (2015). Several
X in males, MECP2 sequencing in females with important statements, based on the review of a
ASD can be considered with intellectual dis- range of studies, and expert opinion were com-
ability, MECP2 duplication testing in males if piled. These included the following:
phenotype is suggestive, and PTEN testing if
head circumference is >2.5 SD above the mean • “Current best practices for interventions for
(Schaefer et al. 2013; Anagnostou et al. 2014). children aged 3 years with suspected or con-
Where available, whole-exome sequencing may firmed ASD should include a combination of
also be considered (Tammimies K et al. 2015). developmental and behavioral approaches and
Other testing should be dictated by the circum- begin as early as possible.
stances or history, for example, in a child with • Current best practices for children aged
ASD who has highly selective dietary intake, 3 years with suspected or confirmed ASD
nutritional screening for iron, zinc and vitamin should have active involvement of families
B12 and others, could be considered (with the and/or caregivers as part of the intervention.
assistance of a dietician). • Interventions should enhance developmental
progress and improve functioning related to
both the core and associated features of ASD,
reatment Options for Autism
T including social communication, emotional/
Spectrum Disorders behavioral regulation, and adaptive behaviors.
• Intervention services should consider the
An excellent summary of treatments found to be sociocultural beliefs of the family and family
effective in the management of ASD is provided dynamics and supports, as well as economic
by Anagnostou et al. (2014) in their review. capability, in terms of both the delivery and
In their review they very succinctly summa- assessment of factors that moderate outcomes.”
rize the treatment of autism spectrum disorders
by stating: “The goal of existing interventions is They also acknowledged the need to simul-
to facilitate the acquisition of skills, remove bar- taneously address the comorbid conditions such
riers to learning and improve functional skills as sleep disorders, gastrointestinal disorders
and quality of life.” (Bauman 2010), anxiety, and other maladaptive
Management is divided into Behavioral and behaviors, in addition to seeking the assistance
Biomedical approaches. of occupational therapy and speech language
pathology, when required.
Behavioral Interventions
Biomedical Interventions
Applied behavioral analysis (ABA) utilizing
empirically derived basic learning principles, Several studies have unsuccessfully attempted
has been shown by many studies to produce to identify pharmaceutical interventions which
meaningful and positive changes in behav- alter the core symptoms of ASD creating dys-
ior (Peters-Scheffer et al. 2011; Reichow et al. function. However, there are a number of stud-
2012) There are several models of ABA interven- ies now published which support the use of
tion all of which have some evidence to support pharmacological agents to alleviate comorbidi-
their efficacy. There are still questions around ties affecting day-to-day functioning and qual-
timing, intensity and patient-selection for treat- ity of life of child and caregivers. These will
ment to produce optimal effects, but in general it be covered in more detail in the discussion of
appears that early intervention is critical for this. comorbidities later in this chapter. However,
A comprehensive review of this is provided in a few brief general points will be made here.

Perhaps the neuroleptics and stimulants have Attention Deficit/Hyperactivity

the most support for their use in the manage- Disorder
ment of irritability/aggression. With the use of ADHD occurs in 41–78% off children with ASD
neuroleptics, the CAMESA guidelines should be (Murray 2010). The DSM-IV did not allow the
carefully followed to monitor metabolic effects diagnosis of ASD and ADHD, however in the
as well as potential hormonal impacts of their new DSM-5 this has been changed. It is impor-
use (Pringsheim et al. 2011). tant to consider the patient’s ability to attend to
Comorbidities can significantly impact the both preferred and non-preferred activities since
quality of life of the child, caregivers at home and individuals with ASD may be able to focus for
at school and therefore should be addressed, if it prolonged periods when engaged in preferred
is possible to do this safely. The general premise activities. ASD patients may be less respon-
is that it is often difficult to disentangle symp- sive to methylphenidate than those with pri-
toms/comorbidities/ASD symptoms in every mary ADHD with a response rate of 50% and
child. As a result, success in management is often have a higher rate of side effects (e.g., irritabil-
not easily attained. For example, sleep disorders ity, self-injury, and stereotypy) (Mahajan et al.
(see later discussion) are highly prevalent in the 2012; Reichow et al. 2013; Davis and Kollins
ASD population and can often result in irritable 2012). Stimulants are recommended as first
behavior, self-injurious behaviors, impaired line choice in children with ASD and ADHD
focus, and hyperactive symptoms. In turn, sleep followed by atomoxetine and alpha agonists
can be affected by anxiety, ADHD, medica- (guanfacine, clonidine) as second line and atypi-
tion use, etc. (Frye 2016). It is also important to cal antipsychotics as third line (Mahajan et al.
recognize that children with ASD can also have 2012). Symptoms of ADHD can overshadow the
medical problems, for example migraine head- symptoms of ASD, making diagnosis challeng-
aches, which similarly can cause or exacerbate ing. Children initially diagnosed with ADHD
sensory and other issues. Sensory Integration received their ASD diagnosis 3 years later then
Disorder (SID), now included in the DSM 5 as the children in whom ADHD was diagnosed at
part of the ASD diagnosis also can significantly the same time or after ASD (Miodovnik et al.
exacerbate other behaviors, and consultation 2015). The coexistence of ADHD with ASD can
with an occupational therapist competent with significantly negatively impact the management
managing SID should be undertaken (McDonnell and prognosis of ASD.
et al. 2015). Sensory disorders can affect a range
of behaviors including feeding, sleep, attention, Irritability/Aggression (IA)
and can exacerbate as well as be exacerbated by Approximately 20% of patients with ASD
anxiety. Management of GI issues, are beyond exhibit irritability/aggression at a moderate to
the scope of this update, but can be treated with severe range (Lecavalier 2006). Currently only
the assistance of a gastroenterologist (Coury two psychotropic medications, risperidone and
2010). The Autism Treatment Network (Autism aripiprazole, have been approved by the FDA
Speaks) also has excellent resources available for for treatment of IA in individuals with ASD
physician and parent use (The Autism treatment (Fung et al. 2016). Mood stabilizers such as
Network 2017). Divalproex sodium (Hollander et al. 2010) and
opioid antagonists (naltrexone) may decrease
irritability in ASD but more clinical trials are
Comorbidities in ASD required (Fung et al. 2016). Medication com-
bined with behavioral intervention appears to be
Comorbid conditions are common in ASD indi- more effective for reducing aggressive behav-
viduals though overlapping symptoms of ASD ior than medication alone (Dawson and Burner
and other disorders often make diagnosis difficult. 2011). Novel treatments with glutamatergic

agents (amantadine, memantine, riluzole, NAC) interventions (Coury et al. 2012). Available data
are underway and encouraging results have been do not support the use of casein-free, a gluten-free
seen with N-acetylcysteine (NAC) when used as diet or combination diets as a primary treatment
an adjunctive therapy to risperidone in deceas- for children with ASD, but results have largely
ing irritability in children with ASD (Ji and been controversial as to whether there is any role,
Finding 2015). in the absence of diagnosed sensitivity or frank
celiac disorder (Buie et al. 2010). In a largest
Seizures study of its kind, researchers did not find any
The prevalence of epilepsy in ASD varies from links between autism and celiac disease, though
5% to 38% and is related to underlying co- there was a strong association between autism
morbid medical and intellectual disability. The and presence of antibodies to gluten suggesting
risk of seizures and epilepsy increase with age. gluten sensitivity (Ludvigsson et al. 2013).
Every clinical seizure type has been noted in
ASD. The prevalence of subclinical electrical dis- Anxiety
charges (SED) in ASD range from 30% to 61% At least one anxiety disorder is seen in 39.6% of
in studies that have used long term EEG moni- the youth with ASD (Van Steensel et al. 2011).
toring (Richard 2015). Studies have suggested There is now evidence that anxiety may be
that SED is common in childhood, while clinical “underdiagnosed” in this population, and stan-
seizures become increasingly prevalent with age dard anxiety screening tools may under-diagnose
(Parmeggiani and Barcia 2010). In individuals anxiety in these patients (White SW et al. 2009).
with ASD, the SED is multi-focal and includes The range of prevalence of anxiety disorders in
temporal and frontal cortical areas and it has the latter review was 11-84%.
been suggested that SED may be associated with Treatment recommendations include psy-
more severe speech and intellectual impairment choeducational coordination of care and modi-
in children with ASD (Richard 2015). Studies on fied cognitive behavior therapy, which has been
individuals with SED but no ASD are associated clearly shown to be beneficial especially in high
with cognitive and behavior impairment which functioning patients with ASD. It should be noted
improve with antiepileptic medication (Pressler that anxiety can often present as inattention and
et al. 2005). Treatment of children with SED and restlessness, and therefore can mimic features of
ASD may be beneficial but further research is ADHD. It can also present as a sleep disorder,
needed. Treating epilepsy in children with ASD affecting both sleep initiation and night awak-
follow the same principles as treatment of epi- ening. Patients with anxiety and ASD can also
lepsy in any individual. present with self-injurious behaviors and aggres-
sion. Specific phobias such as elevators, insects,
Gastrointestinal (GI) thunder and lightning, etc. are not unusual.
Gastrointestinal disorders are commonly associ- SSRI’s are frequently prescribed for anxiety in
ated with a subset of children with autism spec- youth with ASD though there is limited evidence
trum disorder. The prevalence of GI problems unlike in typically developing youth with anxiety.
reported in children with autism spectrum disor- Children with ASD may respond to far lower dos-
der range from 9% to 91% depending on the defi- ages than would be typically expected. As such,
nition used (Mannion and Leader 2014). The most a liquid formulation is preferred, as this allows
common GI complaints in children with autism for lower titration (Folstein and Carcache 2016).
are constipation, diarrhea and gastroesophageal SSRI’s should be prescribed cautiously in youths
reflux and are treated in a standard manner. There with ASD with close monitoring (Folstein and
is emerging evidence on GI dysfunction in ASD Carcache 2016; Vasa et al. 2016). Some research
and the relationship of increased intestinal perme- also suggests the use of buspirone, or mirtazapine
ability, gut microbiome, immune function though if SSRIs fail (Politte et al. 2015). It is also impor-
scientific conclusions cannot be reached yet on tant to inquire about a family history of the mood

or anxiety disorder in these children, as there is with motor tasks like writing, dressing, self-care,
some evidence that a high proportion of children and participating in sports, etc. This further nega-
with ASD and a mood/anxiety disorder also have tively impacts social acceptance by peers. With
a parent with a mood/anxiety disorder (Mazefsky the change to the DSM 5 a formal diagnosis of
et al. 2008). DCD can be made if the ASD individual meets
the motor criteria, which is a change from the
Sleep Problems DSM IV-TR. Referral to a physiotherapist (PT)
Sleep problems are common in autism spec- and occupational therapist (OT) is recommended
trum disorder, with prevalence rates of 40–80% in this scenario. Treatment modalities vary,
(Cohen et al. 2014; Cortesi et al. 2010). Sleep depending on the areas of need (e.g. fine (FM)
issues include increased sleep latency, frequent or gross motor skills, and presence of intellectual
night waking, and shorter sleep duration (Cortesi impairment). Generally, individual sports (e.g.
et al. 2010). It is worth noting that sleep onset and swimming, or martial arts) are recommended for
night-waking problems are often associated with gross motor skills, and the OT will recommend
poor sleep hygiene or maladaptive sleep asso- FM adaptive devices, where applicable or com-
ciations. Good sleepers with ASD showed fewer puter software. For a great review of this topic
affective problems and better social interaction please see Paquet et al. (2015).
then ASD poor sleepers (Cohen et al. 2014;
Marlow et al. 2006; Cortesi et al. 2010). The rea- I ntellectual Disability (ID)
sons for sleep difficulties in children with ASD Intellectual Disability (IQ < 70) has been reported
are multifactorial: poor sleep hygiene, medical in 31% of children with ASD while 23% was in
issues (GI, seizures), medications, psychiatric the borderline range (IQ 71–85) and 46% in the
issues (anxiety, depression, ADHD), abnormal average or above range (IQ have increased >85)
melatonin regulation among others. Management range. However, because of a variety of behav-
requires addressing any medical or psychiatric ioral, language and mental health co-morbidities,
issues that may interfere with sleep. Behavioural getting an accurate assessment of intellectual
intervention (including sleep hygiene) can be functioning in children with ASD can be chal-
effective in decreasing sleep problems and should lenging. These individuals often “march to their
be tried first, before medication (Cortesi et al. own drum” and may not demonstrate their opti-
2010). Addressing sensory issues may facilitate mal abilities on queue. Children with IQ in the
sleep in some children (e.g. weighted blankets). average to above range have increased in the last
Light therapy can be considered for children with decade from 32% in 2002 to 46% in 2010. This
ASD who present with circadian dysfunction shift in IQ may be attributed to a larger propor-
(Cortesi et al. 2010). Melatonin has been shown tion of children with average to above average IQ
to be effective in a subgroup of children with being diagnosed with ASD (Buio 2014). As with
ASD by decreasing the onset and improving the all other co-morbidities, ID significantly impacts
duration of sleep (Goldman et al. 2014). Low fer- prognosis negatively. As noted earlier, all patients
ritin levels have been found to be associated with with ID warrant specific genetic, and possibly
sleep disturbances in both children and adults, metabolic work-up.
notably periodic leg movements and ADHD and
studies have been done in the ASD population as ics and Tourette Syndrome (TS)
T
well (Dosman et al. 2007). Burd et al. (2009) studied 7288 participants from
the Tourette Syndrome International Database
evelopmental Coordination Disorder
D Consortium Registry and found that 4.6% had a
(DCD)/Dyspraxia co-morbid autism spectrum disorder. Increased
Numerous studies have described motor impair- risk was noted in “male gender, no family history
ments (Dyspraxia/DCD) in the ASD population of tics/Tourette syndrome, and an increased num-
(Dziuk et al. 2007). Children with DCD struggle ber of comorbidities (P < 0.001)”. Interesting

questions surface about the similarities between Exciting times are ahead as we endeavour to
the two conditions, namely complex tics versus look into these fascinating questions.
stereotypies, and OCD versus repetitive behav-
iors among others. Ordering and arranging com-
pulsions occur in TS while lining up toys, etc.,
is commonly noted in ASD. Hoarding behaviors
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Update in Pediatric Emergency
Medicine: Pediatric Resuscitation, 8
Pediatric Sepsis, Interfacility
Transport of the Pediatric Patient,
Pain and sedation in the
Emergency Department, Pediatric
Trauma
Tania Principi, Deborah Schonfeld,
Laura Weingarten, Suzan Schneeweiss,
Daniel Rosenfield, Genevieve Ernst,
Suzanne Schuh, and Dennis Scolnik
Resuscitation Airway
Cardiopulmonary arrest in the pediatric popula- The most common cause of pediatric cardiac
tion is infrequent and it is thus important that arrest is usually respiratory distress leading to
physicians who deal with children are comfort- respiratory failure (Shaw and Bachur 2016).
able managing the pediatric airway and using Tracheal intubation is the definitive method to
Pediatric Advanced Life Support (PALS) algo- secure the airway and should be considered when
rithms. With improved evidence and manage- the patient is unable to oxygenate, ventilate, lacks
ment of pediatric cardiac arrests, the rates of respiratory drive and/or has lost his/her airway
survival for pediatric in- hospital arrest have con- protective reflexes. Pediatric airway management
siderably improved over the last 10 years from can be challenging due to the following differ-
24% to 39% (Girotra et al. 2013). ences in anatomy compared to the adult airway:
T. Principi • D. Schonfeld, M.D., F.R.C.P.C.

S. Schneeweiss, M.D., M.Ed., F.R.C.P.C.
D. Rosenfield • G. Ernst, M.D., F.R.C.P.C.
Department of Pediatrics, Division of Pediatric
S. Schuh, M.D., F.R.C.P.(C.), F.A.A.P. (*)
Emergency Medicine, University of Toronto,
Division of Paediatric Emergency Medicine,
Toronto, Ontario, Canada
Research Institute, Hospital for Sick Children,
e-mail: tania.principi@sickkids.ca;
Deborah.schonfeld@sickkids.ca;
e-mail: suzanne.schuh@sickkids.ca
suzan.schneeweiss@sickkids.ca;
Daniel.rosenfeld@sickkids.ca; D. Scolnik, F.R.C.P.(C.), D.C.H., M.Sc.
Genevieve.ernst@sickkids.ca Department of Paediatrics, Faculty of Medicine,
L. Weingarten
Pediatric Emergency Physician and Assistant Clinical Divisions of Paediatric Emergency Medicine
Professor, Department of Pediatrics at McMaster and Clinical Pharmacology and Toxicology,
University, Hamilton, Canada The Hospital for Sick Children, Toronto, ON, Canada
e-mail: laura.weingarten@gmail.com e-mail: dennis.scolnik@sickkids.ca


224 T. Principi et al.
Table 8.1 Suggested equipment for intubation (Singh and Frenkel 2013; Mittiga et al. 2015),
• Cardiac monitors with automated blood pressure pediatric research on this issue is limited (Steiner
measurements and continuous pulse oximetry 2016).
• Non-rebreather mask Although uncuffed tubes were previously
• Bag-valve mask recommended in pediatrics due to airway nar-
• Functional suction device rowing at the glottis and concerns about muco-
• Functioning laryngoscope with various blades and sal injury, evidence suggests that pediatric
sizes
cuffed endotracheal tubes are safe to use in the
• Endotracheal tubes with stylet, one size above and
below desired tube size pediatric population. The use of cuffed tubes
• End-tidal CO2 detector: capnography or colorimetery is associated with fewer tube changes,
• 10 mL syringe decreased risk of aspiration and allows for
• Nasopharyngeal and oropharyngeal airway higher airway pressures during ventilation
• Tape to secure the tube without an increased risk of complications
• Laryngeal mask airway (Kleinman et al. 2010a; Weiss et al. 2009; Shi
et al. 2016). It is important that cuffed tubes
are inflated to no more than 20 cm of water.
larger occiput, large tongue in proportion to the The size of tube can be estimated by length-
oral airway, more anterior location of the vocal based tools or by using the following age-
cords and floppy epiglottis (Singh and Frenkel based formulas: age/4 + 3.5 for cuffed tubes or
2013). Prior to intubation, all the necessary per- age/4 + 4 for uncuffed tubes (Kleinman et al.
sonnel and equipment must be readily accessible. 2010a). An endotracheal tube one size above
Table 8.1 lists the necessary equipment for intu- and below the estimated size should also be
bation; intravenous or intraosseous access should available, and consideration should be given
be obtained and all required medications drawn to using a stylet. Successful placement should
up prior to intubation. be confirmed through direct visualization,
Pre-oxygenation is important to minimize CO2 detection, and chest x-ray or ultrasound
desaturation and to increase the safe apnea time confirmation in addition to auscultation
during intubation. Ideally, the patient should be (Mittiga et al. 2015; Kleinman et al. 2010a;
pre-oxygenated for at least 3 min (Weingart and Chou et al. 2015). Cricoid pressure is no lon-
Levitan 2012). If the patient is adequately breath- ger routinely recommended during rapid
ing, oxygenation can be accomplished through a sequence intubation as it has been shown to
100% non-rebreather mask with the rate of oxy- decrease the success of intubation with little
gen flow as high as possible. Bag Mask Ventilation effect on the risk of aspiration (Kleinman et al.
(BMV) should be initiated in the apneic patients 2010a; Ellis et al. 2007). If BMV is unsuccess-
and in those with poor respiratory drive to ensure ful and intubation is not possible a Laryngeal-
adequate pre-oxygenation. To further increase Mask Airway (LMA) may be used to provide a
the safe apnea time and the success rate of the patent airway and ventilation support (de Caen
first intubation attempt, apneic oxygenation is et al. 2015a).
used during rapid sequence intubation (RSI) in
adults (Singh and Frenkel 2013; Weingart and
Levitan 2012; Mittiga et al. 2015). This entails Medications
the application of oxygen via nasal prongs in
addition to pre-oxygenation, and acts as an Medications should be used to help facilitate the
adjunct to pre-oxygenation by providing an oxy- success of intubation and decrease complica-
gen filled pharynx used as a reservoir for alveolar tions. Contrary to previous recommendation to
ventilation (Weingart and Levitan 2012). use atropine to mitigate the risk of pediatric bra-
Although the adult evidence shows promise dycardia, evidence to demonstrate this benefit

8 Update in Pediatric Emergency Medicine 225
has been lacking (Singh and Frenkel 2013; de myopathies or a history of malignant hyperther-
Caen et al. 2015a). The most recent PALS guide- mia and it can cause bradycardia with repeated
lines do not support the routine use of atropine doses (Singh and Frenkel 2013). Rocuronium is a
during pre-intubation in children (de Caen et al. longer-acting paralytic agent at doses of 0.6–
2015a). The use of atropine may be considered in 1.2 mg/kg. Lower doses of rocuronium result in a
children at increased risk of bradycardia (such as shorter duration of action but require a longer
in infants under one year of age, when using suc- time to take effect. Unlike succinylcholine,
cinylcholine in children under 5 years of age or in rocuronium does not have any contraindications
patients receiving multiple doses of succinylcho- but care should be taken in using rocuronium
line) or in those who are bradycardic prior to patients with difficult airways (Singh and Frenkel
intubation (Singh and Frenkel 2013). The recom- 2013; Stollings et al. 2014).
mended dose of atropine when used as a premed-
ication agent for RSI is 0.02 mg/kg, with no
minimum dose (de Caen et al. 2015a). Cardiopulmonary Resuscitation
Common sedatives used for RSI in pediat-
rics include etomidate and ketamine. Etomidate, There in ongoing evidence that cardiopulmonary
at a dose of 0.3 mg/kg is an excellent sedative resuscitation (CPR) should be performed hard
medication for this purpose due to its minimal and fast. In infants and children; the chest should
associated cardiovascular side effects. Given be compressed to one-third of the anterior-
the risk of possible adrenal suppression, etomi- posterior diameter of the chest, at a rate of 100–
date is not currently recommended in the septic 120 compressions per minute (Atkins et al. 2015).
patient (Kleinman et al. 2010a; den Brinker Full recoil should occur between compressions
et al. 2008; Chan et al. 2012; Bruder et al. and all efforts should be made to minimize inter-
2015). Ketamine is a dissociative sedative agent ruptions in CPR. Compressions to ventilation
used at doses of 1–3 mg/kg. Ketamine is par- should occur at a ratio of 15:2 until a definitive
ticularly useful in hypotensive patients or those airway or LMA is present (Atkins et al. 2015).
with severe asthma. Since ketamine does not Respirations can be provided by BMV using
inhibit spontaneous respirations, it is a useful adjuncts such as naso-pharyngeal or oro-
sedative for difficult intubations. Contrary to pharyngeal airways to improve oxygenation. If
previous belief, recent evidence suggests that skilled personal are present, tracheal intubation
ketamine is safe to use in children with may be attempted while minimizing interruptions
increased intracranial pressure. (Filanovsky to chest compressions. If BMV is unsuccessful
et al. 2010; Hughes 2011). Although commonly and intubation is not possible, ventilation via
used for intubation, the use of propofol in the LMA should be considered (de Caen et al.
emergency department should be limited to 2015a). Early vascular access is important to
experienced personnel due to a significant risk allow for the administration of fluids and medica-
of hypotension (Shaw and Bachur 2016; Singh tions. Early insertion of an intraosseous needle
and Frenkel 2013). Other medications such as provides timely and effective access during
benzodiazepines and opiates can also be used resuscitation; intraosseous medications can be
for sedation in RSI but these may not be as reli- given at the IV-recommended doses.
able or effective (Singh and Frenkel 2013; Defibrillation is the asynchronous delivery of
Stollings et al. 2014). an electrical current to the myocardium in an
Rocuronium and succinylcholine are the most effort to established sinus rhythm. Defibrillation
commonly used neuromuscular blocking agents. should be administered as soon as possible in
Succinylcholine at dose of 1–2 mg/kg provides a patients with ventricular fibrillation or pulseless
rapid onset of action with a short duration. It is ventricular tachycardia at an initial dose of 2 J/kg
contraindicated in patients with hyperkalemia, (de Caen et al. 2015a). Adult size paddles should

be used for patients older than a year of age or response to infection that the offending pathogen
weighing more than 10 kg and can be placed on itself.
the right upper chest and apex. If unsuccessful,
repeated doses can be given at 4 J/kg (de Caen
et al. 2015a). Definitions
Cardioversion is the synchronous delivery of
an electrical current to the myocardium in an Definitions for sepsis and organ dysfunction in
effort to prevent ventricular fibrillation. It is children have been developed by the International
indicated for the treatment of perfusing rhythms Consensus Conference on Pediatric Sepsis
when a pulse is present, such as stable ventricu- (Goldstein et al. 2005). SIRS is a non-specific
lar tachycardia or supraventricular tachycardia. inflammatory reaction in response to insults such
The initial recommended cardioversion dose is as infection, trauma, burns, pancreatitis and
0.5–1 J/kg, which can be increased to 2 J/kg other diseases. SIRS in children is characterized
with subsequent attempts (Kleinman et al. by a temperature abnormality (fever or hypother-
2010a). mia) or an age-specific abnormality in the white
In depth review of all the PALS algorithms are blood cell count, and one of the following:
beyond the scope of this book. Please refer to tachycardia (or bradycardia in infants under 1
PALS algorithms for further details. year of age), tachypnea or an acute respiratory
condition requiring mechanical ventilation.
SIRS in the presence of confirmed or suspected
Post-cardiac Arrest Hypothermia infection constitutes sepsis. Severe sepsis is
defined as sepsis associated with cardiovascular
After return to spontaneous circulation, every dysfunction, acute respiratory distress syndrome
effort should be made to maintain normothermia (ARDS), or dysfunction in two or more other
and to treat any hyperthermia. Although there organ systems (specific definitions of respira-
have been several studies evaluating the neuro- tory, cardiovascular, neurologic, hematologic,
protective effects of hypothermia in pediatrics, a hepatic and renal dysfunction are based on
recent randomized controlled trial and meta- expert opinion). Septic shock is defined as sepsis
analysis both demonstrated lack of improved sur- in the presence of cardiovascular dysfunction.
vival after permissive hypothermia (Moler et al. Compensated shock refers to a shock state in
2015; Bistritz et al. 2015). which the blood pressure remains in age-appro-
priate range. Hypotension represents a late and
often ominous sign in pediatric patients. The
Introduction presence of hypotension is the hallmark of
decompensated shock.
Sepsis is a systemic and often deleterious host
response to infection. It is widely accepted that the
onset and progression of sepsis results from a dys- Epidemiology and Risk Factors
regulated inflammatory response that leads to
widespread tissue injury and end organ dysfunc- The global burden of illness from pediatric sep-
tion (Hotchkiss and Karl 2003). Practically speak- sis is very high. Infectious diseases such as
ing, sepsis represents a spectrum of disease malaria, gastroenteritis and pneumonia, often
ranging from the systemic inflammatory response culminating in severe sepsis and septic shock,
(SIRS) to septic shock and multi-organ system are the most common cause of death in infants
dysfunction. The tendency to proceed along this and children worldwide. In the United States the
spectrum is more likely determined by the host prevalence of severe sepsis has been rising over

the past decade (Ruth et al. 2014; Balamuth et al. identified. This is commonly referred to as
2014), with estimated pediatric hospitalizations “culture-negative” sepsis.
due to severe sepsis exceeding 75,000 cases
annually (Hartman et al. 2013). Young infants,
especially low birth weight neonates, are at the Pathophysiology
highest risk, and children with co-morbid medi-
cal conditions account for more than half the The longstanding pediatric mantra that “children
cases. This includes children with chronic lung are not little adults” certainly applies to sepsis.
disease, congenital heart disease, malignancy, The differences between the pediatric and adult
and those with conditions impacting the immune response to infection have important implications
system (Hartman et al. 2013). Children with on the presentation and treatment of sepsis in
indwelling devices and anatomic abnormalities children compared to older patients (Brierley
are also at high risk for bacterial seeding and et al. 2009). First, severe hypovolemia, likely due
infection. In North America, the mortality rate to a combination of dehydration and increased
from pediatric severe sepsis and septic shock is microvascular permeability, is a hallmark of
estimated to be 5–15% but approaches 30% in pediatric septic shock. Therefore, children fre-
those with comorbid disorders and significant quently respond well to aggressive fluid resusci-
organ dysfunction (Ruth et al. 2014; Hartman tation. Second, the hemodynamic response to
et al. 2013; Watson et al. 2003; Kutko et al. 2003; sepsis is significantly different in the two popula-
Weiss et al. 2015a). tions (Fig. 8.1). Up to 90% of adult patients pres-
ent with a “hyperdynamic shock”, otherwise
known as “warm shock”. Despite myocardial
Etiology and Microbiology dysfunction, cardiac output (CO) is typically
maintained by an increase in heart rate and
The most common primary sites of infection in decrease in systemic vascular resistance (SVR).
children are respiratory (40–50%) and blood- Thus, the adult response to sepsis is characterized
stream (10–20%) (Weiss et al. 2015a), with by tachycardia, hypotension and a normal, or
abdominal, genitourinary, central nervous sys- increased, cardiac output. The predominant cause
tem and skin infections accounting for the of mortality in adult septic shock is vasomotor
majority of remaining cases. Although bacterial paralysis (when SVR cannot be further increased
and viral pathogens are most common, fungal, with vasopressor agents). In contrast, at least
parasitic, or rickettsial infections can also lead 50% of infants and children present with “cold
to sepsis. The most commonly implicated bacte- shock”. Although an increase in heart rate is a
rial organisms are staphylococcal species child’s principal means of maintaining CO, a pre-
(including Staphylococcus aureus in previously dominant response to a decreased CO in children
healthy patients and coagulase-negative staphy- is vasoconstriction. Blood flow is redistributed
lococci in those with indwelling catheters) and from non-essential vascular beds such as the skin,
streptococcal species. Gram-negative organisms to essential organs such as the heart, brain and
are frequently responsible for urinary tract lungs. This increase in SVR maintains a normal
infection (UTI)-related sepsis and sepsis in blood pressure, even with significant decreases in
immunocompromised hosts. The most common CO. Hypotension is therefore a late sign in pedi-
viral pathogens include the respiratory viruses atric septic shock, and often signifies impending
(influenza, parainfluenza, respiratory syncytial cardiovascular collapse. Thus, the pediatric
virus (RSV), adenovirus) (Gaines et al. 2012). It response to sepsis is often characterized by tachy-
should be noted however, that in up to two thirds cardia, normal blood pressure and decreased car-
of septic shock cases, no infectious pathogen is diac output. In children, low CO is most often

Fig. 8.1 Comparison of COLD SHOCK WARM SHOCK

cold and warm septic
shock. HR heart rate, Hemodynamics ↑HR, ↑SVR, ↓CO, ↑HR, ↓SVR, ↑CO, ↓BP
SVR systemic vascular BP maintained until late
resistance, CO cardiac
output, BP blood Clinical Features Capillary refill >2sec, Flash capillary refill <1sec,
pressure Cool, mottled skin, Warm, flushed skin,
Weak pulses, Bounding pulses,
Narrowed pulse pressure Widened pulse pressure,
Altered mental status, Altered mental status,
Decreased urine output Decreased urine output
First Line Vasoactive Epinephrine (0.05- Norepinephrine (0.03-

Support for fluid- 0.3mcg/kg/min); 0.05mcg/kg/min)
refractory shock Can use Dopamine (5-10 Can use Dopamine
mcg/kg/min) if (>10mcg/kg/min)
epinephrine unavailable if norepinephrine unavailable
associated with mortality, in contrast to adults nosis, is confirmatory in a child with suspected
who often succumb to low SVR. It should be infection. Although no laboratory test is sensi-
noted however, that the clinical presentation of tive or specific enough to be used alone, some
septic shock in children can be highly variable experts recommend using lactic acid (a by
and can include a combination of hemodynamic product of anaerobic metabolism and marker
abnormalities. of tissue hypoperfusion) as a diagnostic
adjunct. Elevated initial lactic acid levels
(≥4.0 mmol/L), and failure of lactate levels to
Diagnosis normalize (<2 mmol/L) or progressively clear
with resuscitative efforts may be poor prognos-
Although the specific definitions of cardiovas- tic indicators in pediatric sepsis (Scott et al.
cular dysfunction set forth by the international 2012, 2016).
consensus criteria help standardize patient
populations for research purposes, they may be
less pertinent in the everyday clinical setting Management
(Weiss et al. 2012, 2015b). Clinical suspicion
for septic shock should always supersede reli- Early recognition and aggressive treatment of
ance on the presence of specific consensus cri- septic shock are essential to reducing morbidity
teria. The diagnosis of septic shock should be and mortality. The American College of Critical
made in children with sepsis (SIRS with infec- Care Medicine (ACCM) and the Pediatric
tion) and signs of inadequate tissue perfusion Advanced Life Support (PALS) course have
including any of the following: decreased or published internationally recognized guidelines
altered mental status, decreased urine output for the management and hemodynamic support
(<1 ml/kg/h), capillary refill >2 s (cold shock), of pediatric septic shock (Brierley et al. 2009;
cool or mottled extremities (cold shock), Kleinman et al. 2010a, b). The two guidelines
diminished pulses (cold shock), flash capillary outline a similar step-wise approach to resusci-
refill (warm shock), bounding peripheral pulses tation directed at restoring physiologic indica-
(warm shock), and wide pulse pressure (warm tors of perfusion: normal mental status,
shock) (Brierley et al. 2009). The presence of threshold heart rates, normal peripheral perfu-
hypotension, although not necessary for diag- sion (cap refill <3 s), palpable distal pulses and

0 min
Recognize decreased mental status and perfusion.
Begin high flow O2 and establish IO/IV access according to PALS.
5 min
If no hepatomegaly or rales/ crackles then push 20 mL/kg isotonic saline boluses
and reassess after each bolus up to 60 mL/kg until improved perfusion. Stop for
rales, crackles or hepatomegaly. Correct hypoglycemia and hypocalcemia.
Begin antibiotics.
15 min Fluid refractory shock?
Begin peripheral IV/IO inotrope infusion, preferably Epinephrine 0.05 - 0.3 µg/kg/min
Use Atropine/Ketamine IV/IO/IM if needed for Central Vein or Airway Access
Titrate Epinephrine 0.05 - 0.3 mg/kg/min for Cold Shock.

(Titrate central Dopamine 5-9 µg/kg/min if Epinephrine not available)
Titrate central Norepinephrine from 0.05 µg/kg/min and upward to reverse Warm Shock.
(Titrate Central Dopamine ≥ 10 µg/kg/min if Norepinephrine not available)
60 min Catecholamine-resistant shock?
If at risk for Absolute Adrenal Insufficiency consider Hydrocortisone.

Use Doppler Us, PICCO, FATD or PAC to Direct Fluid, Inotrope, Vasopressor, Vasodilators
Goal is normal MAP-CVP, ScvO2 > 70%* and CI 3.3 – 6.0 L/min/m2
Fig. 8.2 First hour goals for the management of hemody- College of Critical Care Medicine. Crit Care Med
namic support in infants and children with septic shock 2009;37:666. **Of note, this guideline and algorithm is
(intensive care unit goals not shown). Reproduced with undergoing review by the American College of Critical
permission from from Brierley J, Carcillo JA, Choong K, Care Medicine. The updated version of these guidelines is
Cornell T, DeCaen A, Deymann A et al. Clinical practice expected to support epinephrine as the first line vasoactive
parameters for hemodynamic support of pediatric and agent for cold shock
neonatal septic shock: 2007 update from the American
normal blood pressure. The ‘first-hour’ thera- bation is necessary, hemodynamic stability
peutic actions outlined in the ACCM guidelines should first be optimized with fluids. Ketamine is
should be regarded as best practices for emer- the sedative of choice. Etomidate should be
gency department resuscitation (Fig. 8.2). It has avoided due to the potential for adrenocortical
been shown that adherence to PALS-ACCM axis suppression (Brierley et al. 2009; den
guidelines significantly reduces mortality and Brinker et al. 2008).
hospital length of stay (Han et al. 2003; Paul Intravenous access should be established
et al. 2012; Carcillo et al. 2009; Oliveira et al. within 5 min. If a peripheral IV cannot be estab-
2008). lished within this timeframe, an intraosseous
Within the first 5 min of septic shock recogni- catheter should be inserted. Laboratory tests,
tion, 100% oxygen via a non-rebreathing mask including blood cultures, should ideally be
should be applied to maximize oxygen delivery obtained at the time of intravenous access.
to tissues. A significant amount of cardiac output Patients in septic shock are at risk for hypogly-
supports work of breathing so ventilation should caemia and hypocalcemia, so clinicians should
be supported as required. If rapid sequence intu- be prepared to administer dextrose and calcium

as needed. Children with hypoglycaemia should ampicillin to cover for Listeria.

be administered and IV bolus of 0.25 g/kg of dex- Immunocompromised children at risk for pseudo-
trose (2.5 mL/kg of D10W OR 1 mL/kg of monas infections should also be treated with
D25W). Hypocalcemia can be corrected via infu- broader spectrum agents including carbapenems.
sion of calcium gluconate 10% solution in a dose Piperacillin with tazobactam, aminoglycosides
of 50–100 mg/kg (0.5–1 mL/kg). and/or metronidazole should be used when enteric
Volume resuscitation is the cornerstone of the organisms are suspected, and clindamycin is rec-
ACCM management. Initial therapy should ommended in cases of suspected toxic shock or
begin with a bolus of 20 mL/kg of isotonic crys- necrotizing fasciitis.
talloid solution infused over 5 min or as rapidly Based on expert opinion, the ACCM recom-
as possible, preferably with a manual “push- mends starting a vasoactive agent when a
pull” technique or rapid infuser. Repeated patient remains in shock despite 40–60 mL/kg
20 mL/kg fluid boluses should be given until of fluid resuscitation (‘fluid-refractory shock’).
markers of tissue perfusion (discussed above) Although central access is preferred, periph-
normalize, or signs of fluid overload (lung rales, eral intravenous access can, and should be,
gallop rhythm, hepatomegaly) develop. Many used for initial vasoactive infusions (Brierley
children require up to 60 mL/kg within the first et al. 2009). Due to widespread availability and
hour. Recently, a large trial in sub-Saharan clinician familiarity, dopamine has tradition-
Africa demonstrated increased mortality from ally been the first line vasoactive agent.
fluid boluses in children with compensated sep- However, recent evidence suggests that epi-
tic shock (Maitland et al. 2011). Although it is nephrine is likely a safer and more effective
the only study of its kind to date, it highlights the first choice, especially for those with cold
potential for harm if fluid resuscitation is used shock (Ventura et al. 2015). According to the
indiscriminately in children in resource-poor most recent ACCM guidelines, peripheral epi-
settings with limited availability of mechanical nephrine is the preferred first line agent for
ventilation and vasoactive support. The most fluid-refractory shock. Thereafter, cold shock
recent PALS update maintains, that in resource should be reversed by titrating epinephrine (or
rich settings, fluid resuscitation remains a key low dose central dopamine), and warm shock
component of goal directed therapy but empha- reversed by titrating central norepinephrine (or
sizes the need for individualized clinical evalua- high dose central dopamine). Please see
tion and frequent reassessments to determine the Fig 8.2. Patients with catecholamine-resistant
appropriate volume of fluid resuscitation in shock often need a variety of vasodilators,
every patient (de Caen et al. 2015b, c). Studies afterload reducing agents and/or other vaso-
are currently underway to determine whether pressors that should be titrated in an intensive
children in developed countries might benefit care setting.
from fluid-sparing strategies. The use of corticosteroid therapy in those
Intravenous antimicrobial therapy should be with catecholamine-resistant shock remains con-
administered within 60 min of recognition. troversial as consistent, high quality evidence is
Appropriate antibiotic regimens depend on age, lacking (Pizarro et al. 2005; Atkinson et al. 2014;
likely responsible pathogens and known local pat- Menon et al. 2013; Zimmerman and Williams
terns of infection and resistance. Generally speak- 2011). Adjunctive steroid therapy is likely most
ing, a third or fourth generation cephalosporin important for patients at risk of adrenal insuffi-
plus vancomycin for methicillin-resistant ciency, children with purpura fulminans, those
Staphylococcal aureus coverage represent an with a history of chronic steroid therapy or
appropriate regimen for most children. In addition known hypothalamic, pituitary or adrenal
to the above, neonates should be treated with abnormalities.

Summary 1. Which transport team should provide care for

this child?
Signs and symptoms of shock may be subtle in 2. What is the best mode of transport?
children, leading to delays in recognition and 3. How can medical care be optimized prior to
underestimation of the severity of illness. The transport?
best approach to diagnosis involves a high 4. What supplies and equipment should be pre-
level of clinical suspicion combined with the pared for transport?
clinical history, vital signs and physical exami-
nation. Altered mental status and persistent References at the end provide additional infor-
tachycardia (often a sign of circulatory dys- mation on the transport of neonates (Whyte and
function) should not be overlooked. Jefferies, 2015) and pediatric trauma patients
Standardized emergency department sepsis (Michailidou et al. 2014; Meyer et al. 2016).
screening tools and protocols, which rely on
abnormal vital signs and physical examination
findings to help identify patients at risk, have Team Composition
been shown to reduce time to both fluid and
antibiotic administration (Cruz et al. 2011; Healthcare providers and parents often feel pres-
Larsen et al. 2011; Paul et al. 2014; Tuuri et al. sured to quickly move children to the centre
2016). where they will receive definitive care. However,
Emergency department nurses and physicians most experts agree that the majority of children
are in a unique position to affect sepsis outcomes are best served by stabilization at the referral
since the therapies that a child receives during centre prior to departure (Ramnarayan et al.
the initial treatment largely determine their prog- 2010; Barry and Leslie 2003). The child’s
nosis. It is therefore crucial that every clinician expected clinical course is the most important
who cares for children has a reliable approach to factor in determining transport team composi-
the recognition and resuscitation of pediatric tion and urgency of dispatch (Barry and Leslie
septic shock. 2003). For a critically ill child who is expected to
Ill and injured children often seek medical deteriorate or require significant support, it is
care at physician offices and community hos- usually better to wait for dispatch of a special-
pitals (McPherson et al. 2008). Healthcare ized team than for an ad-hoc team to be hastily
providers working in these settings must know assembled.
how to safely transport a child who requires Most evidence examining significant out-
additional resources or an escalation in level comes for children who require transport to a
of care. The regionalization of pediatric inten- PICU comes from small retrospective and a few
sive care units and trauma services has made it prospective studies. A Cochrane review found
imperative for providers to understand general there is no high quality evidence from random-
principles of transport medicine (Lorch et al. ized controlled trials to support or refute that spe-
2010). cialist teams for neonatal transport reduce
Despite existing recommendations by expert mortality or morbidity among newborns requir-
working groups, there are major variations in ing retrieval to a newborn intensive care unit
transport practice across North America and the (NICU) (Chang et al. 2008). Nevertheless, spe-
world (Lorch et al. 2010; Whyte and Jefferies cialized transport teams are recommended as
2015). This chapter provides an overview of being the best option for most critically ill infants
pediatric inter-facility transport and is divided and children who require inter-facility transport
into four sections, each exploring a different clin- (Whyte and Jefferies 2015). Ramnarayan et al.
ical question: (2010) found that use of a specialized retrieval

team was associated with decreased mortality (Whyte and Jefferies 2015; Barry and Leslie
risk in children transported to a pediatric inten- 2003). The referring physician is generally
sive care unit (PICU). Orr et al. also found that responsible for patient care until arrival at the
children transported by specialized teams had a receiving, facility unless alternate arrangements
lower death rate of 9%, versus 23% for those have been made. Additional medication orders,
transported by nonspecialized teams (Orr et al. supplies or resources should be anticipated and
2009). They also found that nonspecialized teams provided before departure.
who transport children have more significant Emergency medical services (EMS) teams are
adverse events including airway issues, cardio- often appropriate for infants and children who
pulmonary arrest, sustained hypotension, loss of require ongoing care, medications or fluids dur-
a crucial intravenous access and equipment failing transport e.g. an adolescent with suspected
ure with deterioration of patient status (Orr et al. appendicitis who requires surgical consultation.
2009). Although the majority of critically ill chil- EMS personnel and clinicians such as a nurse,
dren benefit from transport by a specialized team respiratory therapist or physician may work
once they are stabilized at the referring centre, together as a temporary team.
exceptions to this rule include children with epi- Parents and caregivers can transport stable
dural hematomas or bowel ischemia requiring children with no active airway or hemodynamic
emergent surgery. The relative benefits of imme- issues e.g. a child who requires foreign body
diate transport versus stabilization prior to depar- removal from an ear, by a specialist physician.
ture should be carefully weighed in these
children.
It is important to assess the transport team’s Transport Mode
comfort and experience with stabilizing children
before transferring patient care. A clear team The relative merits of different transport modes
handover should take place with each team mem- are outlined in Table 8.2. Transport specialists in
ber’s responsibilities being clearly outlined the PICU or NICU, emergency departments or
Table 8.2 Modes of transport

Transport mode Advantage Disadvantage
Private vehicle No dispatch time No medical providers
Already has car seat or booster
Land ambulance Easily available Slower than long distance flight
Fast dispatch time Traffic can be slow
Can stop for procedures Potholes and poor road conditions can
Accommodates extra team or family members worsen pain
Can be safer than helicopter for crew and
patient (Meyer et al. 2016)
Helicopter/rotor-wing Faster than long distance drive Affected by weather or night visibility
Can do scene calls in remote and austere Pressure at altitude can worsen some
settings injuries and diseases
Can land on helipad at hospital May not be able to accommodate family
members
Fixed wing Can be faster than driving long distances Requires additional transport leg to/from
airport
Affected by weather or night visibility
Small work area, loud and turbulent
Pressure at altitude can worsen some
injuries and diseases
May not be able to accommodate family
members

regional air ambulance service should always be recommended to optimize oxygenation and ven-
available to guide decisions about the safest and tilation parameters immediately before
most effective way to transport children. This departure.
decision depends on many factors, including: Oxygen saturation and end-tidal C02 should
be continuously monitored in all ill infants and
• The child’s current condition and expected children. Before departure, oxygen tanks and
clinical course. suction should be checked to ensure adequate
• Out-of-hospital time. supply for the full duration of transport.
• Distance. Tube thoracostomy should be considered for
• Traffic conditions. children with pulmonary injury or pleural
• Weather. effusion.
• Availability of specialized teams for air/land There are two special considerations in chil-
transport. dren who will be transported by air. First,
hypoxia will worsen during flight as the fraction
Pediatric trauma patients are frequently thought of inspired air (Fi02) decreases with altitude.
to require inter-facility transport by helicopter; Children with pulmonary injury or disease
although transport by helicopter is typically faster, should receive supplemental oxygen during
the decreased transport time comes at the expense flight, and flight plans may need to be reconsid-
of increased risk to the patient and may not neces- ered for children with an Fi02 requirement >0.8
sarily result in time-sensitive interventions at the on the ground. Second, the possibility of air
receiving facility (Michailidou et al. 2014; Meyer entrapment in a closed body cavity should be
et al. 2016). considered. Air expands at higher altitudes and
this can cause pain and organ damage in chil-
dren with pneumocephaly, pneumothorax and
Preparation for Transport ocular, dental or bowel injury. The operations
planner or flight team should be asked to limit
Critically ill children should be stabilized and altitude, or pressurize the cabin, when caring for
trauma patients should have a full primary and children with either of these real or potential
secondary survey prior to departure, unless problems.
extenuating circumstances are present. Many
transport teams now use pre-departure checklists
or EMS protocols. These resources can be invalu- Circulatory Considerations
able for ad-hoc teams tasked with infrequent
pediatric transport. Adequate and/or ongoing volume resuscitation
should be provided for children with tachycardia
or signs of poor perfusion. At least one, and pref-
Airway and Breathing Considerations erably two, reliable intravenous or intraosseous
lines should be available for transport. The can-
The airway should be patent or adequately pro- nula sites must be visible with ports readily
tected, and the cervical spine should be immobi- accessible and sufficient fluids, blood products
lized in injured patients. Children may require and/or inotropic supports should be available for
intubation for oxygenation failure, ventilation the duration of transport.
failure, pulmonary toilet or expected clinical Pediatric trauma patients need to be inspected
course. If the child is intubated, their endotra- for signs of external bleeding, which should be
cheal tube should be well secured after place- managed with direct pressure, sutures, staples or
ment is confirmed according to local practice other hemostatic controls. Sources of internal
guidelines. A gastric tube should be left open to hemorrhage such as thoracic or abdominal injury,
drainage in these children. A blood gas is strongly as well as significant external hemorrhages

should be clearly delineated to the receiving Table 8.3 Essential equipment and supplies
facility. Urinary catheterization to monitor urine Type of
output in critically ill children should be intervention Equipment and supplies
considered. Airway and Bag-valve device, endotracheal
breathing tubes, laryngoscope
Oxygen and nonrebreather masks
Portable ventilator and circuit
isability and Exposure
D Portable oxygen and air cylinders
Considerations Suction unit and catheters
Chest tubes
Difficult airway adjuncts – e.g.
Blood glucose should be measured prior to depar- LMA, oropharyngeal airway
ture and normoglycemia assured. A focused neu- Cervical immobilizers
rologic examination, including Glasgow Coma Circulation Intravenous cannulas
Scale, assessment of pupillary response, motor Intraosseous needles
Infusion pumps
activity and tone in all limbs, should be per-
Extra tubing, stopcock,
formed prior to administration of sedatives or T-connectors
paralytic agents. Targeted treatments should be Defibrillator
considered if increased intracranial pressure is Backboard
suspected. Monitoring and Pulse oximetry
investigations EtC02 monitors
Temperature should be recorded for all chil-
Cardiorespiratory monitors
dren and measured continuously for infants, Blood pressure cuffs
small children and unconscious patients. Thermometer
Thermoregulation can be maintained with a head Glucometer
Point-of-care laboratory testing
covering, warm blankets or increasing the ambi-
device and analyzer
ent temperature as needed. Fever and hyperther- Medicationsa Useful medications to consider
mia should be treated with antipyretics. A include:
head-to-toe physical examination to document Analgesics and sedatives – e.g.
rashes, bruises or skin marks should be per- ketamine, fentanyl, morphine,
nitrous oxide
formed and recorded prior to departure. Anaphylaxis – e.g. epinephrine
1:1000, epinephrine auto-injector
Anti-arrhythmics and cardiac
Supplies and Equipment medications – e.g. epinephrine
1:10,000, adenosine, amiodarone,
atropine, lidocaine, prostaglandin,
Many transport teams use pre-departure packing inotropes and pressors
lists to organize supplies and equipment prior to Antimicrobials –e.g. ceftriaxone,
transport. One example of a simplified checklist ampicillin, cefotaxime and/or
gentamycin
is provided in Table 8.3. A variety of neonatal, Anti-epileptics – e.g. lorazepam,
pediatric and adult sizes should be available for midazolam, diazepam,
all equipment listed. fosphenytoin, phenytoin,
Essential medications depend on the child’s phenobarbital
Blood products and fluids – e.g.
condition and expected course. Most regions normal saline, dextrose 10%,
have local EMS protocols for paramedics to dextrose 50%, 3% hypertonic
deliver necessary and life-saving medications in saline, sterile water, albumin
the prehospital setting. As a general rule, most Other – e.g. steroids
(dexamethasone, hydrocortisone,
specialized teams carry cardiac drugs, antibiot- methylprednisolone), paralytics
ics, anticonvulsants, analgesics, sedatives, para- (succinylcholine, rocuronium),
lytics and intravenous fluids on each transport. activated charcoal, salbutamol,
Blood products may also be prepared for trans- diphenhydramine, glucagon,
insulin, magnesium sulphate,
port of a trauma patient. sodium bicarbonate

Table 8.3 (continued) Grant 2006; Alexandre and Manno 2003; Krauss

Type of et al. 2016). An addition, fear of procedures is
intervention Equipment and supplies reported by children to be a significant anxiety-
Moving the Stretcher or incubator provoking aspect of their emergency room visit
child safely Safety belts and the pain experience itself can have long term
Metal pole or shelf to secure
monitors, pumps and equipment consequences (Kennedy et al. 2008). Pain and
Record- Patient transport record anxiety in infants and children can be success-
keeping Resuscitation drug chart fully treated in the emergency room with use of
and Mobile telephone age-appropriate pain assessment tools and imple-
communication Information package for parents
mentation of non-pharmacologic and pharmaco-
with contact numbers
Pen and medication/infusion labels logic pain management strategies.
Additional Personal protective equipment—
supplies gowns, gloves, and masks
Extra batteries for all electronics Pain Assessment
Personal Warm clothing and appropriate
footwear
Personal items
Pain assessment can be difficult particularly in
Food and beverage younger children and infants as they are unable
a
Local EMS and specialized teams may carry a wide range to verbalize their pain and often have associ-
of medications depending on their protocols and scope of ated anxiety related to fear of procedures or the
practices. Never assume a given medication will be avail- emergency setting itself. Pain assessment tools
able. The child’s expected clinical course should dictate
are widely available and ideally should be used
which medications are prepared and drawn up prior to
departure from the referring hospital in triage as the first step in pain management
(Srouji et al. 2010; Drendel et al. 2011). Early
use of pain assessment scores has been shown
It is challenging and rewarding to care for to increase provision of analgesia and decrease
an infant or child who requires inter-facility time to provision of analgesia (Boyd and Stuart
transport. An organized approach can be help- 2005; Nelson et al. 2004). Measures of pain
ful to ensure the child, family and team are pre- include physiologic measures (e.g. heart rate and
pared for transport. The transport team should blood pressure), observational and behavioral
have the appropriate skills and expertise to measures and self-report. Self-report is the gold
care for the patient, based on the child’s antici- standard as behavioral measures may also reflect
pated clinical trajectory. Choice of transport anxiety and fear. Physiologic measures may
mode should be established collaboratively reflect stress reactions and hence are often used
based on several extraneous factors, but includ- as adjuncts to other pain assessment tools. The
ing the child’s clinical condition. Checklists Children’s Hospital of Eastern Ontario pain scale
are useful, if not essential, to ensure that all is a widely used behavioral scale for younger
necessary supplies, equipment and medica- infants and non-verbal children. Children as
tions are available for the entire transport. The young as 3–4 years can self-report pain using
references below provide additional checklists visual scales such as the Faces Pain Scale (FPS-
and further reading for those interested in neo- R), Wong-Baker FACES scale or the OUCHER
natal, trauma and other specialized pediatric pain scale. Numerical and 10-cm visual analogue
populations. scales are generally reserved for children older
Acute pain in children is a common present- than 8 years with cognitive abilities to under-
ing symptom in the emergency setting, account- stand these abstract concepts (Srouji et al. 2010;
ing for up to 78% of visits. (Dong et al. 2012; Drendel et al. 2011).

Non-pharmacologic Management treat moderate pain. Codeine, however often lacks

of Acute Pain analgesic potency as the enzyme necessary to
metabolize the inactive prodrug codeine (CYP
A child-centred approach is a key factor for suc- 450 2D6) to morphine is missing in 10–12% of the
cessful management of pain in the emergency Caucasian population (Le May et al. 2013).
department. Parents and caregivers play a role in CYP2D6 polymorphisms can also result in ultra-
responding to their child’s pain and should be rapid metabolism of codeine with potential for sig-
encouraged to act as positive assistants for proce- nificant adverse effects including death (Kelly et al.
dures rather than negatively restraining their child 2012). NSAIDs can also be used for moderate pain
(Srouji et al. 2010). Open communication and and have been reported to be equally effective to
preparation of the child and family for procedures low dose opioids with less side effects in some
with explanation of the procedure using non-med- studies (Poonai et al. 2014).
ical jargon helps to reduce anxiety and fear.
Cognitive or psychological measures such as age
appropriate distraction techniques (e.g. bubbles, Severe Pain
stories, videos and music) are useful adjuncts to
reducing anxiety associated with procedures. Intravenous morphine is the gold standard for
Other behavioral strategies such as breastfeeding management of severe pain. Fentanyl is a syn-
or non-nutritive sucking, kangaroo care (skin-to- thetic opioid, 100 times more potent than mor-
skin contact), swaddling/tucking and rocking/ phine. With a rapid onset of action (30 s), short
holding have also been shown to be beneficial in duration of action (20–40 min) and lack of seda-
neonates and young infants (Ali et al. 2016). tive properties at low dosing, fentanyl is an ideal
agent for short painful procedures (Sahyoun and
Krauss 2012). Intranasal fentanyl is well toler-
Pharmacologic Management ated and has been shown to be equally effective
of Acute Pain for pain reduction to intravenous morphine
(Borland et al. 2007). Hydromorphone is a potent
Mild Pain opioid with a longer duration of action and gener-
ally used for patients with poor response or habit-
Oral analgesics such as acetaminophen or ibupro- uated response to morphine (e.g. sickle cell
fen are safe and effective for the treatment of mild patients) (Sahyoun and Krauss 2012). Equipotent
to moderate pain and are also used in conjunction doses of all commonly used opioid agents pro-
with opioids for management of moderate to severe duce similar degrees of nausea, vomiting, biliary
pain (Perrott et al. 2004). A higher initial loading tract spasm, pruritus, constipation and respiratory
dose of acetaminophen can be given, however, it is depression, however, individual responses may
important to not exceed the recommended daily be variable and careful monitoring and titration
maximum doses. Ibuprofen is generally well toler- of these agents is essential. Rigid chest syndrome
ated in children with minimal adverse renal or gas- with inability to ventilate a patient has been
trointestinal effects. More recently, alternating or reported with large boluses of rapidly adminis-
simultaneous use of acetaminophen and ibuprofen tered fentanyl, hence careful titration is necessary
strategies have been used if monotherapy is inef- (Sahyoun and Krauss 2012). Dosage guidelines
fective (Ong et al. 2010). for use of opioid for acute pain management are
listed in Table 8.4.
Moderate Pain
Procedural Pain
Oral opioid agents such as morphine in conjunction
with NSAIDS (non-steroidal anti- inflammatory Fear of procedures is reported by children to be a
agents) and/or acetaminophen are generally used to significant anxiety-provoking aspect of their

Table 8.4 Dosage guidelines for use of opioid agents for ment are highly painful requiring a higher degree
acute pain in infants and older children
of analgesia and sedation.
Opioid Route of Procedural sedation is a technique whereby
agent administration Dosage
sedative or dissociative agents with or without
Morphine PO Analgesia:
O.2–0.5 mg/kg/dose
analgesic agents are used to induce a state that
Usual dose limit: 15 mg/ allows a patient to tolerate unpleasant procedures
dose while maintaining cardiorespiratory function
Sedation: (American College of Emergency Physicians
0.3 mg/kg, given
30–60 minutes prior to
2014). It has increasingly been adopted by emer-
procedures gency physicians skilled in advanced airway
IV Analgesia: management and cardiopulmonary resuscita-
0.05–0.1 mg/kg q2–4 h tion. Safe sedation does require implementation
Usual dose limit: 5 mg/ of appropriate sedation guidelines and policies
dose
Continuous infusion:
to minimize potential adverse effects (American
10–40 μg/kg/h College of Emergency Physicians 2014).
Moderate Sedation: Commonly used agents for minor procedures
0.05–0.1 mg/kg IV, may for anxiolysis with minimal sedative effects
repeat X 1 in 15 min prn
include midazolam (PO, IN) and inhaled nitrous
Fentanyl IN 1.5 μg/kg, repeat q5 min
prn for total of three doses oxide. Midazolam has no analgesic effects and
Maximum volume: 0.5 mL hence requires additional analgesics for pain
per nostril in infants or control. Intravenous midazolam is often com-
1 mL/nostril in children. bined with intravenous fentanyl and, with care-
Larger volumes should be
divided between both ful titration, produces more moderate sedation.
nostrils Inhaled nitrous oxide is blended with oxygen
IV 1–2 μg/kg/dose IV and induces mild to moderate sedation and anal-
q30–60 min gesia and has the advantage of onset and offset
Continuous infusion: within 2–5 min. It is often used as an adjunctive
0.5–2 μg/kg/h
agent for more painful procedures. Ketamine
Hydro PO Children ≤50 kg 0.04–
morphone 0.08 mg/kg/dose q3–4 h prn (IV, IM) is a dissociative agent characterized by
Children >50 kg 2–4 mg/ potent analgesic and amnestic effects with rela-
dose q3–4 h prn tive lack of cardiopulmonary depression. It is a
Dose limit: 4 mg/dose commonly used agent for procedural sedation in
IV 0.015–0.2 mg/kg/dose
children and ideal for intensely painful proce-
q2–4 h
Continuous infusion: dures. Propofol is a deep anesthetic agent with
4–8 μg/kg/h rapid onset and pleasant recovery and is increas-
Dose limit: 1 mg/dose ing being used in the emergency setting. It has
a narrow therapeutic window and may result in
significant respiratory depression and hypoten-
emergency room visit and the pain experience sion. It can be used alone for painless procedures
itself can have long term consequences (Kennedy requiring motion control such as CT scan and
et al. 2008). Although some procedures such as MRI, but additional analgesic agents are neces-
venipuncture and intravenous cannulation are sary for painful procedures (American College
viewed as minor, they often result in significant of Emergency Physicians 2014).
distress and anxiety for children and their care-
givers (Kennedy et al. 2008). Even non-painful
procedures for diagnostic imaging such as a CT Sucrose Solution
scan which requires a child to lie motionless may
provoke a high degree of anxiety. Other proce- Sucrose is a safe and effective method for reduc-
dures such as fracture reduction and burn debride- ing pain in infants for minor procedures such as

venipuncture and heel lance (Stevens et al. 2013). pared by pharmacy or available commercially as
This sweet solution can be prepared by pharmacy a gel and is applied directly to wounds for
or available commercially and is generally 20–30 min. It is most effective on the scalp and
instilled with a syringe in the infant’s mouth face in producing wound anesthesia but also sig-
2 min prior to a procedure with or without a paci- nificantly reduces pain of subsequent injection of
fier. Although the mechanism of action is lidocaine if needed (Eidelman et al. 2011).
unknown, pain reduction is thought to be medi- Generally, use of LET on mucous membranes or
ated by both endogenous and non-opioid sys- end organs such as fingers is avoided, but small
tems. While it appears most effective in neonates, amounts applied with a cotton tip have been
it is often used in infants up to 12 months of age shown to be safe and effective (Bonadio 1996;
(Ali et al. 2016). White 2004). Pain associated with injection of
lidocaine can also be reduced by slow injection,
use of a fine needle and buffering with a solution
Topical Agents for Pain of sodium bicarbonate (1 mL of 8.4% sodium
bicarbonate to 9 mL of 1% or 2% lidocaine) (Fein
Application of topical agents prior to needle et al. 2012).
insertion for venipuncture and intravenous can-
nulation are effective for reducing pain associ-
ated with these procedures. Comparison Introduction
between commonly used topical agents includ-
ing amethocaine (4% tetracaine, Ametop™), Trauma and injury are the biggest killers of chil-
eutectic mixture of local anesthetics (lidocaine dren in the developed world. Although primary
2.5% and prilocaine 2.5%, EMLA™) and lipo- prevention is the best way to reduce casualties,
somal lidocaine (Maxilene™) are comparable robust and systematic management of traumatic
in effectiveness with minimal side effects. injuries have been critical to reducing morbidity.
Lidocaine-prilocaine requires an application This chapter reviews the basics of trauma man-
time of 60 min and is associated with some agement including the ABCDE approach (“pri-
blanching of the site, whereas amethocaine mary survey”), with specific focus on pediatric
requires an application time of 30–45 min and physiology, interventions and management. We
can be associated with some erythema at the site also provide an overview of the adjuncts to the
(Ali et al. 2016). Concerns have been raised primary survey, including, but not limited to radi-
with use of lidocaine-prilocaine in young infants ography, ultrasound and CT scans. You will also
for methemoglobinemia due to a reduced level find the basics of the “secondary survey”, and a
of methemoglobin reductase. Hence, alternative review of specific high yield injury topics, includ-
topical agents or a single dose of 1–2 g lidocaine- ing C-spine injury, thoracic trauma, and abdomi-
prilocaine cream with limited application time nal trauma.
of 60 min should be considered (Taddio et al.
1998). Liposomal lidocaine is a newer topical
anesthetic with a shorter application time of Scope of Pediatric Trauma
30 min and has been associated with higher can-
nulation success rates (Taddio et al. 2005). Traumatic injuries are the biggest killer of chil-
Vapocoolant sprays are rapid acting evapora- dren in the developed world. Often referred to as
tion-induced skin cooling agents that are also ‘accidents’, most traumatic injuries represent dis-
effective for reducing pain associated with IV crete, potentially preventable events. Therefore,
cannulation (Farion et al. 2008). trauma has patterns, risk factors, and identifiable
LET (4% lidocaine, 0.1% epinephrine and high-risk populations with preventative interven-
0.5% tetracaine) solution is a topical local anes- tions. Traumatic injuries cost Canadian society
thetic agent for laceration repair. It can be pre- millions of dollars annually (Public Health

Agency of Canada 2015); leading causes include bodies such as loose teeth, and any debris
include motor vehicle collisions (MVC), pedes- removed. If the child is alert and crying, airway
trians and cyclists struck by vehicles, suffocation, patency is usually not of concern, with the nota-
falls from height, fires, and drowning. Blunt ble exception of neck trauma, where a rapidly
trauma accounts for >90% of injuries in children. expanding hematoma may occlude the airway if
Children are at greater risk of serious injury than not identified early. Specific details related to the
adults when operating all-terrain vehicles and pediatric airway are beyond the scope of this
snowmobiles (Yanchar et al. 2012). chapter.
In trauma, ‘A’ includes c-spine control, as it is
prudent to assume any blunt trauma victim has a
Pre-hospital Care c-spine injury until proven otherwise. This can be
established through placement of a cervical col-
Trauma systems and regionalized trauma care lar until injury to the spine can be excluded (to be
have been shown to improve outcomes in severely discussed below). Endotracheal intubation may
injured trauma patients. Although critically ill be difficult due to distorted anatomy or due to
injured children may have better outcomes when blood, foreign bodies or teeth occluding the air-
treated in designated pediatric trauma centers and way. Since in-line stabilization is initially
tertiary intensive care units, specific criteria and required for all airway manipulation, airway sup-
age cut-offs for transfer to the pediatric trauma port in trauma is considered ‘difficult’, with
centers vary across the country. Pre-hospital tri- adjuncts such as laryngeal mask airways (LMAs),
age scores used by pre-hospital care providers bougie, video laryngoscopy and surgical airways
consider factors such as age, weight, airway com- sometimes being required.
promise, hemodynamic instability, level of con-
sciousness or Glasgow Coma Scale (GCS), and
the presence of open or multiple fractures (Tepas Breathing
et al. 1987).
The majority of traumatic injuries occur in Once a definitive airway is established, breathing
adults, and thus the standard Advanced Trauma adequacy must be assessed. A significant propor-
Life support (ATLS) course focuses primarily on tion of traumatic deaths occur due to hypoxia,
adult trauma. While there are numerous differ- and adequate oxygenation and ventilation of the
ences in pediatric trauma management, the gen- trauma patient is of paramount importance.
eral approach to assessing the child with multiple Immediate placement of all trauma patients on a
injuries is the same. non-rebreather face mask with 100% oxygen
should be considered. The patient should be
assessed for bilateral breath sounds and signs of
ABCDE Approach hemo-pneumothorax, such as uneven or
decreased breath sounds and subcutaneous
The traditional “ABCDE” (airway with cervical- emphysema. Progressive buildup of air in the
spine [c-spine] control, breathing, circulation pleural space, often from a lung laceration, can
with hemorrhage control, disability, exposure) lead to a tension pneumothorax. The ‘one-way
approach to trauma should be employed in all valve’ effect can be exacerbated by positive pres-
injured children. sure ventilation. Classic signs of a tension pneu-
mothorax are tracheal deviation away from the
side of tension, hyper-expanded chest with poor
Airway chest wall movements, decreased breath sounds
and increased percussion note on the affected
A is for airway, which needs to be managed first. side, although these signs can be difficult to
The oropharynx should be examined for foreign appreciate in a busy trauma bay. Increasing

tachypnea, tachycardia and hypoxia should raise quets have limited indications in trauma
the suspicion of a tension pneumothorax. Left management, they can be considered if direct
untreated, ensuing circulatory collapse with pressure does not stop the bleeding. Full expo-
hypotension may lead to traumatic arrest due to sure of the patient should be performed early to
impaired venous return to the heart (obstructive identify additional sources of blood loss. If
shock). there are signs of shock but no obvious exter-
Procedural interventions required include nee- nal hemorrhage, internal bleeding sources must
dle decompression of a tension pneumothorax be identified. Massive hemorrhage can occur in
and tube thoracostomy (chest tube) to drain air or the chest (hemothorax), in the abdomen and
blood from the chest. Needle decompression can pelvis, in fractured long bones in adolescents
be achieved using a large gauge (14–16 G) over and the scalp in infants. Obstructive shock
the needle catheter inserted in the second inter- from cardiac tamponade or tension pneumo-
costal space at a mid-clavicular line. The chest thorax (see ‘B’ above) must also be considered
tube should be inserted between the anterior and in the differential diagnosis of the hypotensive
mid-axillary lines of the fourth or fifth intercostal trauma patient.
space. In trauma, the open procedure with a large
size chest tube is preferable as blood may block
smaller tubes. Fluid Resuscitation and Hemorrhage
In patients with abnormal hemodynamics and

Circulation and Hemorrhage Control signs of hemorrhagic shock, an initial bolus of
normal saline or lactated Ringers’ (20–40 ml/kg)
Hemodynamic status can be monitored clinically is indicated. If the patient is unresponsive to the
through frequent assessment of vital signs, men- initial fluid bolus, blood products should be
tal status, skin color, pulses, capillary refill and given, as excessive fluid resuscitation with crys-
urinary output. Tachycardia is the most sensitive talloids can be harmful.
sign of blood loss, with pain and fear also being Close monitoring of coagulation parameters is
major contributors. A fall in blood pressure is a necessary, as disseminated intravascular coagula-
late sign of blood loss in children who frequently tion (DIC) is a frequent result from trauma, with
maintain a perfusing pressure with up to 35–40% or without major hemorrhage. Massive transfu-
blood volume loss prior to becoming hypotension protocols are becoming widely adopted by
sive. Since a drop in hemoglobin takes time, ini- trauma centers to minimize the coagulopathy
tial blood results are not reliable in identifying associated with trauma (Chidester et al. 2012;
ongoing blood loss. Hendrickson et al. 2011). Balanced blood resus-
Two large bore intravenous lines (IV) are citation using packed red blood cells, fresh fro-
often needed for resuscitation, especially if there zen plasma (FFP) and platelets has been
is hemodynamic compromise. As obtaining IV advocated, although ideal ratios of these products
access can be difficult in young children, an remain unknown and the use of massive transfu-
intraosseus needle should be inserted if no IV sion protocols varies considerably across the
access has been obtained within 90 seconds. country (Horst et al. 2016). A foundation 2:1
Central venous access in young traumatized chil- ratio of red blood cells to platelets may be con-
dren is discouraged, as it can be procedurally dif- sidered, along with goal directed therapy for
ficult and time consuming and the length of replacement of platelets, cryoprecipitate and cal-
catheter often precludes delivery of the high vol- cium (Dzik et al. 2011).
umes of fluid/blood required. Tranexamic acid (TXA) has been shown to be
Any obvious hemorrhage should be con- safe and effective in high doses in pediatric sur-
trolled with direct pressure. Although tourni- gery (Hasegawa et al. 2014). Although there is

minimal evidence supporting its use in pediatric Keeping the patient warm is imperative as
trauma, many experts feel that it should be con- temperature instability and hypothermia are part
sidered within three hours of injury if there is of the ‘trauma triad of death’ (along with coagu-
obvious blood loss (Beno et al. 2014; Eckert lopathy and acidosis) (Mikhail 1999). The trauma
et al. 2014), or if any blood transfusion is room should be appropriately warm, and warm
required. blankets should be covering the patient. This is
particularly true in children, who lose much more
heat than adults due to increased body surface
Disability and GCS area to weight ratio. If the patient remains hypo-
thermic or need for ongoing fluid resuscitation is
A pediatric GCS (described elsewhere) and anticipated, warmed crystalloids and blood prod-
AVPU (alert, verbal, pain, unresponsive) scale ucts should be considered (this can be achieved
should be used serially to describe all trauma through a level 1 infusion pump/rapid infuser if
patients. After establishing GCS or AVPU, a available).
rapid assessment of neurologic status in all
trauma patients is required. Pupils should be
examined, and a brief neurologic exam should be Adjuncts to Primary Survey
performed if possible prior to intubation or use of
drugs that may alter the neurologic exam. Imaging, such as radiography and a focused
Significant bradycardia and hypotension refrac- assessment of sonography in trauma (FAST) are
tory to fluid resuscitation should alert the trauma important adjuncts that may need to be consid-
team to the possibility of an upper C-spine injury ered. While there is no standard set of images to
leading to neurogenic shock. Presence of hyper- be done on every trauma patient, plain films of
tension and bradycardia may signal increased the c-spine, chest and pelvis are frequently per-
intracranial pressure. formed. Recent evidence suggests that hemody-
namically stable children with multiple trauma
and GCS ≥13 who have normal examination of
Exposure and Temperature Control the pelvis and hip, no hematuria and do not have
a femur fracture can safely forego pelvic imag-
The final step in the primary survey of all trauma ing (Haasz et al. 2015). Radiographs for sus-
patients is exposure, whereby the child should be pected skeletal injuries may be performed but
fully exposed and log-rolled to assess for injuries should not delay definitive care for life threating
to the back of the head and deformities or tender- injuries. Other imaging modalities can be
ness of the spine. Although an external genito- employed, depending on clinical and radio-
urinary exam is an important, a digital rectal graphical findings. Although adult trauma
exam (DRE) should only be considered in select patients often get ‘pan CTs’, this approach is
patients where there is concern about spinal strongly discouraged in children due to the long
injury. It has poor sensitivity in detecting spinal term effects of ionizing radiation (Nellensteijn
cord injuries, bowel and rectal injuries, pelvic et al. 2016; Pandit et al. 2016). Additionally, if
fractures or urethral disruptions. It adds little to the patient is being transferred to a trauma cen-
the assessment, can be falsely reassuring and ter, CT scan can usually be safely deferred (Fahy
may be upsetting for the pediatric patient et al. 2016).
(Shlamovitz et al. 2007). Since iatrogenic injury The FAST exam, traditionally incorporated
from prolonged stay on a backboard has been into adult trauma activations, is a recent addition
described, the patient should be removed from to pediatric trauma care. Since the utility of this
the backboard at this point (Totten and Sugarman exam is currently being investigated in children,
2009; Langevin 2016). a negative FAST in children does not rule out

intra-abdominal injury (Scaife et al. 2013) and a bones palpated, and the oral cavity examined for
positive FAST does not necessarily indicate the missing teeth or signs of malocclusion. The
need for operative intervention (Berona et al. chest should be re-examined for respiratory
2016), and it is insufficiently sensitive to replaceeffort, heart/breath sounds, flail chest or other
CT (Menaker et al. 2014). Extending the FAST injuries. Any bruising on the abdomen (espe-
exam may be useful, as it can detect small pneu- cially in seatbelt distribution, abdominal tender-
mothoraces, heart function and more (Marin ness or peritoneal irritation) should be noted.
et al. 2015). These examinations should only be The genitourinary system should be examined
performed in conjunction with traditional imag- for vaginal bleeding, blood at the urethral
ing, and interpreted within appropriate clinical meatus or perineal or scrotal bruising, which
context. may suggest injury to the genitourinary system.
Blood work, often referred to as a ‘trauma Extremities should be examined for deformity,
panel’ can be drawn upon insertion of the two open fracture or neurovascular compromise.
large bore IVs (see Circulation). Suggested Finally, a mental status assessment and periph-
bloodwork includes complete blood count, blood eral neurologic exam should be performed,
gas, group and screen/crossmatch, amylase and/ including sensation, motor function (power,
or lipase, liver function tests (AST, ALT), coagu- tone), deep tendon reflexes, and paresthesias,
lation profile including fibrinogen, renal func- with special attention to focal neurologic defi-
tion, electrolytes, glucose as well as βHCG and cits. This examination aspect may be challeng-
toxicology screen. Urinalysis should be assessed ing in young children.
for macroscopic hematuria (>50 red blood cells/ Children and infants are at a much higher risk
hpf) to screen for renal or genitourinary injury for spinal ligamentous injury, due to ligamentous
(Santucci et al. 2004; Perez-Brayfield et al. laxity and skeletal immaturity. Additionally, spi-
2002). nal cord injury without radiographic abnormality
(SCIWORA) is much more common in children
compared to adults.
Secondary Survey Radiography of c-spine rules out the majority
of related injuries (Connelly et al. 2016).
After the primary survey is completed and the However, given the higher incidence of
child stabilized, a secondary survey should be SCIWORA in children compared to adults, MRI
performed. The secondary survey is a compre- may be required in select cases. Important ana-
hensive examination of the patient’s history, a tomic differences that predispose children to
detailed physical examination and the comple- C-spine injury include: ligamentous laxity, shal-
tion of any adjunctive laboratory or imaging tests low angle of facet joints, relatively larger head
not yet performed. An AMPLE history should be leading to a higher rate of axial injuries in young
performed: Allergies, any relevant Medications, children, and multiple vertebral ossification
Past medical history, time of Last meal and centers, all of which make radiological interpre-
Events leading up to the trauma. tation challenging. Risk factors for c-spine
Specifically, the head and face should be injury include: altered mental status, focal neu-
examined for hematomas (boggy or firm), rological deficit, neck pain, torticollis, substan-
depressed skull fractures, and scalp lacerations. tial torso injury, predisposing condition (e.g.
Signs of a basilar skull fracture such as hemo- arthritis, Trisomy 21), diving, high risk MVC
tympanum, periorbital ecchymosis (‘raccoon (Leonard et al. 2011). Although a detailed dis-
eyes’), bruising over the mastoid (‘Battles’s cussion about clearing the pediatric cervical
sign’) and cerebrospinal fluid rhinorrhea/otor- spine is beyond the scope of this text, clinical
rhea should be noted. Pupillary diameter and decision rules such as the NEXUS criteria may
reactivity should be documented, the facial be helpful to aid in clinical clearance in a coop-

erative child (Vinson 2001; Michaleff et al. old, palpable skull fractures, the presence of a
2012). Plain films in children are about 90% scalp hematoma (other than frontal), and abnor-
sensitive for C-spine injury, and therefore mal behavior as per parents may also suggest
should be the first imaging modality in alert, significant head trauma.
non-intubated children who cannot be cleared After a traumatic head injury has occurred, the
clinically. (Nigrovic et al. 2012). If the cervical primary management goal is to minimize second-
spine cannot be evaluated as normal, it is advis- ary injury to the brain, the most common of
able to keep the patient in a soft collar (or bags which are hypoxia, hypotension and hypother-
besides his/her head if the child is too small for mia. Coagulopathy, acidosis and GCS have also
a traditional collar) until detailed imaging (usu- been associated with increased mortality, and
ally MRI) can be performed. may help identify high risk patients (Davis et al.
2017).
Hypoxia is minimized by timely provision of
Traumatic Brain Injury 100% supplemental oxygen via a non-rebreather
mask and by early consideration of intubation
Compared to adults, children are more suscepti- with significant neurologic deterioration.
ble to intracranial injuries due to their larger Children should be intubated by the most experi-
head-to-body size ratio, open sutures and thinner enced individual, as multiple intubation attempts
cranial bones. Additionally, a high brain water can create spikes in intracranial pressure.
content and relative paucity of myelinated tissue Ketamine can be used as a sedative agent for
predispose children to cerebral edema and diffuse intubation in trauma, as the previously held belief
axonal injury. regarding its contraindication has been disproven
Mild head injury is defined as a GCS score (Wang et al. 2014; Bar-Joseph et al. 2009; Chang
>13. Although this may result in concussion, et al. 2013).
detailed discussion about concussion is beyond Physicians need to be aware of the possibility of
the scope of this chapter. A number of clinical brainstem herniation, classically presenting with
decision rules exist to help risk stratify children Cushing’s triad of hypertension, irregular respira-
with respect to the need for neurological inter- tions and bradycardia. Asymmetric pupils and pro-
vention and likelihood of brain injury on CT gressive obtundation are the hallmark of herniation
scan (CATCH rules) (Osmond et al. 2010) as and warrant urgent intervention and an immediate
well as to identify children at low risk of clini- neurosurgical consultation. Management consists
cally important traumatic brain injury of elevating the head of the bed to 30°, assuring that
(PECARN and CHALICE rules) (Kuppermann venous drainage is not blocked by a tight cervical
et al. 2007; Harty and Bellis 2010). Based on collar, administration of IV mannitol (1 g/kg) and/
previous studies, factors that warrant consider- or IV 3% hypertonic saline (3–5 ml/kg), sedation
ation for a CT scan to rule out a clinically and appropriate airway management with ventila-
important traumatic brain injury in children tion parameters targeting a low normal end tidal
>2 years old include GCS <15, altered metal CO2 (approximately 35 mmHg). Hyperventilating
status and signs of a basal skull fracture. the patient below the lower limit of normocapnia
Vomiting more than once, loss of consciousness may reduce cerebral blood flow to the point of
for more than five seconds, severe headache or impaired oxygen delivery, leading to brain isch-
severe mechanism of injury (fall >5 ft, MVC emia (Skippen et al. 1997), and, is therefore
with rollover, ejection or fatality, pedestrian/ reserved for refractory patients with a ‘blown’
bicycle without helmet versus vehicle or struck pupil while awaiting definitive operative
by high velocity object) should also raise suspi- management.
cion of a possible intracranial bleed Temperature must be strictly monitored, and
(Kuppermann et al. 2007). In children <2 years the patient should be warmed to normothermia.

There is currently no role for therapeutic kinetic energy to thoracic and upper abdominal
hypothermia in children with traumatic brain
organs, and their weaker abdominal musculature
injuries (Hutchison et al. 2008, 2010). and thinner abdominal wall provides less organ
protection. Furthermore, intra-abdominal organs
in children are in closer proximity to each other
Thoracic Trauma increasing the risk of multiple organ injury.
Clinical predictors of blunt abdominal injury
After head injury, thoracic trauma is the second include: (in order of importance): (1) Evidence of
most common cause of injured related mortality abdominal wall trauma or seat belt sign, (2) GCS
in children. Children are less likely to have rib score <14, (3) Abdominal tenderness, (4)
fractures than adults due to increased chest wall Evidence of thoracic wall trauma, (5) Abdominal
compliance, with forces preferentially transmit- pain, (6) Decreased breath sounds, (7) Vomiting.
ted to internal organs. This results in more pul- Penetrating abdominal injuries involve the
monary contusions and hemo/pneumothorax. gastrointestinal tract more often than the solid
Tension pneumothorax can also develop more organs—most children with these injuries
rapidly. Children are more prone to hypoxia due require operative management. A seatbelt sign
to higher metabolic rate, increased oxygen con- (transverse abdominal ecchymosis caused by
sumption per kg body weight and reduced func- acute flexion over a lapbelt) should raise suspi-
tional residual capacity. cion of injury of the small bowel and duode-
High energy mechanisms can still lead to rib num, mesenteric avulsions, and associated
fractures. A flail chest occurs when two or more lumbar distraction injuries (Chance fracture).
ribs are fractured in two or more places, leaving a As these may be missed on initial imaging,
‘floating’ segment which in turn results in para- they warrant close monitoring as well as serial
doxical chest movement with respiratory pres- exams.
sure changes. If associated with an underlying
pulmonary contusion, this scenario can lead to
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Update in Pediatric Endocrinology
9
Endocrine
Seth D. Marks and Brandy A. Wicklow
Adrenal Insufficiency Etiology
Introduction The most common cause of AI in children is

acquired secondary AI due to exogenous gluco-
Adrenal insufficiency refers to a state of decreased corticoid treatment of non-endocrine pediatric
glucocorticoid and/or mineralocorticoid produc- illnesses. Congenital adrenal hyperplasia (CAH)
tion. It can be categorized as primary, or second- is the most common cause of primary AI in chil-
ary adrenal insufficiency. Primary adrenal dren. In contrast, in adults, autoimmune adrenal
insufficiency (AI) results from defects in the disease is the most common etiology and, per-
adrenal cortex itself. Secondary AI is the result of haps surprising to some, tuberculosis is still the
impaired signaling to the adrenal gland due to second most common cause of primary AI in
diminished adrenocorticotropin (ACTH) release adults.
from the pituitary gland or corticotropin-releasing While CAH is the underlying etiology in the
hormone (CRH) from the hypothalamus. large majority of children with primary AI, other
AI is relatively rare in children. AI was first causes include autoimmune disease (Addison’s
described over 160 years ago and treatment with disease), adrenoleukodystrophy, adrenal hypo-
glucorticoids has been available for half a decade, plasia congenita (AHC), infection, infiltrative
yet the diagnosis is often overlooked and our disease, medication, and syndromes such as
understanding of optimal treatment regiments is Wolman, Triple A and Zellweger (Shulman et al.
still not complete (Shulman et al. 2007; Addison 2007; Perry et al. 2005). Children with CAH tend
1980). The initial symptoms of AI are often to present earlier than the other etiologies even in
vague resulting in a missed diagnosis, often until jurisdictions without newborn screening pro-
the patient is in life threatening adrenal crisis grams and obviously even more so in those with
with associated vascular collapse. these screening programs. With the goal of
decreasing mortality in infant males and severely
virilized females, the Pediatric Endocrine Society
(formerly known as the Lawson Wilkins Pediatric
S.D. Marks (*) • B.A. Wicklow
Assitant Professor, Pediatric Endocrinology and Endocrine Society) and the European Society for
Metabolism, Department of Pediatrics and Child Pediatric Endocrinology jointly recommended
Health, Max Rady College of Medicine, newborn screening for CAH in a 2002 statement
University of Manitoba, Winnipeg,
(Joint LWPES/ESPE CAH Working Group
R3E 0Z2 Manitoba, Canada
e-mail: smarks@hsc.mb.ca; bwicklow@exchange. 2002). With the onset of widespread screening
hsc.mb.ca programs, the gender ratio has been found to be


252 S.D. Marks and B.A. Wicklow
equal in contrast to previous reports indicating a ence of central lesions. Secondary AI may also
female predominance likely due to early mortal- be identified due to general pituitary hormone
ity in affected male patients and subsequently screening in patients presenting with symptoms
underreporting of male infants. of other pituitary deficiencies; including
Outside of exogenous glucorticoid use, sec- decreased growth velocity from growth hormone
ondary AI in children is most commonly caused deficiency, delayed puberty from gonadotropin
by congenital hypopituitarism. Secondary, or deficiency, polyuria and polydipsia from diabetes
central, AI may be isolated but is more com- insipidus, or various symptoms of central
monly associated with other pituitary hormone hypothyroidism.
deficiencies. Congenital hypopituitarism is com-
monly due to transcription factor mutations
including HESX1 mutations resulting in septo Investigations
optic dysplasia and POP1 mutations resulting in
multiple anterior pituitary hormone deficiencies. The biochemical profile of primary AI includes
While these transcription factor mutations have decreased cortisol, elevated ACTH, and elevated
been identified as part of clinical research, they renin with associated hyponatremia and hyperka-
are not routinely tested in clinical care. lemia. Secondary AI’s profile includes decreased
Hypopituitarism may also be acquired from a cortisol, and a decreased or inappropriately
central tumor, radiation, surgery, trauma, central normal ACTH.
infection, and infiltrative processes (Shulman Insulin induced hypoglycemia is the gold
et al. 2007; Perry et al. 2005). The most common standard stress test to elicit a cortisol response.
pediatric tumor resulting in secondary acquired However, due to concern and caution around the
hypopituitarism is craniopharyngioma. risk of hypoglycemic seizures and perhaps over-
Symptoms of AI can be vague and include all discomfort by health care providers, this test is
fatigue, fever, abdominal pain, weight loss, seldom done in children. However, a critical sam-
anorexia, emesis, nausea, back pain, dehydration, ple collected during clinical hypoglycemia can
hypotension, hyperkalemia, hyponatremia, and be diagnostic. The need for a critical sample with
hypoglycemia. Salt craving is quite common in clinical hypoglycemia should be reinforced in all
primary AI, but may also be present in secondary medical teaching given its invaluable diagnostic
AI. Primary AI also presents with hyperpigmen- contribution. A critical sample should include a
tation due to elevated levels of POMC a cleavage confirmatory serum glucose along with cortisol,
product of ACTH, which stimulates melanocor- growth hormone, insulin, ketones (beta hydroxy-
tin production. Other symptoms are based on the butyrate), carnitine, free fatty acids, ammonia,
etiology of the AI including virilization as a lactate, and bicarbonate (Shulman et al. 2007;
major presenting symptom in CAH. Bornstein et al. 2016).
Congenital adrenal hyperplasia is most com- After hypoglycemia induced stimulation,
monly caused by a 21-hydroxylase deficiency. ACTH stimulation testing remains a gold stan-
Clinically it presents with ambiguous genitalia in dard to diagnose primary AI. Recent guidelines
newborn females. These infants are best man- advocate that standard dosing with 250 μg corti-
aged by a specialized interprofessional team cotropin is recommended for children 2 years old
including an endocrinologist, geneticist, urolo- and older. For children under 2 years old, the rec-
gist and psychosocial supports. Newborn males ommended dosing is 125 μg, and 15 μg/kg for
have normal genitalia, and if not picked up in infants. Cortisol levels are measured at 0, 30, and
newborn screening, often present around 2 weeks 60 min with a peak level below 500 nmol/L sug-
of age in adrenal crisis with failure to thrive, gestive of AI. This level may be assay dependent
dehydration and emesis. and may require some interpretation. A low dose
Secondary AI may present with headaches 1 μg corticotropin stimulation test has been pur-
and visual field disturbances related to the pres- ported by some to be more reflective of a natural

9 Update in Pediatric Endocrinology 253
stress stimuli and therefore more sensitive in stable liquid suspension of hydrocortisone often
diagnosing secondary AI (Shulman et al. 2007; makes the use of prednisolone suspension a
Bornstein et al. 2016). necessity in young infants to allow precise dos-
First morning cortisol and ACTH levels may ing. Traditionally described hydrocortisone to
also be used for screening but are less accurate prednisolone equivalency ratios of 4:1 or 5:1 are
and not diagnostic in most scenarios. A cortisol likely too high and may increase the risk of side
level less than 140 nmol/L and an ACTH 2.5 effects, such as growth suppression. Punthakee
times above the upper limit may indicate primary et al. suggests a lower starting point of a 15:1
AI if paired with a consistent clinical scenario, relative potency (Punthakee et al. 2003). It is
but is less diagnostic than an ACTH stimulation important to monitor linear growth and weight
test. Generally, while an undetectable cortisol gain in all children on glucocorticoids in addition
level with an elevated ACTH can be diagnostic to assessing control of AI symptoms, virilization
with the correct clinical picture, other “lowish” in CAH, and biochemistry.
cortisol levels are less helpful. In addition, using Children with primary AI and mineralocorti-
first morning or random cortisol and ACTH lev- coid deficiency require fludrocortisone treatment
els in infants is less sensitive. at a starting dose of 100 μg/day. Infants often
Early primary AI may be evident with an ele- require a higher starting dose of 200 or 300 μg/day.
vated renin level prior to changes in the cortisol Salt supplementation of 1–2 g sodium chloride
levels. divided throughout the day (17–34 mmol/day) is
also required in infants under 12 months.
Adrenal crisis requires urgent management
Treatment with an intravenous or intramuscular hydrocorti-
sone dose of 50 mg/m2 followed by 50 mg/m2
The evidence for appropriate glucocorticoid dos- divided q 6 h for the next 24 h. Hydrocortisone is
ing and regimes is surprisingly limited. In 2016, the preferred glucocorticoid due to its mineralo-
the Endocrine Society published evidence based corticoid effects at high doses in contrast, to
clinical practice guidelines on the diagnosis and Dexamethasone. Glucose levels should be moni-
treatment of primary AI (Bornstein et al. 2016). tored for the risk of hypoglycemia and, if present,
While the guidelines are adult focused there are treated accordingly with a dextrose infusion.
pediatric specific recommendations for treat- Intermittent stress such as intercurrent ill-
ment. Treatment of children with primary AI is nesses with fever should be treated with increased
recommended with hydrocortisone with a total glucocorticoid oral or IM “stress” doses equiva-
starting daily dose of 8–12 mg/m2 divided three of lent to two to three times the patient’s usual dose
four times through the day based on the known to prevent adrenal crisis. Adrenal crisis, precipi-
normal endogenous production of 5–8 mg/m2/day. tated by intercurrent illness is quite common and
This starting dose should then be adjusted accord- occurs annually in about 1 in every 12 adults with
ingly to achieve the lowest possible dose to treat primary AI (Bornstein et al. 2016). Evidence for
the underlying AI while limiting the risk of side optimal stress dosing is limited. Essentially,
effects. CAH will generally require higher dosing patients require more corticosteroids when ill
to suppress the axis and androgen production but with the exact amounts less clear. It is safest to
a maximum of 17 mg/m2 in older children, and err on the side of caution with a low threshold to
20 mg/m2/day in infants is a suggested goal (Joint stress dose and “rounding up” to higher dosing.
LWPES/ESPE CAH Working Group 2002; Although, too frequent stress dosing can result in
Bornstein et al. 2016). Hydrocortisone is the pre- growth suppression. Patient education of self-
ferred glucocorticoid in children as it is shorter management for intercurrent illness, medical
acting than others like prednisolone and dexa- alert identification, and, if capable, home admin-
methasone. However, the limited availability of istration of intramuscular hydrocortisone can be
low dose hydrocortisone tablets (<10 mg), or a lifesaving.

The use of stress dosing for milder stresses “find their growth curve” consistent with their
such as mild viral illnesses without fever, immu- genetic potential (Smith et al. 1976; Rose et al.
nizations, school exam stresses and exercise are 2005). Control of growth during this period
controversial with limited evidence (Weise et al. seems to move away from the major influence of
2004). Recent consensus statements do not rec- nutrition with an increasing emphasis on hor-
ommend stress dosing for these milder scenarios, monal control of growth, specifically the growth
yet anecdotally many patients practice this milder hormone-insulin like growth factor I axis and
stress dosing. thyroid hormone. There is a normal deceleration
in growth velocity before the onset of the puber-
tal growth spurt. The pubertal growth spurt
Growth results from an increase in GH-IGFI axis due to
the stimulation of the axis by the subsequent rise
Introduction in sex steroids (Giustina et al. 1997; Coutant
et al. 2004). In early puberty (tanner 2) girls will
Normal growth in childhood and adolescence is a attain a peak growth velocity of 8 cm/year while
marker of overall health status and can be viewed boys attain a higher peak velocity of 10 cm/year
as a sign of normal internal (genetics, hormones but at a later pubertal stage (Tanner 3–4). Linear
and signaling pathways) and external (nutrition, growth is completed upon fusion of the epiphy-
psychological stimuli) influences. Growth is in seal growth plates under the influence of estrogen
part predetermined by the genetic potential for action on the estrogen receptor (Smith et al.
adult height attainment and therefore growth 1994; Morishima et al. 1995).
must be evaluated in this context. Growth in
humans can be divided into four distinct phases
(1) fetal growth (2) Infant growth (3) Childhood Clinical Evaluation of Growth
growth and (4) adolescent growth. Each phase
having its own normal growth trajectory Clinically growth velocity is followed longitudi-
(velocity) and each having its own distinct
nally to detect growth failure and investigate for
influences (nutrition in early growth and hor-
potential pathology. It requires accurate sequen-
mones in later growth) (Touwslager et al. 2011a, tial growth measurements and charting of growth
b). Fetal growth is the most rapid growth phase in on appropriate growth charts to prevent unneces-
human development with rates up to 20 cm. in sary investigation and evaluation in children
the second trimester and 12 cm in the third tri- with a normal growth velocity. Prior to 2010 the
mester. This rapid growth is supported by mater- CDC/NCHS growth charts (Kuczmarski et al.
nal fetal circulation and fetal nutrition. Hormonal 2002) were used almost exclusively to track
influences on fetal growth include IGF I and II childhood growth. In 2006 and 2007
and insulin. Postnatally growth slows with infants growth charts derived from the World Health
attaining an average of 25 cm in the first year of Organization (WHO) Multicenter Growth
life, 10–12 cm in the second year of life, 6–8 cm Reference Study (MGRS) were published to
in the third year of life, and then decreasing to represent normal growth of a multi-national
4–8 cm/year in the childhood growth period until cohort in optimal growth conditions (WHO
the onset of puberty. Infant linear growth rates Multicentre Growth Reference Study Group
change over the first 2 years of life with infants 2006; Natale and Rajagopalan 2014).
crossing percentiles to settle on the percentile In 2010 the WHO growth charts were adapted
more closely correlating with the final adult for Canadian use and were endorsed by The
height. Thus, Infants may cross one to three Canadian Pediatric Endocrine group (CPEG)
major percentiles during these first 2 years as and Dieticians of Canada and the Canadian
they transition from intrauterine and early post- Pediatric Society, the college of family physi-
natal nutrition as the main regulators of growth to cians of Canada, Community health nurses of

Canada and the public health agency of Canada. Guidelines outlining the child requiring further
In 2014 due to concerns from Canadian practi- investigation related to short stature have been
tioners regarding deficiencies in these new outlined in recent reviews (Cohen 2014; Allen
growth charts (particularly the inability to plot and Cuttler 2013; Murray et al. 2016). In brief,
weight for age after age 10 years) a CPEG work- children who have severe short stature (height >3
ing group designed a new version of the WHO SD below the mean), a height percentile signifi-
growth charts for use in Canada (Lawrence et al. cantly discrepant from mid parental height or less
2015). These new growth charts use the same than the 1% for age, or growth failure as deter-
individual growth data used to create previous mined by a velocity more than 1.5–2SD below the
charts but includes the addition of weight for mean (less than the 10% for bone age) with a
age in older children and a clear shading system resultant crossing of percentiles on a growth chart
to identify children at high risk of growth failure require further investigation. Other indications
(Rodd et al. 2014; Lawrence et al. 2013). These include other multiple pituitary hormone deficien-
current growth charts are available for public cies, signs of an intracranial lesion, and neonatal
access at http://www.whogrowthcharts.ca/. signs and symptoms of growth hormone defi-
Separate growth charts are available for children ciency (hypoglycemia, characteristic facies).
with specific syndromes affecting growth
including Trisomy 21, Turner Syndrome,
Williams Syndrome and Achondroplasia. For I nvestigations in Children
children with trisomy 21 updated growth charts with Growth Failure
have recently been published (Zemel et al.
2015). New growth charts have also been Children who have been identified as having an
derived for children with Prader Willi syndrome abnormal growth pattern require evaluation of
(not on growth hormone) (Butler et al. 2015) the multiple components regulating growth. A
and 22 q.11 deletion syndrome (DiGeorge) thorough history will identify children with intra-
(Tarquinio et al. 2012). uterine growth restriction due to placental insuf-
Short stature is defined as a height which falls ficiency, maternal malnutrition or illness in
below 2 SDs from the mean for age, sex and pop- particular with the determination of weight,
ulation (Cohen et al. 2008). Short stature can be length and head circumference at birth.
related to familial growth potential, failure of Developmental history and previous medical his-
infants born small for gestational age to achieve tory can identify children with short stature
adequate catch up growth, failure to achieve related to a syndrome (trisomy 21, Russel Silver
pubertal growth acceleration at the average age of syndrome, Noonan’s syndrome) or a poorly con-
puberty (constitutional delay), chronic illness, trolled chronic medical illness (cardiac, renal,
hormone deficiency (thyroid hormone and growth pulmonary). Family history including parental
hormone) or excess (cortisol). Evaluation of the heights and age of attainment of puberty guides
rate of growth (using growth chart percentiles) in the determination of a component of familial
will help to distinguish the short but normally short stature or constitutional delay of growth
growing child from the child who is failing to and puberty. Baseline biochemical evaluations
grow. In addition, a recent study has reported that include creatinine, urea and electrolytes, liver
children born small for gestational age are more transaminases, complete blood count, transgluta-
likely to have poor catch up growth (and be minases and ESR, and thyroid hormone. Skeletal
stunted in growth at 5 years) if the mother has maturity is determined from a bone age (radio-
short stature, there was inadequate maternal ges- graph of the left hand and wrist) which is delayed
tational weight gain, with a much higher risk of in children with constitutional delay of growth
stunting in infants born to mothers who smoked and puberty, endocrinopathies, nutritional
in pregnancy and had poor gestational weight deficiencies and chronic illness (Martin et al.

gain (Xie et al. 2016). 2011a, b).

Children on inhaled corticosteroids and stimu- ure (described above) and/or children with other
lant medications have been reported to have a pituitary hormone deficiencies or intracranial
slower growth velocity than expected. The impact pathology. Stimulation of growth hormone secre-
of inhaled steroids on adult height seems to be tion can be performed with arginine, glucagon,
dependent on the age at initiation of treatment clonidine, GHRH, levodopa, pyridostigmine,
and the dose of inhaled steroid. The overall effect insulin, sleep and exercise. Due to superior per-
on the final adult height however appears mini- formance and lower side effects of testing, gluca-
mal with the benefits of treatment outweighing gon and arginine stimulation are the most
risks of therapy (Kapadia et al. 2016). common test used. Due to poor reproducibility
A random sampling of growth hormone is not and false positive rates (between 8.0% and 23.7%
clinically useful as growth hormone is secreted in dependent on the testing method and cut off val-
a pulsatile manner with peak levels being reached ues used (Bellone et al. 1996; Carel et al. 1997;
overnight and in the early morning hours. Hilczer et al. 2006), failure of two separate pro-
Therefore, in children who have growth failure vocative tests is needed for the diagnosis. In chil-
and who do not have evidence of another condi- dren with intracranial pathology only one
tion a provocative growth hormone testing is stimulation test may be required. Sex steroid
warranted. An insulin like growth factor (IGF)—1 priming for growth hormone testing often is rec-
or IGF binding protein 3 level can be a useful ommended as it increases peak growth hormone
screen but IGF deficiency is nonspecific as IGF concentrations and reduces false positive rates
can be affected by nutrition, intercurrent or (Marin et al. 1994). In addition, obesity reduces
chronic illness, and physiological age in addition growth hormone peak concentration in some
to growth hormone level and function. studies resulting in higher rates of false positives
in this population (Stanley et al. 2009). In Canada
growth hormone is currently licensed for use in
Growth Hormone children with growth hormone deficiency (as
determined by auxological and stimulation test
Growth hormone deficiency is a rare disease in data), Turner syndrome, chronic renal insuffi-
childhood with a reported prevalence in the UK ciency, small for gestational age infants who fail
of 1 in 4000. (National Institute for Health and to attain catch up growth, and idiopathic short
Care Excellence [NICE] Guidelines on the use of stature (ISS). Due to the lack of strong evidence
growth hormone 2010). Complete or near com- for significant height gain and the potential for
plete growth hormone deficiency is clinically evi- harm the treatment of ISS is controversial (Cohen
dent with significant growth failure. In children 2014). A recent small pilot trial examining the
who have other multiple pituitary deficiencies it utility of treatment of boys with ISS at a later
is also a more likely diagnosis for growth failure. pubertal stage suggest there may be benefit to
However, it is more difficult to distinguish chil- short term (1 year) GH therapy to increase adult
dren with more mild or partial forms of growth height above predicted adult height (Rothenbuhler
hormone deficiency with those children who et al. 2015).
have short stature but normal growth hormone. A Recent reports from France have suggested
recent review examining the controversies in children treated with growth hormone have an
growth hormone deficiency diagnosis and treat- increased mortality due to stroke and cancer
ment in children (Murray et al. 2016) reports on (Swerdlow et al. 2002; Carel et al. 2012; Poidvin
the suboptimal performance of current growth et al. 2014). However, recent reports using
hormone testing and the clinical variability in national cohort data and matched untreated con-
treatment. To improve the clinical utility of pro- trols did not find an association of growth hor-
vocative testing, children are selected for testing mone treatment with mortality (Berglund et al.
with high pretest probability of test failure. These 2015). In addition, the pediatric endocrine soci-
include the children with significant growth fail- ety has published a recent report summating the

evidence of cancer risk in children on growth increase in growth velocity however no studies
hormone therapy. They report no association in have reported effects on final adult height in chil-
low malignancy risk children, for an increased dren with ISS (Albanese et al. 1994; Schroor
malignancy risk with the use of growth hormone. et al. 1995; Dunkel 2011). A moderate increase
Data at present is insufficient to report on the in final adult height has been reported in girls
risks in children with previous cancer or high with Turners syndrome when oxandrone is used
cancer risk due to familial risk and the cautious in combination with growth hormone therapy
use of growth hormone with surveillance is pro- with no significant side effects (Sas et al. 2014;
posed for these children who are growth hormone Freriks et al. 2013).
deficient (Raman et al. 2015). Gonadotropin- releasing hormone agonists
Recombinant growth hormone currently is (GNRH i.e. Lupron) have been tried to prolong
supplied only as an injectable medication which the period of growth by delaying skeletal matura-
due to a short half-life requires daily or every tion in children with typical pubertal timing with
other day dosing. Due to the pain of injection and little to no benefit to final adult height (Yanovski
the cumbersome daily routine, multiple alterna- et al. 2003; van Gool et al. 2007). The addition of
tive treatment strategies are being evaluated. A GNRH to GH in children who are growth hor-
recent review article details the advances in the mone deficient may be beneficial to children who
field that are covered in brief in this chapter (Cai remain significantly short at the time of puberty
et al. 2014). These include longer acting growth despite growth hormone treatment (Mericq et al.
hormone agents which may be dosed weekly or 2000; Saggese et al. 2001; Mul et al. 2001).
even monthly due to their combination with Zinc Aromatase inhibitors have been trialed in boys
complexes, microspheres or hydrogels. In addi- with short stature to delay the estrogen effects on
tion to extending the half-life, recent research is skeletal maturation. Currently it is considered an
focused on alternative delivery systems including experimental treatment as only few trials report out-
intranasal delivery, transdermal delivery. Finally come data on adult height with little benefit while
needle free devices which inject the drug subcu- safety concerns regarding its use remain (Wickman
taneously through gas pressure have been et al. 2001; Mauras et al. 2008; Wit et al. 2012).
launched by several drug companies but pain,
access and cost have prevented them from reach-
ing most clinical practices. Puberty
Introduction
ther Therapies to Increase Final
O
Adult Height Puberty can be defined as the period over which
children attain secondary sexual characteristics and
Other potential treatments for short stature focus reproductive capacity. Pubertal timing varies
on delaying growth plate closure or stimulating between individuals and is influenced by adiposity
an earlier growth spurt (in boys with CDGP). The and nutrition, general health, metabolism, and is
evidence behind the additive benefit of these ther- also influenced by genetics, and environment. This
apies is weak with many studies showing con- chapter will review recent literature on the etiology,
flicting results. A recent review of alternative diagnosis, and treatment of disorders of puberty.
therapies discusses in more depth the evidence
behind their use (Wit and Oostdijk 2015).
The use of low dose testosterone in boys with Pubertal Control
CDGP appears to increase final adult height
without advancing closure of the growth plates The onset of puberty occurs when the hypothala-
(Palmert and Dunkel 2012). Studies using the mus increases its pulsatile secretion of GnRH
anabolic steroid oxandrone have suggested an which in turn stimulates the pulsatile secretion of

pituitary hormones LH and FSH which in turn itary or hypothalamic pathology in boys (Chen
stimulate gonadal maturation and sex hormone and Eugster 2015). PPP is rare with progressive
secretion. The inciting event for the increase in pul- PPP often due to a genetic gain of function of
satile GnRH has been difficult to elucidate however the stimulation pathways of the gonads, result-
the last decade has resulted in a number of impor- ing in McCune Albright in girls and male lim-
tant discoveries (Lomniczi et al. 2013). Human and ited familial precocious puberty (testotoxicosis)
non-human primate studies have uncovered a com- in males.
plex integration of signaling pathways including Traditionally central precocious puberty
the expression of KISS1R (Seminara 2007; (CPP) is diagnosed with a GnRHa stimulation
Seminara et al. 2003), TAC3, TAC3R and LEPR test with post stimulated levels of LH (and occa-
genes (Lomniczi et al. 2013). Importantly the first sionally FSH) being within the pubertal range.
report of a monogenetic disorder of puberty was Originally these stimulation tests measured LH
published revealing mutations in the gene MKRN3 and FSH out to 24 h with more recent testing pro-
resulting in familial central precocious puberty tocols measuring at 30, 60, 90 (and occasionally
(Abreu et al. 2013). Pubertal delay has been associ- 120 min). Newer evidence suggests precocious
ated with increased levels of FGF21 (a growth fac- puberty may be diagnosed with a single post sim-
tor which increases with fasting) by inhibiting the ulation level of LH at 30 min (captures >95% of
kisspeptin stimulatory pathway (Owen et al. 2013). positive cases) (Yazdani et al. 2012; Chi et al.
2012). This change in clinical practice would sig-
nificantly change the resources and time required
Precocious Puberty to perform this testing and presumably, improve
the patient experience. Treatment of central pre-
Precocious puberty is traditionally defined as breast cocious puberty has seen recent advances in the
development or testicular growth (testicular size methods of treatment available. Currently depot
>3 cc) prior to 8 years and 9 years for girls and boys Lupron (GnRHa) is available in monthly and
respectively. Recently longitudinal cohort data every 3 monthly injections. Recent evidence has
including physical examination in girls has reported shown that every 3 month injections have equal
up to 23% of African American, 15% of Hispanic effectiveness in pubertal suppression to monthly
and 10% of Caucasian girls will have breast devel- treatment (Fuld et al. 2011; Lee et al. 2014).
opment begin between ages 7–8 years (Biro et al. More recently the final report from a phase 3
2010). There is some evidence to suggest that the multicenter trial of once yearly subcutaneous
average onset of puberty in boys (between ages 8 Histrelin (GnRHa) has shown good effectiveness
and 9) is also lowering (Herman-Giddens et al. and safety profiles and improves overall adult
2012). Due to conflicting reports suggesting up to height in children with central precocious puberty
13% of girls with puberty at 7–8 years (Caucasian) (Silverman et al. 2015). Indeed, a follow up study
or 6–7 years (African American) have pathological reported that a single implant was effective in
etiologies for pubertal onset (Midyett et al. 2003) suppressing puberty for up to 2 years in girls with
these newer lower age cut-offs have been slow to CPP (Lewis et al. 2013). A 6-month depot injec-
be adapted by clinical practice. tion triptorelin is currently in clinical trials and
Precocious puberty can be divided into two may provide a long term therapeutic option for
main etiologies. Central precocious puberty those not wanting to undergo the subcutaneous
(CPP) is physiologically identical to the nor- implant (clinicaltrials.gov NCT01467882).
mally timed pubertal process, only it occurs at
an abnormally early age. Peripheral precocious
puberty (PPP) occurs due to an abnormal secre- Pubertal Delay
tion of sex hormones either from the gonads or
from a sex hormone secreting tumor. The most Pubertal Delay is defined as an absence of sec-
common diagnosis for CPP in girls is idiopathic ondary sexual characteristics (testicular growth
whereas it is more often found to be due to pitu- to >3 cc or breast bud development) by age

13 in girls and 14 in boys. The single most Environmental Exposures
common etiology for pubertal delay is constitu- and Puberty
tional delay of growth and development and is
a diagnosis of exclusion after investigations fail A developing area in the investigation of preco-
to determine another etiology, with spontane- cious or delayed puberty is the potential influ-
ous onset of puberty (Palmert and Dunkel ence of environmental exposure. Studies have
2012). This is considered to be a normal variant found some conflicting results on the influence of
of development which does not require treat- environmental exposure on pubertal timing in
ment. The underlying etiology of the delay in part due to studies being limited to case control
pubertal onset is still unclear however, there investigation many requiring recall of the partici-
appears to be a genetic component. pant/family for exposure risk. Sample sizes
Constitutional delay must be differentiated remain small but it is an interesting and novel
from permanent hypogonadotropic hypogonad- area of investigation in the field of puberty.
ism (central pituitary or hypothalamic defi- Elevated Phalates (a known anti-androgen) have
ciency as is seen in Kallmans syndrome), been associated with constitutional delay of
transient hypogonadotropic hypogonadism growth and puberty (Xie et al. 2015; Ferguson
(often the result of underweight or high physi- et al. 2014). Phalates belong to a group of plasti-
cal stress including chronic disease states such cizers and have been shown to be ingested,
as Crohn’s disease (DeBoer and Denson 2013)), inhaled and absorbed by exposed individuals
and primary gonadal failure. It is difficult to (Koch et al. 2011; Wittassek et al. 2011).
distinguish CDGP and hypogonadotropic hypo-
gonadism by any laboratory test. Newer evi-
dence suggests that serum inhibin B levels may Thyroid Disease
be able to distinguish between CDGP and HH
(Binder et al. 2015; Harrington and Palmert Introduction
2012). Treatment of HH (or severe CDGP) is
aimed at developing secondary sexual charac- Thyroid disease in children can be congenital or
teristics and growth. Adolescents with perma- acquired. Acquired thyroid disease can result in
nent HH will require long term hormone hypothyroidism or hyperthyroidism. Acquired
replacement therapy for optimal bone mineral hypothyroidism is classified as primary, or sec-
accrual and bone health and for cardiovascular ondary. Primary thyroid disease results from
health. Estrogen dosing in girls and testoster- defects in the thyroid gland itself while second-
one dosing in boys is aimed to mimic the physi- ary hypothyroidism results from impaired signal-
ologic progression of puberty gradually ing of the thyroid gland due to diminished thyroid
increasing doses over time. There is some evi- stimulating hormone (TSH) release from the
dence to suggest that the use of the transdermal pituitary gland or thyrotropin-releasing hormone
estrogen patch has less impact on the growth (TRH) from the hypothalamus. While the diag-
hormone—IGF1 axis and may permit improved nosis and initial treatment of congenital hypothy-
linear height attainment (Phelan et al. 2012). roidism is obviously unique to pediatric age
New evidence in girls with Turner syndrome range, the management of acquired thyroid dis-
suggests the earlier initiation of estrogen at low ease is quite similar in children and adults not
doses in childhood (as early as age 5), and esca- withstanding some unique pediatric issues.
lating to pubertal induction doses at age
12 years normalizes the tempo of puberty and
improves linear growth outcome (Quigley et al. Congenital Hypothyroidism
2014). The introduction of progesterone late in
the course (often after the first spontaneous pel- Congenital hypothyroidism occurs in 1 in 2000 to
vic bleed) provides safe regular endometrial 1 in 4000 newborns with some geographical
shedding. variation. Recent studies show an increasing


incidence possibly due to lower newborn screen- include lethargy, a protruding large tongue, large
ing cutoffs and identification of milder cases. fontanel, hoarse cry, poor feeding, myxedema,
There is a female predominance. A prompt diag- hypotonia, prolonged jaundice, hypothermia, and
nosis and initiation of treatment with levothyrox- umbilical hernia.
ine is important as delayed treatment results in a A recent update on Congenital Hypothyroidism
lower intelligence quotient identified by school was published jointly by The American Academy
aged testing. While the aim is to start treatment as of Pediatrics, the American Thyroid Association,
quickly as possible, the goal of most programs is and the Pediatric Endocrine Society (formerly
to have treatment initiated by 2 weeks of age. known as the Lawson Wilkins Pediatric
Newborn screening programs initiated in the Endocrine Society) in 2006 (Rose et al. 2006).
1970s have successfully prevented severe intel- The report includes a useful algorithm for screen-
lectual disability in this population. Most screening and follow up. Infants with abnormal screens
ing programs measure TSH levels alone, while require prompt assessment with a history and
others measure thyroxine (T4) in combination physical examination. History should include
with TSH. Congenital hypothyroidism is diag- queries of maternal thyroid disease. Treatment
nosed by a TSH elevated above a defined thresh- should be initiated promptly after confirmatory
old such as 20 mU/L measured ideally after 48 h serum testing is drawn. The recommended initial
of age. The timing of the screen is important, as dosage of levothyroxine is 10–15 μg/kg once
there is an initial surge in TSH in the first 24 h of daily. Due to the instability of levothyroxine
life. Thresholds have been adjusted, and gener- when mixed in suspension, pills and not a sus-
ally lowered, over time. T4 if measured will be pension should be used. Repeat T4 and TSH
low. Most algorithms recommend confirmatory should be drawn 2–4 weeks after initiation of
serum testing after an abnormal screen. If the treatment. The aim of treatment is normalization
TSH on newborn screen is >40 mU/L then treat- of TSH within 1 month. The normal reference
ment should be initiated once the confirmatory range for serum TSH at 2–6 weeks of age drops
testing is drawn to avoid a delay in treatment to 1.7–9.1 mU/L. Many will simply follow TSH
awaiting the verifying results to be reported to monitor treatment but if FT4 is measured it
(Rose et al. 2006). should be in the upper range of normal. The 2006
Congenital hypothyroidism results from update suggests serum monitoring every
thyroid dysgenesis such as agenesis, hypopla- 1–2 months in the first 6 months, 3–4 months
sia or ectopy of the gland. Thyroid hormone from 6 months to 3 years old, and then every
synthesis or secretion defects can also cause 6–12 months. However, if the monitoring is sta-
congenial hypothyroidism. Congenital hypo- ble, some practices will monitor less frequently,
thyroidism is generally permanent but transient every 6 months, after 1–2 years of age. The report
congenital hypothyroidism may result from comments that thyroid uptake scans or ultra-
several etiologies including iodine deficiency, sounds are optional diagnostic studies to help
iodine exposure, transfer of maternal antibod- further identify etiology but are not mandatory.
ies, or maternal antithyroid drug transfer. The use of diagnostic imaging is controversial
Central or secondary hypothyroidism may also but is considered important by some p ractitioners.
present in the newborn period as hypopituita- If done, imaging should not significantly delay
rism often with involvement of other pituitary treatment (Rose et al. 2006).
axes deficiencies. Screening programs gener- In an often-quoted relatively recent study, ini-
ally will not detect central hypothyroidism so a tial dosing in the higher range of 14.5 μg/kg vs.
clinical suspicion is often required in order to 10.9 μg/kg resulted in a quicker normalization of
diagnose these infants. FT4 and TSH levels. Further follow up revealed
Most children are diagnosed from newborn higher full scale IQ scores in the higher dosing
screening programs and are asymptomatic at group. Verbal and performance IQ scores, how-
birth. If undiagnosed or untreated, symptoms can ever, did not differ (Selva et al. 2005, 2002).

The possibility of transient congenital hypo- TSH levels but normal FT4 levels. Recent litera-
thyroidism can be considered if imaging was per- ture indicates that a large majority of these chil-
formed and there’s no evidence of ectopic or dren with TSH levels between 5.5 and 10 mU/L
absent thyroid, and/or initial screening revealed a will have resolution of their biochemistry without
TSH <50 mU/L, and/or there has been no further treatment (Radetti et al. 2012; Lazar et al. 2009).
elevation in TSH requiring an increase in the There is also no evidence of negative clinical
l-thyroxine dose after the initiation of treatment. consequences without treatment in this group.
However, a trial of discontinuing treatment While still controversial, treatment is therefore
should wait until the child is 3 years of age to not generally recommended in this group
limit the risk of developmental effects of stop- (Jonklaas et al. 2014).
ping therapy if the hypothyroidism is in fact per- The recommended treatment of hypothyroid-
manent. TSH and FT4 levels should be performed ism is levothyroxine. Some patients and practi-
30 days after stopping therapy. An elevation of tioners advocate for treatment with liothyronine
TSH and low FT4 would confirm permanent (T3). There are some controversial studies in
hypothyroidism and therapy should be restarted. adults but in the recent 2014 guidelines, T3 treat-
ment is not routinely recommended in adults
with hypothyroidism. There is no good evidence
Acquired Hypothyroidism of its use in children.
Acquired hypothyroidism in children is similarly

managed as in adults. The most common cause of Acquired Hyperthyroidism
acquired hypothyroidism in children is autoim-
mune disease, commonly known as chronic lym- The most common cause of hyperthyroidism in
phocytic thyroiditis or Hashimoto’s thyroiditis. children is Grave’s Disease, or autoimmune
As confirmed by recent ATA guidelines, all chil- hyperthyroidism. Other causes include toxic nod-
dren with overt hypothyroidism should be treated ules, multinodular goiters, and subacute thyroid-
with levothyroxine replacement to normalize bio- itis but these are much less common than Grave’s
chemistry (Jonklaas et al. 2014). Children can be disease in children. Thyrotoxicosis symptoms are
diagnosed at all ages but there is a peak in adoles- similar in children and adults although children
cence with a female predominance. While chil- tend to tolerate the symptoms better. Symptoms
dren develop similar symptoms and signs of include hyperactivity, tremor, tachycardia, palpi-
hypothyroidism as adults, the additional clinical tations, heat intolerance, and weight loss. In chil-
parameters in children are poor linear growth and dren, hyperthyroidism can also cause increased
delayed pubertal development. Conversely, pro- linear growth. Ophthalmopathy is less common
found elevations in TSH can lead to precocious in children than adults and if present has a greater
puberty, perhaps due to cross reactivity of the likelihood of resolution with treatment (Rivkees
alpha subunits of TSH and the gonadotropin et al. 1998).
receptors, but this is rare. Investigations in hyperthyroidism reveal sup-
Dosing requirements of levothyroxine in chil- pressed TSH and elevated T4 and T3 levels. In
dren are age dependent. Young toddlers require Grave’s disease TSH receptor antibodies or thy-
4–6 μg/kg per day, adolescents require 2–4 μg/kg roid stimulating immunoglobulins are elevated.
per day and then transition to adult requirements Treatment options include anti-thyroid medi-
of 1.6 μg/kg per day (Jonklaas et al. 2014; cations, radioactive iodine 131 (I131), and thy-
Lafranchi 1992). Aim of treatment is normal roidectomy. Anti-thyroid medications are
TSH and Free T4 levels. generally considered first line therapy in chil-
Much of the recent controversy around hypo- dren. However, in older children, above age
thyroidism revolves around treatment of subclini- 10 years, some will consider I131 as a first line
cal hypothyroidism, defined as mildly elevated alternative. Under age 5 years, I131 is generally

not considered an option. Surgery should be con- 23738509. Pubmed Central PMCID: PMC3808195.
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sidered in centers with highly skilled and experi-
Addison T. On the constitutional and local effects of
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Stanhope R. Oral treatment for constitutional delay
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of growth and puberty in boys: a randomised trial
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Update in Pediatric Gastroenterology,
Hepatology and Nutrition 10
A. Jay Freeman, Tatyana Hofmekler,
John-Paul Berauer, and Sirish Palle
Reflux and evaluated for in patients suspected of hav-

ing GERD. However, care must be exercised to
Gastroesophageal reflux (GER), the physiologi- not overestimate the effects of reflux on certain
cal passage of gastric contents into the esopha- conditions. Specifically, recent systematic
gus, occurs in over two-thirds of otherwise reviews have failed to show significant evi-
healthy infants with daily “spitting-up” and rep- dence associating GERD with apnea or the cry-
resents a common topic of parenteral concern at ing/irritable infant (Smits et al. 2014;
well child visits within the first year (Lightdale Gieruszczak-Białek et al. 2015). Additionally,
and Gremse 2013). Gastroesophageal reflux dis- while GERD may effect wheezing and asthma,
ease (GERRD), is reflux associated with trouble- recent publications suggest the impact is much
some symptoms and is estimated to occur in less than previously thought and additional pul-
10–20% of infants and 5–8% of children in North monary care for uncontrolled asthma and/or
America (Nelson et al. 2000; Dent et al. 2005). wheezing should not be delayed even with the
Peak incidence of GERD occurs for most patients addition GERD therapy (Sheikh et al. 1999;
around 4 months of age with only 5–10% of Littner et al. 2005; American Lung Association
patients continuing to experience symptoms at Asthma Clinical Research Centers et al. 2009;
12 months (Martin et al. 2002). GERD can pres- Kiljander et al. 2010, 2013).
ent in a variety of manners depending on age (see
Table 10.1), and should be monitored closely in Table 10.1 Common GERD symptoms by age
populations that are high-risk for GERD associ- Older children and
ated complications (e.g. patients which are neu- Infants adolescents
rologically impaired, obese, preterm infants and/ Feeding refusal/ Abdominal/chest pain
or have chronic respiratory conditions) (Hassall inadequate volumes by (heartburn)
et al. 2007). mouth
Established and proposed extra-esophageal Recurrent emesis Recurrent emesis
manifestations of GERD must be considered Poor weight gain/failure Dysphasia
to thrive
Irritability Asthma
A.J. Freeman (*) • T. Hofmekler • J.-P. Berauer
Sleep disturbances Recurrent pneumonia
S. Palle
Division of Pediatric Gastroenterology, Hepatology Respiratory symptoms/ Upper airway symptoms
and Nutrition, Emory University School of Medicine, cough (cough, horse voice)
Atlanta, GA, USA Modified and adapted from Lightdale and Gremse (2013)
e-mail: afreem6@emory.edu


268 A.J. Freeman et al.
Diagnostic Considerations respiratory compromise (Vandenplas et al. 2009).

Additional overfeeding, seated or supine posi-
GERD is a clinical diagnosis and diagnostic test- tions and environmental tobacco smoke should
ing is not generally required. Despite the devel- be avoided. Thickening of the infants formula
opment and validation of a number of GERD with rice cereal (1 tablespoon per ounce) may
questionnaires, there remains no single symptom, also be attempted but all thickening agents should
cluster of symptoms or subjective tool to diag- be avoided in preterm infants given the risk of
nose or predict esophagitis, other complications developing necrotizing enterocolitis (Clarke and
of GERD and/or determine which patients will Robinson 2004). Although data suggests that
respond to therapy. As no single test definitively reflux is decreased in infants in the prone posi-
diagnoses or excludes GERD, testing should be tion, the risk of sudden infant death syndrome far
conducted only to exclude other diagnosis that outweighs the benefits and therefore prone posi-
may explain the patient’s symptoms, evaluate for tion should only be considered when the child is
complications of GERD, to establish a causal awake or directly observed (Vandenplas et al.
relationship between GERD and other symptoms 2009). In older children, dietary avoidance of caf-
and/or monitor therapy effectiveness (Lightdale feine, alcohol, spicy foods and other food triggers
and Gremse 2013). Despite its wide-spread use, may be sufficient to control symptoms (Lightdale
Upper GI tract radiographic imaging serves no and Gremse 2013).
role in the evaluation of reflux but rather may be If lifestyle modifications fail, acid suppression
useful in ruling out anatomical causes of persis- with histamine2 receptor antagonists (H2RAs) or
tent emesis (Vandenplas et al. 2009). Multiple proton pump inhibitors (PPIs) are often effective.
intraluminal impedance (MII) has replaced tradi- Several studies have shown clinical benefit of
tional pH probes due to their ability to detect not H2RAs but they are often limited in their long-
only acid but also non-acidic reflux. This allows term use by either tachyphylaxis or patient toler-
MII to access a number of key variables includ- ance making PPIs a better choice in those patients
ing; (1) anterograde and retrograde esophageal expected to be on longer acid suppressive therapy
boluses, (2) volume, speed and length of reflux (Gremse 2004). PPIs are generally considered
event, (3) temporal association between reflux safe for long periods of time with highest efficacy
event and specific symptom(s) and (4) effective- when taken ~30 min before a meal (Rudolph
ness of GERD therapy. Lastly, endoscopy with et al. 2001; Chan et al. 2011; Kierkus et al. 2014).
esophageal biopsies may be used to determine Additionally, children tend to metabolize PPIs
the extent of mucosal damage secondary to faster than adults and often need higher per kilo-
GERD, evaluate for anatomical abnormalities gram dosing or twice a day dosing (Kierkus et al.
and/or Barrett esophagus and exclude other con- 2014). For break through symptoms while on
ditions that may mimic GERD including EoE acid suppression medication, over the counter
and infectious esophagitis (Hassall 2002). antacids may be used to provide relief.
Prokinetic agents such as metoclopramide and
erythromycin have become trendy in GERD ther-
Management apy but there is insufficient data at this time to
support their routine use in infants or older chil-
Life style modifications should be attempted as dren (Vandenplas et al. 2009).
first line therapy against GERD. Milk protein In patients with severe GERD in which life-
sensitivity is often overlooked as a condition that style changes and medical therapy have failed
can mimic GERD and a 2- to 4-week trial of and also have either; (1) growth failure or (2) risk
maternal exclusion of milk and eggs is recom- for significant aspiration or other respiratory
mended for breastfeeding infants, or partially compromise, then transpyloric feeds via a nasoje-
hydrolyzed or amino acid formula in formula fed junal tube or surgical management may be
infants assuming adequate weight gain and no required, typically a fundoplication. Ideally a

10 Update in Pediatric Gastroenterology, Hepatology and Nutrition 269
patient should be seen by both a pediatric gastro- disease (Furuta and Katzka 2015). Repeated case
enterology and a pediatric surgeon to ensure series have shown environmental and food hyper-
medical management has been optimized prior to sensitivities, with symptomatic and mucosal
undergoing surgery due to its risks and long-term responses to elimination of exposure and subse-
complications. quent relapse upon reintroduction of antigen, fur-
ther supporting the role of food and environmental
hypersensitivity as an important component of
Eosinophilic Esophagitis the pathophysiology of EoE (Markowitz et al.
2003).
Previously thought of as an extremely rare condi-
tion, eosinophilic esophagitis (EoE) is now
known to be one of the most commonly diag- Presentation
nosed conditions during the assessment of feed-
ing difficulties in children (Straumann et al. Reflux symptoms are a common initial presenta-
2008). EoE has been described worldwide and tion for all patients with EoE, but other symp-
effects all age groups with a prevalence between toms may be more non-specific and vary by age.
1 and 5 per 10,000 persons in the United States Adolescents are more likely to present with clas-
and Europe, most commonly effecting white sic symptoms of dysphasia and food impaction
males with an onset from school age to midlife while younger children are more likely to present
(Furuta and Katzka 2015). Among those patients with feeding difficulties, nausea, emesis and fail-
undergoing endoscopic assessment for food ure to thrive. Due to patient accommodation,
impaction, prevalence rates of EoE increase dra- symptoms may be subtle including slow oral
matically to nearly 55% (Desai et al. 2005). intake, cutting food into very small pieces, exces-
sive lubrication of foods with sauces, diluting
foods with increased fluid intake, fear of eating in
Pathogenesis public and avoidance of pills and/or certain foods
which may cause dysphasia (Furuta and Katzka
The exact cause of EoE remains unclear but 2015).
increasing prevalence of disease has led to Endoscopic evaluation is necessary for the
focused attention on environmental exposures. diagnosis of EoE with an increased number of
Several risk factors have been identified support- eosinophils in the esophageal epithelium repre-
ing environmental influences to the development senting the histologic hallmark of disease.
of EoE including birth by cesarean section, pre- Utilizing a cutoff value of 15 eosinophils per
maturity, early antibiotic exposure during infancy, high-powered field results in a sensitivity of
food allergies, lack of breast feeding, smoking 100% and specificity of 96%, although patients
exposure and residency in low population density with classic phenotypic features and lower levels
areas (Jensen et al. 2013, 2014; Slae et al. 2015). of eosinophilia have been described (Ravi et al.
Additionally, clustering amongst families, male 2011; Dellon et al. 2015). Although not diagnos-
predominance, strong twin concordance and tic, the most common gross findings on endos-
genome-wide association studies (GWAS) all copy include white specks/exudate, mucosal
suggest a genetic component as well (Furuta and edema, linear furrowing, esophageal rings and
Katzka 2015). At the cellular level, it is believed esophageal stricturing (see Fig. 10.1). Barium
that impaired barrier function (dilated inter- esophagography may also have a role in the eval-
epithelial spaces, increased epithelial permeabil- uation of patients with EoE as up to 55% of chil-
ity and down-regulation of proteins associated dren who had no signs of stricturing at time of
with barrier function and molecular adhesion) endoscopy have been found to have esophageal
along with increased activity of type 2 helper T narrowing on esophagography (Menard-Katcher
(Th2) cells represents the underlying cause of et al. 2015).

Table 10.2 Overview of EoE therapies

Recommendation or
Therapy dosage
Elemental diet therapy Amino-acid based
∗ formula for 4–6 weeks
Elimination diet therapy
∗
Six-food elimination Elimination of milk,
wheat, eggs, soy,
seafood and nuts
Four-food elimination Elimination of milk,
wheat, eggs and soy
Allergy testing-based Not recommended
Proton pump inhibitors 10–20 kg body weight:
(Omeprazolea) 10 mg twice a day
>20 kg body weight:
20 mg twice a day
∗ Glucocorticosteroids
Fluticasone 220–440 μg twice a
day
Fig. 10.1 Common histological appearance of Budesonide 0.25–0.5 mg twice a
EoE. Classic appearance of EoE with white specks/exu- day
date (black arrow head), vertical furrowing (blue stars) Modified and adapted from Furuta and Katzka (2015)
and esophageal rings, also known as furrowing (white a
An alternative, equivalent PPI may be used
asterisk)
then that food should be excluded form the

Management patient’s diet (Peterson and Boynton 2014;
D’Alessandro et al. 2015).
The management of EoE can be summarized as In older children a 4- or 6-food elimination
the “3 D-approach”: Diet, Drugs and Dilation diet may be attempted and has been shown to
(D’Alessandro et al. 2015). Although the goal of have an approximately 70% rate of clinical
therapy is clinical and histological remission, this response (see Table 10.2). Similar to the elemen-
is rare and clinical improvement along with sig- tal diet, selected foods are eliminated from the
nificant reduction of mucosal eosinophilia are diet and are only reintroduced after clinical and
considered signs of effective therapeutic response histological response are confirmed by endos-
(Dellon et al. 2013). copy with those foods eliciting clinical symp-
toms and/or increased mucosal eosinophilia
Diet removed from the patient’s diet (Rodríguez-
An elemental diet represents the therapy with the Sánchez et al. 2014).
highest clinical response with nearly 90% of chil- Allergy, skin-prick driven therapy has been
dren demonstrating clinical improvement and is shown to have much poorer response rates with
associated with histological remission. Patients only 45% of patients showing sustained response
are placed on an amino-acid based formula for and therefore is not routinely recommended
4–6 weeks. If clinical and histological response is (Arias et al. 2014).
seen, foods are slowly reintroduced one-food
group at a time every 5–7 days. If no reoccur- Drugs
rence of symptoms is seen, endoscopic evalua- Proton-pump Inhibitor (PPI) use is a mainstay of
tion is performed to ensure histological disease EoE therapy. As essentially all patients experi-
progression is not seen before reintroducing each ence reflux-like symptoms, lack of PPI response
new food group. If a specific food elicits clinical is the only current method to rule out gastro-
symptoms or increased mucosal eosinophilia, esophageal reflux as a cause of the patient’s

symptoms (Furuta and Katzka 2015). gluten in genetically predisposed individuals”

Additionally, nearly 40% of patients with histo- (Ludvigsson et al. 2013). Classic celiac disease
logically confirmed EoE experience a clinical presents with symptoms suggestive of malabr-
response to PPI therapy alone and therefore is soption: diarrhea, steatorrhea, weight loss, and/
considered first-line therapy in all patients with or growth failure (Ludvigsson et al. 2013).
EoE (Molina-Infante et al. 2015). However, there has been an increasing number
The use of systemic corticosteroids results in of non-classical cases that present with a num-
high rates of remission but long-term use is lim- ber of intestinal and extra-intestinal manifesta-
ited by relapse after tapering of the medication tions (Rampertab et al. 2006).
and side effects. Therefore, systemic steroids
may be used to rapidly induce remission but
should not be considered as a long-term thera- Pathogenesis and Immunology
peutic option (Mukkada and Furuta 2014).
Topical steroids (fluticasone and budesonide) The pathogenesis of Celiac disease is linked to a
have also shown significant response rates with combination of genetic, environmental and
much lower side effect profiles as compared to immunological risk factors, although no clear
systemic steroids and is now considered first- pathway for each has ever been defined (Tran
line therapy after a PPI trial (Contreras and 2014). The microbiome has been studied exten-
Gupta 2014; Gupta et al. 2015). The preferred sively with mixed results both in favor and
route of administration is via an oral viscous opposed to its role in the development of Celiac
solutions with sucralose creating a slurry disease (de Meij et al. 2013).
consistency, although several alternatives to

sucralose have been show to be effective as well
including applesauce and honey (Lee et al. Genetics and Risk Factors
2016).
The common human leukocyte antigen (HLA)
Dilation class II gene (DR3, DR5/DR7, or DR4) known as
Strictures are a common finding among patients HLA-DQ2 and HLA-DQ8 located on chromo-
with EoE with several studies showing endo- some 6p21 is associated with Celiac disease
scopic dilation to be safe and efficacious (Gutierrez-Achury et al. 2011). HLA typing is
(D’Alessandro et al. 2015). Although dilation not helpful in establishing a diagnosis of Celiac
may result in rapid symptom relief, it does not disease but can be useful to exclude the diagnosis
affect esophageal inflammation and should be in high-risk patients or group of patients. Patients
considered an adjunct therapy only to appropriate that do not have the HLA-DQ2 or HLA-DQ8
dietary and/or medical interventions (Kavitt et al. molecules have a negative predictive value near
2014). 100%, thus essentially ruling out the diagnosis of
celiac. It is important to remember that many
children with the proper HLA typing may not
Celiac Disease have celiac disease at the time of testing, but are
still at risk to develop the disease later in life
Introduction and Epidemiology (Tran 2014).
Multiple risk factors have been associated
Prevalence of celiac disease in pediatric patients with having an increased risk of gluten intoler-
is similar to that of adults, effecting approxi- ance (see Table 10.3) and if present should
mately 1% of the population (Newton and prompt screening for Celiac disease (see diagno-
Singer 2012). Celiac disease is defined as sis section below) (Husby et al. 2012).
“chronic small intestinal immune-mediated Alternatively, breast feeding has been suggested
enteropathy precipitated by exposure to dietary to be protective (Størdal et al. 2013).

Table 10.3 Factors associated with an increased risk for with concerning serology. Biopsies are taken
Celiac disease
from duodenal bulb and affected tissue will be
Signs patchy. The degree of villous atrophy is graded
Unexplained elevated transaminases without known on the Marsh criteria (3c being most severe and 0
liver disease
Iron deficiency anemia being normal). In patients where the routine
Pubertal delay pathology is inconclusive, anti T-cell receptor
Poor growth gamma delta (TCRγδ) positive intraepithelial
Diagnoses lymphocytes detection can be performed on for-
Type I DM
malin fixed paraffin imbedded in small bowel
Selective IgA deficiency
Down’s syndrome biopsies. The (TCRγδ) will remain elevated even
Autoimmune liver disease on gluten free diet (Tran 2014).
Dermatitis herpetiformis Although not routinely the standard of care
Intussusceptions
within the United States, in 2012 the European
Eosinophilic esophagitis
Irritable bowel syndrome society of Pediatric Gastroenterology, Hepatology
Behaviors/family and Nutrition offered times when endoscopy
Introduction of gluten after age 6 months could be avoided for a diagnosis. Pediatric
Relatives with celiac disease patients with signs or symptoms suggestive of
celiac, high anti-TTG IGA titers (>10 times the
Diagnosis ULN) should be offered a second blood test to
check for EMA. If it is positive, then the diagno-
In addition to patients with increased risk factors, sis of celiac can be made without endoscopic
patients with symptoms of diarrhea, poor growth, conformation. It is also advised to check for HLA
stunting, delayed puberty, amenorrhea, nausea or types in these patients (Husby et al. 2012).
vomiting, chronic abdominal pain, fatigue and/or
recurrent aphthous stomatitis should be screened
for Celiac disease (Husby et al. 2012). Patients are Treatment
most commonly screened for celiac disease with
serological tests and this should be done while the The treatment for celiac disease is a gluten free
patient is consuming a gluten containing diet. diet. Unfortunately, about 25% of patients con-
Celiac panels are particularly expensive, and gen- tinue to experience symptoms despite a gluten
erally not as helpful. It is better to select specific free diet (Paarlahti et al. 2013). Patients should
serological tests to check in patients (Hill et al. plan to have less than 20 parts per million (ppm;
2016). Immunoglobulin A (IgA) anti-tissue trans- 6 mg equivalent) of gluten per day. Some patients
glutaminase (TTG) can have a sensitivity of 98% require new appliances that have been gluten free.
if done in a reliable lab with an established upper Following a gluten free diet can add additional
limit of normal. Endomysial antibody IgA should stress to all family members involved as this fre-
be done in a lab with reference standards of a pedi- quently affects the entire family. Gluten free diets
atric population (Husby et al. 2012). Deaminated tend to be higher in fat and should be avoided
gliadin peptide (DGP IgG) has comparable speci- unless a diagnosis of celiac disease is made.
ficity and lower sensitivity as the EMA IgA. In
children under age 2, the TTG IGA and EMA have
a higher chance of being inaccurate. For this rea- Functional Gastrointestinal
son in kids <2 years, they should have a TTG IGA Disorders
and DGP IGG tested. False negatives will occur
with IgA deficiency so total IgA is usually col- Background
lected when a screening TTG-IgA is collected for
the first time for any patient (Hill et al. 2016). Functional GI Disorders (FGID) are better
An esophagogastroduodenoscopy is usually defined as Disorders of the Gut-Brain Interaction
preformed to confirm the diagnosis in patients and can affect anyone from young age through

adulthood. FGIDs did not always receive scien- we will focus on functional diarrhea, functional
tific rigor until the last several decades and so constipation and functional abdominal pain.
scientific historic data is lacking. However, with
increasing categorization and scientific interest,
research is suggesting several complex processes eonate/Toddler Functional GI
N
such as microbial dysbiosis, altered mucosal Disorders
immune function, visceral hypersensitivity and
central nervous system dysregulation all contrib- Functional symptoms in infants and toddlers can
uting to the etiology of FGIDs (Drossman and be a result of normal development, as in the case
Hasler 2016). With emerging understanding, it is of infant regurgitation, or it can be a “maladap-
important to keep in mind that functional disor- tive behavioral response to an internal or external
ders can coexist, or even be worsened, with other stimuli”, as in the case of functional constipation.
underlying gastrointestinal pathologies (Hyams Young children cannot distinguish between emo-
et al. 2016). tional and physical distress, and both can result in
Most recently, the Rome IV criteria were pub- similar behavior. Because young children are
lished in the Journal of Gastroenterology unable to express themselves clearly, physicians
(Drossman and Hasler 2016), updating the typi- must rely on caregiver’s history and clinical
cal definitions and treatments of FGIDs. The full insight for diagnosis and treatment. For this rea-
list of pediatric FGIDs is seen in Table 10.4. Here son, in the management of functional disorders, it
is of the outmost importance that clinicians
develop a trusting relationship between the care-
Pediatric
Table 10.4 functional gastrointestinal
disorders
givers and themselves. Conversations should
include the assessment of family dynamic and
G. Childhood functional GI disorders: neonate/toddler
inquiry on how disruptive the FGID is to the fam-
G1. Infant regurgitation
ily relationship. Treatments and interventions
G2. Rumination syndrome
should certainly be targeted to the child, but
G3. Cyclic vomiting syndrome (CVS)
should also consider and attend to the family as
G4. Infant colic
well.
G5. Functional diarrhea
G6. Infant dyschezia
Functional Diarrhea
G7. Functional constipation
Diagnostic criteria for functional diarrhea are in
H. Childhood functional GI disorders: child/adolescent
H1. Functional nausea and vomiting disorders
Table 10.5. Physiologically, children with func-
H1a. Cyclic vomiting syndrome (CVS)
tional diarrhea maintain normal hydration, elec-
H1b. Functional nausea and functional vomiting trolyte balance and glucose absorption, and there
H1b1. Functional nausea is no steatorrhea (Milla et al. 1978). Etiology is
H1b2. Functional vomiting typically nutritional: overfeeding, excessive fruit
H1c. Rumination syndrome juice intake, excessive fructose intake, low fat
H1d. Aerophagia diet, and/or excessive sorbitol intake. Stools can
H2. Functional abdominal pain disorders become progressively less formed throughout
H2a. Functional dyspepsia the day and may have undigested food or
H2a1. Postprandial distress syndrome
H2a2. Epigastric pain syndrome Table 10.5 Diagnostic criteria for functional diarrhea
H2b. Irritable bowel syndrome (IBS) Must include all of the following:
H2c Abdominal migraine 1. Daily painless, recurrent passage of 4 or more
H2d. Functional abdominal pain—NOS large, unformed stools
H3. Functional defecation disorders 2. Symptoms last more than 4 weeks
H3a. Functional constipation 3. Onset between 6 and 60 months of age
H3b. Nonretentive fecal incontinence 4. No failure to thrive if caloric intake is adequate
Table adapted from Drossman and Hasler (2016) Table adapted from Benninga, et al. (2016)

mucous. If the patient is growing well, malab- extreme short segment Hirschsprung’s disease is
sorption is unlikely. No specific treatment is suspected (Benninga et al. 2016).
indicated other than reassurance (Benninga et al. Treatment for FC should include education of
2016). the caregivers, reassurance, and implanting inter-
ventions early when symptoms start. Duration of
Functional Constipation treatment can be months to years in certain situa-
Functional constipation (FC) is the result of a tions. Pharmacological treatments should include
child having repeated voluntary attempts to with- stool softeners such as polyethylene glycol, lactu-
hold feces in an attempt to avoid defecation due lose or milk of magnesia. Stool softners will soften
to a fear. The fear can be due to a previous the actual stool making it less painful for the child.
discomfort, pain, or other negative experience Over time, the goal would be to minimize the dis-
associated with defecation (Tabbers et al. 2014). comfort and normalize defecation for the child.
In children, one episode of painful stool due to a Although these medications are commonly pre-
diet change can be the initial negative experience scribed in children, there is no large well-designed
that can result in withholding in the future. randomized trial studying these interventions.
Continued retention of feces in the colon results Additionally, no randomized control studies exist
in continued water absorption from the stool that study dietary supplement or laxatives in infants
causing the fecal matter to become harder and and toddlers (Benninga et al. 2016). However, lax-
more painful to evict. Diagnostic criteria for FC atives such as senna, are frequently added in com-
are listed in Table 10.6. bination with stool softners. There is all together
Differential diagnosis for FC in childhood limited data on probiotics in children. Reports
should include anatomical obstruction, evaluating cow milk allergy causing constipation
Hirschsprung’s disease, spinal problems, meta- have been inconsistent with conflicting data
bolic and neuroenteric abnormalities. (Iacono et al. 2006; Kiefte-de Jong et al. 2010). It is
Hirschsprung’s disease should be suspected in reasonable to consider a 2–4 week trial of hypoal-
those infants that did not pass meconium passage lergenic formula in infants and toddlers in whom
in the first 24 h of life. Barium enemas may be laxative treatment failed (Tabbers et al. 2014).
unhelpful until after 4–6 weeks of life and colonic Behavior techniques such as strict toilet training
distention has taken place. Rectal suction biopsy should be avoided due to potential to cause addi-
is the gold standard for diagnosis although ano- tional anxiety. For preschoolers, reward system
rectal manometry is sometimes appropriate if with “stars” can work to provide incentive.
Table 10.6 Diagnostic criteria for functional unctional Disorders of Childhood

F
constipation and Adolescence
Must include 1 month of at least 2 of the following in
infants up to 4 years of age: unctional Nausea and Functional
F
1. 2 or fewer defecations per week Vomiting
2. History of excessive stool retention Functional Nausea and Vomiting are new diagno-
3. History of painful or hard bowel movements
ses that present in the Rome IV criteria.
4. History of large-diameter stools
Diagnostic criteria are listed in Table 10.7. Their
5. Presence of a large fecal mass in the rectum.
inclusion was based on clinical experience with
In toilet-trained children, the following additional
criteria may be used:
having patients complaining of these symptoms
1.At least 1 episode/week of incontinence after the
without underlying pain that would otherwise
acquisition of toileting skills make the diagnoses of functional dyspepsia.
2. History of large-diameter stools that may obstruct These patients may experience autonomic symp-
the toilet toms such as dizziness, sweating, pallor and
Table adapted from Benninga, et al. (2016) tachycardia. Postural orthostatic tachycardia

Table 10.7 Diagnostic criteria for functional nausea and Irritable bowel syndrome is a type of func-
vomiting
tional abdominal pain disorder and it is divided
H1b1. Functional nausea into diarrhea predominant, constipation predomi-
Must include all of the following fulfilled for the last nant, constipation and diarrhea predominant, and
2 months:
unspecified. Diagnosis criteria are in Table 10.8.
1. Bothersome nausea as the predominant symptom,
For patients with constipation and abdominal
occurring at least twice per week, and generally
not related to meals pain, it is recommended to treat constipation first.
2. Not consistently associated with vomiting If there is continued discomfort, then patient
3. After appropriate evaluation, the nausea cannot should be treated for irritable bowel syndrome—
be fully explained by another medical condition constipation predominant (Hyams et al. 2016).
H1b2. Functional vomiting Etiology for IBS is still thought to be a disease
Must include all of the following: of the brain gut syndrome. Sensitizing medical
1. On average, 1 or more episodes of vomiting per events such as abdominal distention, inflamma-
week tory processes (infections and allergies), and
2. Absence of self-induced vomiting or criteria for motility problems superimposed with a potential
an eating disorder or rumination
genetic predisposition can lead to changes in pain
3. After appropriate evaluation, the vomiting cannot
be fully explained by another medical condition processing and develop visceral hypersensitivity.
Table adapted from Hyams et al. (2016) Visceral hypersensitivity in combination with
a
Criteria fulfilled for at least 2 months before diagnosis sensitizing psychosocial events such as depres-
sion, family stressors, coping problems and sec-
ondary gains can all lead to abdominal pain and
should be considered during the workup. other gastrointestinal complaints (Iovino et al.
Additionally, anatomical variations (such as mal- 2009; Saps et al. 2009). During evaluation of
rotation), gastroparesis, and pseudo-obstruction IBS, other pathologies causing a mucosal disease
should also be considered and evaluated for if and/or malabsorption should be considered.
necessary. Electrolytes, calcium, cortisol and Alarm symptoms listed in Table 10.9 should be
thyroid hormone levels should all be evaluated. warrant further investigation for etiologies such
Psychological evaluations are important in these as celiac, inflammatory bowel disease, and other
children (Hyams et al. 2016). (Hyams et al. 2016). Fecal calprotectin is being
There is no established treatment for patients used increasingly to evaluate for mucosal inflam-
with nausea and vomiting. Cognitive behavioral mation that is commonly present in patients with
therapy and/or hypnotherapy can be helpful.
Cyproheptadine has been shown to be helpful in
functional dyspepsia with nausea. Gastric elec- Table 10.8 Diagnostic criteria for irritable bowel
tric stimulation can be considered in severe cases syndrome
under the guidance of a specialized neurogastro- Must include all of the following:
enterologist (Benninga et al. 2016). 1. Abdominal pain at least 4 days per month associated
with one or more of the following:
unctional Abdominal Pain Disorder
F (a) Related to defecation
and Irritable Bowel Syndrome (b) A change in frequency of stool
Previously known as “abdominal pain related (c) A change in form (appearance) of stool
functional gastrointestinal disorder” the term has 2. In children with constipation, the pain does not
now been changed to “functional abdominal pain resolve with resolution of the constipation (children
in whom the pain resolves have functional
disorders”. There is emphasis to use specific constipation, not irritable bowel syndrome)
names to differentiate between various functional 3. After appropriate evaluation, the symptoms cannot
disorders (Table 10.4) and to acknowledge that be fully explained by another medical condition
more than one functional disorder may occur at Criteria fulfilled for at least 2 months before diagnosis
the same time (Hyams et al. 2016). Table adapted from Hyams et al. (2016)

Table 10.9 Potential alarm features in children with exam are frequently, but not always useful in
chronic abdominal pain
evaluations degree of stool burden in the rectum.
Family history of inflammatory bowel disease, celiac Regular abdominal x-rays should be avoided
disease, or peptic ulcer disease except in those patients where physical exam and
Persistent right upper or right lower quadrant pain
history are not sufficient. Barium enemas should
Dysphagia
not be used early in the evaluation process.
Odynophagia
Laboratory screening with hypothyroidism,
Persistent vomiting
celiac and hypercalcemia are not indicated with-
Gastrointestinal blood loss
out other concerning symptoms (Hyams et al.
Nocturnal stools
2016).
Arthritis
Treatment should comprise of rectal disim-
Perirectal disease
paction and then a routine regiment to avoid re-
Involuntary weight loss
accumulation. Disimpactions can either be done
Deceleration of linear growth
Delayed puberty
by large amounts of polyethylene glycol or rectal
Unexplained fever
enemas. Routine regiments should include small
amounts of polyethylene glycol as a stool soft-
Clinical judgment should be exercised, putting what
might be considered an alarm sign into the whole context ener and/or a stimulant such as Senna.
of the history and physical exam Unfortunately, those children that suffer with
Table adapted from Hyams and Di Lorenzo Gastro; fecal incontinence require long term follow up
1456–1468
without always full resolution of symptoms
inflammatory bowel disease (Henderson et al. (Hyams et al. 2016). At 2 year follow up, 29% of
2012). patients with fecal incontinence were free of soil-
There are few randomized control studies for ing at 2 years following intensive therapy
IBS. However, there is evidence to try probiotics (Tabbers et al. 2014). High fiber diets have not
(Zhang et al. 2016), peppermint oil (Pittler and been shown to improve constipation.
Ernst 1998; Grigoleit and Grigoleit 2005; Khanna
et al. 2014), FODMAP (Fermentable, Oligo-, Di,
Mono-saccharides And Polyols) diet (Halmos Inflammatory Bowel Disease
et al. 2014). In addition to pharmacotherapy and
food interventions, cognitive behavior therapy, Inflammatory bowel disease (IBD) is an emerg-
relaxation techniques, biofeedback and hypno- ing inflammatory condition of the gastrointesti-
therapy have all been found to be helpful (Bursch nal (GI) tract in children that includes Crohn’s
2008). disease (CD) and ulcerative colitis (UC). UC and
CD are grouped together as they have similar
Functional Constipation epidemiology, immunologic, genetic, clinical

Functional constipation in childhood and adoles- features and diagnostic features but they differ in
cents is similar to that in toddlerhood. As in the treatment and prognostic approach. In this sec-
younger child, the triggering event is frequently a tion, we will use a common IBD approach where
painful experience with defecation or social appropriate but differentiate CD from UC wher-
occurrences that become more meaningful at this ever necessary.
age. Repeated withholding leads to continued
absorption of water from the feces while they are
in the colon and thus resulting in a hard stool Epidemiology
mass. This mass becomes more painful to pass
and causes a continued cycle of withholding due Worldwide, population studies show that IBD is
to the associated pain (Hyams et al. 2016). unevenly distributed with the highest disease
Diagnosis of constipation should ideally be rates occurring in developed nations like Europe
made by history and physical exam. Digital rectal and North America (Lashner 1995; Lakatos

2006). However recent many small series on IBD inflammation in CD is often patchy which can be
epidemiology published form Asia, Eastern helpful in distinguishing UC from CD. The most
Europe and South America show increased inci- common site of involvement for Crohn’s disease
dence. Data published from Canada and United is the terminal ileum but more than 2/3 pediatric
Kingdom show an increased incidence of IBD in patients have some colonic involvement and up
second and third generation immigrants espe- to 10–15% have only colonic disease. In approxi-
cially from South Asia. Based on few systematic, mately 10% of cases it is difficult to distinguish
population- based studies the incidence of IBD in UC from CD and these patients are diagnosed
the pediatric population is estimated to be around with “indeterminate colitis”.
7–12 per 100,00 children in North America The most common presentation of UC is diar-
(Kugathasan et al. 2003). IBD in children differs rhea, rectal bleeding and abdominal pain while
from adults with more cases seen among males CD is more likely to present with more subtle and
patients and CD comprises about 2/3 of all new varied abdominal pain, diarrhea, poor appetite,
IBD diagnosis, where as in adults prevalence of and weight loss. The insidious onset and nonspe-
CD and UC are equal (Perminow et al. 2006). cific presentation can often cause a delay in the
diagnosis of CD.
Abdominal pain is the single most common
Pathophysiology presenting symptom in IBD, but may have sev-
eral other less obvious presentations such as
The underlying etiology of IBD is not well under- growth failure, anemia, arthralgias and rashes
stood. Environmental, genetic, microbial and without notable GI symptoms (Fish and
immune factors have been proposed as underly- Kugathasan 2004; Heuschkel et al. 2008).
ing causes (Oliva-Hemker and Fiocchi 2002). Knowing the varied presentations of IBD can aid
Over 200 genetic loci have been discovered that in early referral and initiation of treatment (see
are linked to IBD suggesting an underlying Table 10.10).
genetic component, yet the changing epidemiol-
ogy of IBD implies that, in addition to genetic
susceptibility for disease, environmental triggers Extra-intestinal Manifestations
such as diet and commensal microbiota signa-
tures may likely impact disease presentation and Although usually more rare, many extra-intestinal
ultimate phenotypic expression. manifestations have been reported in the litera-
ture. Up to 25–30% of patients exhibit extra-
intestinal manifestations that cause varying
Clinical Presentation degree of morbidity and mortality. The exact eti-
ology of these conditions is unknown but autoim-
UC and CD are both chronic inflammatory dis- mune reactions, induction of immune complexes
eases of the gastrointestinal tract with periods of and inflammatory response, and genetic factors
remission and flares. Although UC and CD share are all postulations. Extra-intestinal manifesta-
many similarities, they each have distinguishing tions can correlate with GI symptoms but some
characteristics depending on location of involve- will be present even in GI remission. The most
ment, disease extend and extra intestinal mani- common extra-intestinal manifestations are listed
festations (Baldassano and Piccoli 1999). In UC, in Table 10.11.
inflammation is continuous starting in the rectum
and extending proximally to varying extents and
this inflammation only involves mucosa of the Evaluation
colon. In contrast, CD typically exhibits transmu-
ral inflammation and can be located anywhere in If IBD is suspected, laboratory tests that should
the GI tract, from mouth to anus. Additionally, be ordered to include complete blood count

Table 10.10 Potential “red flags” on history and exam suspicious for inflammatory bowel disease
History Physical exam
Abdominal Pain Pallor/anemia
Distant from umbilicus
Interferes with sleep
Discrete, acute episodes
Precipitated by eating
Dysphasia/Odynophagia
Involuntary weight loss Decreased growth velocity
Rectal bleeding Delayed puberty/maturation
Nocturnal stooling Oral ulcerations
Extra-intestinal manifestations Abdominal tenderness/mass
Recurrent low-grade fevers
Erythema nodosum
Pyoderma gangrenosum
Joint pain/swelling
Severe eye pain/ Persistent conjunctivitis
Unexplained jaundice
Strong family history of IBD Perianal fistula/fissures
Table 10.11 Extra-intestinal manifestations of IBD and good indicators of the presence of IBD are
Extra-intestinal the elevated ESR (>20 mm/h) or CRP, thrombo-
locations Symptoms cytosis (>400,000), decreased albumin level
Skin Erythema nodosum (2.0–3.5 g/dL), and decreased haemoglobin level
Pyoderma gangrenosum indicating iron deficiency anemia. If any of these
Mouth Aphthous stomatitis labs are abnormal, referral to a specialist should
Gingivitis be made in a timely manner so that the diagnosis
Eye Uveitis is confirmed with further work up (Mack et al.
Episcleritis 2007).
Bone Spondyloarthritis/axial arthritis Serologic markers such as anti-Saccharomyces
Osteoporosis/osteopenia cervisiae (ASCA), pANCA (anti-neutrophil
Finger clubbing cytoplasmic antibodies), antibody to outer mem-
Hepatobiliary Sclerosing cholangitis brane protein (Anti-OmpC) and others are used
Chronic hepatitis by few clinicians to identify IBD subtypes in
Fatty liver cases where there is a significant overlap in the
Pancreatitis results after conventional diagnostic work up.
Blood Anemia
Currently there is no sufficient evidence in use of
Thrombocytosis
these serological markers for therapeutic strate-
Vascular Thromboembolism
gies or monitoring treatment response of IBD
Deep vein thrombosis
patients (Zholudev et al. 2004).
Kidney Renal calculi (oxalate or uric
acid) The diagnosis of inflammatory bowel disease
Amyloidosis is dependent on endoscopic, histological, and
radiological findings. Radiography is necessary
at diagnosis to determine extent of disease, loca-
(CBC), erythrocyte sedimentation rate (ESR), tion of disease, and severity. In the past, upper
albumin, aminotransferases, C reactive protein gastrointestinal series (UGI) with small bowel
(CRP), iron studies, and stool calprotectin. The follow through was the “gold standard”. However,
four lab tests that are most commonly abnormal technology has made great strides in the last

decade and other modalities like magnetic reso- part of ileum for evidence of IBD. Endoscopy
nance imaging (MRI) and computed tomography aids in diagnosing IBD, differentiating between
scans (CT) are now standard of care with pelvic UC and CD, and assessing extent and severity of
MRI the imaging modality of choice for perianal disease. After diagnosis, it is used to monitor
disease (Sauer et al. 2016). Most children with response to therapy (mucosal healing), for can-
IBD receive multiple radiological exams through- cer surveillance, and to perform therapeutic pro-
out their life, increasing their lifetime exposure, cedures, such as stricture dilatation (Beattie
making MRI especially promising in the pediat- et al. 1996). Several studies showed that per-
ric population because of the lack of ionizing forming an esophagogastroduodenoscopy dur-
radiation (Fig. 10.2). ing the work-up for pediatric IBD resulted in
Video Capsule Endoscopy (VCE) has been a higher rates of confirming a diagnosis and is now
crucial addition in imaging in IBD. VCE allows considered standard practice. Macroscopic find-
small bowel visualization with no radiation and is ings may include patchy or continuous inflam-
well tolerated in the pediatric population. In most mation, ulcerations, nodularity, and strictures
cases it requires no sedation; in the young/small (Fig. 10.3).
child endoscopy may be necessary to place the
capsule in the small bowel via endoscopy but in
larger/older children this is not necessary. This Histology
technology has made evaluation of the small bowel
more sensitive and can aid in diagnosing suspected Combined together with macroscopic appear-
IBD and distinguishing between UC and CD. ance of the mucosa, biopsies aid in the diagnosis
Endoscopy with biopsy is the most sensitive of IBD and differentiation between UC and
and specific evaluation of the colon and terminal CD. During endoscopy and colonoscopy,
Fig. 10.2 MRE of patient with Ulcerative Colitis. MRE of ulcerative colitis—sequential coronal T2 weighted showing
thickened transverse colon and featureless thick walled descending colon

Fig. 10.3 Video capsule endoscopy images of ulcers in the small bowel suggestive of Crohn’s disease. Video capsule
endoscopy showing large ulcers with erythematous base in the small bowel of a patient with CD
biopsies are usually obtained from all areas, Corticosteroids

even in the absence of obvious lesions because Corticosteroids still remains the main therapy for
histological abnormalities, sometimes granulo- the induction of remission in moderate to severe
mas, can be present in biopsies of “normal” CD and UC by providing rapid improvement of
appearing tissue. Certain histological findings inflammation (Beattie et al. 1996). There is not
are helpful in confirming an IBD diagnosis and much evidence to suggest that they provide
distinguishing between UC and CD. Presences mucosal healing, hence they should not be used
of noncaseating granulomas are pathognomonic as maintenance therapy. They are typically started
for CD; however, 60% of the times biopsies will along with a maintenance therapy to induce
not show granulomas and the diagnosis is made remission; while the maintenance drug takes
based on radiological, histological, or endo- effect, the steroids are gradually weaned. IV ste-
scopic findings. roids can be used in severe UC and CD to induce
remission. Rectal steroid enemas can be used for
proctitis and sigmoid disease with no systemic
Management side effects (Wang et al. 2016). The other formu-
lations of steroids like oral budesonide, which
Before the year 2000 the main therapy was corti- has first pass metabolism, can be used to mini-
costeroids, with few other options. Currently mize systemic adverse effects. Systemic steroids
classes of drugs used to treat IBD include amino have many adverse effects in children, particu-
salicylates, immunomodulators and biologics. larly the effects on growth, immunity and adrenal
These classes have allowed practitioners to suppression. For these reasons, plus lack of effi-
greatly decrease their dependence on steroids. cacy in maintenance of remission and mucosal
There is a recent increased focus on IBD path- healing in IBD, they should be used only as short
ways and genetics which will ideally allow period of time, ideally less than 3 months.
focussed targeting of disease pathways in the
future with hopes that such targeting will lead to Aminosalicylates
better outcomes with fewer adverse effects. Many Aminosalicylates (ASAs) are a wide group of
treatment medications overlap between UC and medications that all contain a 5-aminosalicylate
CD but there are some clear indications that (5-ASA) moiety. These medications have shown
differ. to be effective in induction and maintenance of

remission in mild to moderate UC and are the alpha (TNF alpha) agents. TNF alpha is a cyto-
first line of therapy in these cases (Wang et al. kine involved in systemic inflammation and can
2016). They may also have some benefit in main- stimulate the acute phase reaction. Infliximab
tenance of remission in mild CD. Because ASAs blocks the action of TNFα by preventing it from
have varying delivery systems which determine binding to its receptor in the cell and was the first
the segment of bowel targeted, it is imperative to in this class to be approved in paediatric IBD. This
understand disease location prior to initiation of biologic is used in children with moderate to
this therapy. In general these therapies are well severe UC and CD (Hyams et al. 2007; Turner
tolerated. Main adverse effects are headache and et al. 2011). Infliximab is also effective in fistulis-
rash: rare but serious side effects include pancre- ing and perianal CD (Bernstein et al. 2010). Since
atitis, hepatitis, colitis and low sperm count in infliximab is chimeric, it can cause formation of
males. antibodies against the drug and decrease efficacy.
The most common adverse effects for infliximab
Immunomodulators include infusion reactions, infections, and ALT
Azathioprine and its metabolite 6-mercaptopurine elevations. Infusion reactions are usually mild
(6-MP) are primarily used for steroid refractory and respond to antihistamine therapy.
CD and as maintenance of remission in moderate Another anti-TNF agent, adalimumab, has
to severe UC and CD (Markowitz et al. 2000; been approved for treatment of IBD in adults and
Hyams et al. 2007; Turner et al. 2011). These recently approved for paediatrics CD (Sandborn
drugs are not used in the induction of remission et al. 2012). Adalimumab has decreased occur-
because they act slowly and may take up to rence of antibody formation and is given as a sub-
3 months to reach maximal effect. Most often cutaneous injection. Biologic therapies can
they are started in conjunction with steroids in reactivate latent Mycobacterium tuberculosis and
moderate to severe disease and when used in this all patients must have a documented negative
way can minimize the steroid use. Adverse PPD or quantiferon gold before starting therapy.
effects of these drugs are idiosyncratic and dose Other more serious complications with anti-TNF
dependent. Idiosyncratic adverse effects are pan- drugs are increased risk for malignancy.
creatitis, fevers, and myalgias. Dose dependent Infliximab has a black box warning regarding
adverse effects include infection, bone marrow hepatosplenic T-cell lymphoma (Kotlyar et al.
suppression, and elevated liver enzymes 2011), which is a rare and often fatal T-cell lym-
(Kirschner 1998). Patients must be monitored for phoma that has been reported in approximately
these side effects. 12 US cases. All patients had IBD and
Methotrexate has shown to be effective in predominantly were young males. All these

inducing and maintaining remission in adult patients had received infliximab in conjunction
patients with CD (Turner et al. 2011). So far, with azathioprine and/or 6-mercaptopurine. For
there have been no controlled trials of methotrex- this reason, these agents should not be used con-
ate use in paediatric CD but reports from retro- currently in young males, until other options are
spective reviews have shown good remission exhausted and the benefits outweigh the risks.
rates in patients that fail 6-MP or are intolerant to Other malignancies that have been associated
azathioprine. Methotrexate is a known teratogen, with anti-TNF agents include lymphoma and
so birth control counselling must be given to all leukaemia.
females of childbearing age who are started on
this therapy. Surgical Management
IBD first line treatment remains medical therapy.
Biologic Therapies Indications for surgery are relatively similar
Biologics have revolutionized the treatment and between ulcerative colitis and Crohn’s disease,
management of IBD dramatically. One class of however, the approach and the outcomes differ.
these drugs is the anti-tumour necrosis factor Indications for surgery include fulminant colitis,

massive haemorrhage, perforation, stricture, tions” (de Onís et al. 1993). In pediatric children,
abscess, fistula (in Crohn’s disease), toxic mega- the repercussion of malnutrition can be profound
colon, failure of medical therapy, steroid depen- because of child’s need for growth and develop-
dency, and dysplasia. Additional indications for ment (Mehta et al. 2013). International studies
surgery in paediatric patients include growth and have linked malnutrition to majority of childhood
pubertal delay as children often demonstrate post deaths in developing countries (Pelletier et al.
operative catch up growth. 1993, 1995). However, in developed countries,
The current standard surgical procedure for there is less precise data. One problem has been a
UC is total colectomy followed by ileoanal pull- lack of unifying definition. The American Society
through with anal anastomosis (IPAA) (Tilney of Parenteral and Enteral Nutrition (A.S.P.E.N)
et al. 2006). The majority of patients with Crohn’s working group put forth guidelines to use five
disease will need surgery during their life, domains to help define malnutrition. The five
although this number is decreasing due to domains include anthropometric parameters,
advances in medical therapy. As recurrence rates growth, chronicity of malnutrition, etiology and
of CD are very high within 5 years of surgery the pathogenesis, and developmental or functional
aim of the surgery is to resect as little bowel as outcomes (Fig. 10.4) (Mehta et al. 2013).
possible. This is also the reason CD is a relative Anthropometric measurements should include
contraindication to IPAA. a weight, height, body mass index (BMI) (for
children 2 years and older) and mid arm circum-
ference (MAUC) on admission to a hospital.
Outcomes Triceps skin fold (TSF) and mid-arm muscle cir-
cumference (MAMC) measurements can be con-
IBD is a relapsing disease that has high morbidity sidered. Serial measurements should be collected
but low mortality. Most children with IBD lead throughout an admission and plotted on appropri-
active normal lives, with no limitations. However, ate growth charts. Head circumference should be
patients with IBD are at increased risk for some measured for children under age 2 years. Ideally
malignancies. In UC the greatest risk is colonic a single trained individual would be doing these
dysplasia/cancer. The risk has been estimated to measurements. Children under age 2 should have
be up to 25% after 30 years of disease. Risk fac- their lengths measured lying down on a length
tors for development of colorectal cancer in UC board. For older children that cannot stand, tibia
patients are long duration of disease, early onset, lengths, knee height and/or arm span can be used.
chronic inflammation, family history of colorec- Infants and young children should be weighted
tal cancer, and primary sclerosing cholangitis. with minimal clothing. Children that cannot be
Patients with colonic CD share the same risk fac- moved should be weighed in beds with special
tors as UC patients. CD patients are known to technology especially designed for this. Because
have slight increased risk of lymphoma over their using the proper growth chart is important, chil-
lifetime. dren under 2 years should be plotted on the WHO
growth chart. The CDC growth chart should be
used for children 2–20 years. Premature children
Nutrition should have their corrected age used while plot-
ting their growth up until age 3 years. Z-scores
One primary area of progress in pediatric nutri- should be used to express individual variables in
tion has been a unifying effort to define pediatric relation to the population (Mehta et al. 2013).
malnutrition better. The World Health Growth should be assessed with dynamic
Organization (WHO) defines malnutrition as “the changes in weight and length velocity over time.
cellular imbalance between the supply of nutri- A decline in the z-score by more than 1 can be an
ents and energy and the body’s demand for them indication of failing growth. Once growth failure
to ensure growth, maintenance, and specific func- is established, etiology and interventions should

ETIOLOGY &
ANTHROPOMETRY MECHANISM IMBALANCE OF NUTRIENTS OUTCOMES
CHRONICITY
STARVATION
↓ INTAKE
NON-ILLNESS RELATED Anorexia, socia-
Parameters economic, latrogenic LOSS LEAN BODY
Behavioral, socioeconomic MASS
or environmental feeding
Weight, height interruptions, or
or length, skin intolerance MUSCLE WEAKNESS
folds, mid
upper arm OR DEVELOPMENTAL
circumference. MALNUTRITION OR INTELLECTUAL
DELAY
ILLNESS RELATED
MALABSORPTION
↑ NUTRIENT REQUIREMENT
Statistic INFECTIONS
ACUTE (<3 months)
Z-scores e.g.: Infection, Trauma, INTAKE < REQUIREMENT IMMUNE
NUTRIENT LOSS DYSFUNCTION
Burns
ENERGY +/− PROTEIN DELAYED WOUND
Reference IMBALANCE HEALING
CHRONIC (≥ 3 months) HYPERMETABOLISM
charts e.g.: Cystic Fibrosis, Energy expenditure
Chronic lung disease, PROLONGED
WHO MGRS Cancer MICRONUTRIENT HOSPITAL STAY
(0-2 yrs) DEFICIENCIES
+/−
CDC 2000 Altered utilization
(2 – 20 yrs)
of nutrients
INFLAMMATION
Fig. 10.4 Defining malnutrition. Adapted from Mehta et al. (2013)
be discussed and interventions provided based on tant but are not always uniform or reproducible
the diagnosis. Chronicity of malnutrition needs with physical exams (Mehta et al. 2013).
to be established. Children with malnutrition for
less than 3 months are considered to have acute
malnutrition. Malnutrition for 3 or more months I ntestinal Rehab and Short Gut
is considered chronic. Chronic malnutrition can Syndrome
be characterized by stunting, which may be irre-
versible and may present before 3 months if the Definition and Pathogenesis
degree of malnutrition is severe (Mehta et al.
2013). Intestinal failure results when patients cannot
If a disease process is directly responsible for depend on their intestines to maintain protein-
malnutrition, it should be identified. Additionally, energy, fluid, electrolyte or micronutrient bal-
the mechanism(s) leading to malnutrition should ance. This can be the consequence of obstruction,
be described. For example, if the malnutrition is dysmotility, congenital defects, diseases associ-
due to decreased intake/starvation, increased ated with loss of absorption, or surgical resection
requirement, excessive losses or failure to absorb. resulting in short gut syndrome (O’Keefe et al.
Because inflammation can increase the need for 2006). More recently, other definitions have been
calories and decrease the bioavailability of nutri- suggested, including measurements of fecal
tion, inflammatory makers should be measured energy loss, amount of parenteral nutrition
when they are applicable. Development is a criti- needed for growth, and amount of functional
cal part to all pediatric patients. Developmental remaining gut mass, however measurements are
assessment should be considered in patients with still in early stages and not accepted clinically
chronic malnutrition. Muscle mass measure- (Ruemmele et al. 2006). While short gut syn-
ments should also be done via anthropometric drome as a consequence of necrotizing enteroco-
measurements or body composition measure- litis in infancy has historically been the most
ments. Measures of muscle strength are impor- common cause of intestinal failure in pediatric

patients, gastroschisis is now becoming a more promoted by maximizing general nutrition and
common diagnosis (Fig. 10.5). However, many enteral exposure to complex nutrients and mini-
patients continue to have multiple underlying mizing infections. Adaptation in infants is maxi-
factors contributing to their intestinal failure mized in the 3–4 years after bowel resection. For
making them have a spectrum of underlying this reason, it is important to maximize parenteral
pathologies to address (Fig. 10.6). nutrition to have overall growth, encourage gut
exposure to nutrition, and minimize central line
infections, which these patients are at increased
General Management Approach risk for.
Management of intestinal failure individuals

needs to be centered to the underlying pathogen- Parenteral Nutrition Management
esis and cause of intestinal failure. In most cases
of short gut syndrome and dysmotility, efforts Parenteral nutrition should be managed carefully
need to be centered to promote gut adaptation or by experienced individuals. Ideal growth should
process by which the residual bowel increases be maintained at approximately the 25th percen-
absorption of fluids, electrolytes and nutrients to tile. Multidisciplinary teams are ideal for this
compensate for the loss of functional bowel. oversight to provide maximal input in ordering
Structural adaptation should occur by which the proper components. Intravenous drug shortages
absorptive area physically increases in size. are common and require expertise in maneuver-
Functional adaption should occur as the intestine ing the various components in parenteral nutri-
slows the transit of time to allow for more absorption to least affect the patient. In general there
tion (Thompson et al. 2011). Adaptation will be have been few new additions to be able to add to
Other single
diagnoses, 14,
5% NEC, 71, 26%
Multiple
single
diagnoses, 77,
28%
Unknown, 1, 1% Gastroschisis,
Tufting or 44, 16%
Microvillus
inclusion, 3, 1%
Long segment
Hirschprung Intestinal
Volvulus, 24,
disease, 11, 4% Atresia, 27,
9%
10%
Fig. 10.5 Primary diagnosis of patients with intestinal failure. Primary diagnoses of patients with intestinal failure
from the pediatric intestinal failure consortium (N = 272) (Adapted from Squires et al. (2012)

concentration of dextrose, which may also be

hepatotoxic over time, and GIR is recommended
to be maintained below 15 mg/kg/min. For this
reason, there must be closer attention to patient’s
Short bowel clinical changes in adjusting the parenteral
syndrome
nutrition.
Fish oil based lipid infusions are not available
outside of clinical trials in the United States.
However, in countries where it is available, the
Intestinal Intestinal preparation is also known to prevent
mucosal dysmotility
diseases PNALD. More longitudinal studies are needed,
disorders
but there is current evidence showing similar
results of preventing liver disease as in lipid
minimization.
In addition to macronutrients, micronutrient
must also be carefully tracked. Despite having
Fig. 10.6 Underlying causes of intestinal failure.
Spectrum of underlying causes that cause intestinal failure
micronutrients added directly to parenteral nutri-
in pediatric patients. Examples of short bowel syndrome tion, Yang et al. (2011) showed that 50% of
include consequences of surgical resection due to con- patients still experience micronutrient deficien-
genital defects and necrotizing enterocolitis. Examples of cies with copper, iron and selenium being among
intestinal mucosal disease include microvillus inclusion
disease, tufting enteropathy, autoimmune enteropathy.
the most common deficiencies. Regular micronu-
Examples of Intestinal dysmotility include chronic inter- trient monitoring should take place for any
nal pseudo obstruction syndrome. Hirschsprung’s disease patient on chronic parenteral nutrition.
can be a dysmotility disorder but also result in short gut
syndrome based on the extent of bowel involved.
Aggressive Crohn’s disease may result in surgical short
bowel syndrome along with intestinal mucosal disease Enteral Nutrition Management
No consensus exists on types of formulas that

parenteral nutrition in the recent past. Best would be most appropriate for infants with intesti-
advances have been in understanding how to best nal failure. In general, consideration needs to be
utilize the components of parenteral nutrition that placed on the remaining gut and degree of func-
we have. tionality of the remaining gut. Increased exposure
As an example, over the last 10 years new to enteral nutrition is known to improve adaptation
insight has been made in how to utilize soy based by stimulating hyperplasia, promoting peristalsis
lipids in parenteral nutrition. Parenteral nutrition and stimulates flow of GI secretions and secretion
associated liver disease (PNALD) is one of the of humoral factors. However, it is not known
most worrisome complications of chronic paren- whether continuous or bolus feeds are best. Breast
teral nutrition and lipid minimization of soy milk is known to bolster the immune system and
based oil emulsions to 1 or 0.5 mg/kg/day has contain immunoglobulins, nutrients, hormones
been shown to decrease PNLD. Long-term stud- and growth factors to help with intestinal growth
ies are still needed to determine the final outcome (Andorsky et al. 2001; Raphael and Duggan 2012).
of patients receiving lipid minimization. Extreme When breast milk is not available, formula should
lipid minimization may precipitate essential fatty be used. There is no consensus on types of formu-
acid deficiencies and this should be monitored las to use but more complex nutrients are associ-
for by the triene to tetrane ratio. By decreasing ated with improved adherence. Higher Medium
the amount of lipid in parenteral nutrition, dex- Chain Triglyceride formulas have been theorized
trose quantities have needed to be increased to to improve absorption by bypassing the lymphat-
compensate for the calories. Unfortunately, high ics and are able to be absorbed in the colon.

However, they have not shown to decrease time on patients should be evaluated if they have limited
parenteral nutrition and create a higher osmotic vascular access, advancing PNALD, or no chance
load to patients that could result in increased stool- of coming off parenteral nutrition.
ing. Long chain fatty acids are known to produce
adaptation better but are less efficiently absorbed
(Jeppesen and Mortensen 1998; Raphael and Neonatal Cholestasis
Duggan 2012). Thus formulas must the geared to
the individual patient. Background
Neonatal cholestasis, characterized clinically by

Central Access Preservation the prolonged occurrence of jaundice in the new-
born period, is defined physiologically as a
Central lines become the lifeline for intestinal decrease in bile formation or flow due to impaired
failure patients. Preventing central line associ- hepatobiliary membrane transport systems or
ated infections (CLABSI) is critical in preserving mechanical obstruction of bile flow (Balistreri
vascular access. Patients enrolled in multidisci- 1985). The resulting accumulation of biliary con-
plinary clinics for intestinal failure patients have stituents within the liver and bloodstream are
shown to have lower rates of CLABSI. Ethanol important pathophysiologic mechanisms impli-
lock therapies have been established as a novel cated in both acquired and hereditary forms of
practice associated with decreasing cholestasis. While neonatal jaundice due to
CLABSI. There have been studies that showed unconjugated hyperbilirubinemia is common,
increased line breaks with some regiments of affecting up to 84% of term newborns (Kelly and
ethanol lock therapy, but more studies are needed Stanton 1995; Bhutani et al. 2013), and not usu-
to understand if this is only seen in higher con- ally harmful to infants, cholestatic jaundice (con-
centrations or more frequent use of ethanol. jugated hyperbilirubinemia) must always be
considered a pathological state signifying hepa-
tobiliary dysfunction. With an incidence of
Surgery approximately 1 in 2500 live births (Balistreri
1985), cholestatic liver diseases comprise a rare,
Bowel lengthening surgery should be preserved yet critical, group of disorders. Left untreated,
only for the situations when a patient is unable to many of these disorders lead to progressive fibro-
be advanced in their feeds. The Serial Transverse sis of the liver and, ultimately, cirrhosis. Timely
Enteroplasty procedure is the most common differentiation of neonatal cholestasis from sim-
bowel lengthening surgery and could be done in ple unconjugated hyperbilirubinemia is one of
areas of dilated bowel. However, in patients with the major challenges facing clinicians during the
underling dysmotility disorder such as gastros- evaluation of the jaundiced infant because in the
chisis, outcomes may be guarded since it is dys- early stage, the infants can look very healthy
motile bowel that is being lengthened. Thus, except for their jaundice. Early recognition by
although the length is increased, the functionality the primary care provider and prompt referral to
may still be poor. a pediatric gastroenterologist who can perform
an appropriate diagnostic evaluation to identify
the cause may ameliorate potentially catastrophic
Transplant outcomes related to delayed diagnosis.
Transplantation for small bowel or dual small

bowel and liver are rare in the United States. On Pathogenesis
average less than 100 occur per year due to
advances in careful parenteral nutrition prepara- Decreased canalicular secretion of a broad range
tion and avoidance of PNALD. Nevertheless, of biliary constituents that are normally excreted

into bile and retention of these potentially nox- fore, medical practitioners should directly
ious substances within the liver is the fundamen- observe the stool (Matsui and Ishikawa 1994).
tal pathophysiologic defect in all forms of Dark urine (normally colorless in the newborn) is
cholestasis (Trauner et al. 1998). These sub- a common non-specific indicator of conjugated
stances include bile salts, glucuronide conjugates hyperbilirubinemia, but is not pathognomonic.
(e.g. bilirubin diglucuronide), heavy metals (e.g. The impact of bile acid deficiency may result in
copper), inorganic anions (e.g. bicarbonate and steatorrhea, poor weight gain, or fat-soluble vita-
chloride), phospholipids, exogenous drugs, and min deficiency from dietary lipid and fat-soluble
environmental toxins (Boyer 2007). Disturbances vitamin malabsorption. Vitamin D deficiency can
of normal hepatobiliary transport and bile com- cause rickets and some infants present with bleed-
position due to alterations in the uptake, conjuga- ing or bruising secondary to coagulopathy caused
tion, or excretion of these compounds result in by liver failure or vitamin K deficiency. Some
the formation of “toxic bile” and subsequent causes of neonatal cholestasis have specific abnor-
hepatocellular and/or bile duct injury (Trauner malities associated with their underlying etiology,
et al. 1998, 2008). Moreover, retention of bile such as dysmorphic facies and congenital heart
acids within the hepatocyte cause damage to disease (e.g. Alagille’s syndrome), skin lesions
intracellular membrane component, mitochon- and chorioretinitis (e.g. CMV, HSV, toxoplasma),
drial dysfunction, and hepatocyte cell death by abdominal mass (e.g. choledochal cyst), and hypo-
apoptosis and necrosis. Secondary effects of cho- tonia or abnormal reflexes (e.g. mitochondrial dis-
lestasis result from a deficiency of micelle- orders). Hepatosplenomegaly can occur in infants
forming bile acids within the intestinal lumen who have storage diseases or cirrhosis. In some
that are essential for dietary lipid and fat-soluble cases, progression to end-stage liver disease can
vitamin absorption. cause serious life-threatening complications such
as portal hypertension, variceal bleeding, ascites
and peripheral edema, or hepatic encephalopathy
Presentation although these are less common during the neona-
tal period.
The hepatic and systemic effects of chronic cho-
lestasis are profound and widespread. Most
infants with cholestatic liver disease present dur- Etiologies
ing the first month of life with jaundice often the
most readily apparent sign of liver disease (Suchy In the 1970s, up to 65% of infants presenting
et al. 2002). While jaundice occurs more com- with cholestasis were diagnosed with “idiopathic
monly in the neonatal period than at any other neonatal hepatitis” (Balistreri 1985). By the turn
time of life, neonatal jaundice due to a physiolog- of the century, improved diagnostic methods and
ical delay in maturation of the bilirubin conjuga- advances in molecular genetics have decreased
tion pathway or in association with breastmilk this category to no more than 15% (Balistreri and
feeding is common in the first 2 weeks of life, Bezerra 2006). Biliary atresia remains the most
where as neonatal cholestasis must be considered common cause, consistently accounting for
in any infant who remains jaundiced beyond the approximately one third of all cases in multiple
age of 14–21 days or who develops jaundice reports over several decades (Suchy 2004;
within the first month of life. Pale or acholic Balistreri and Bezerra 2006; Hoerning et al.
stools are the hallmark sign of cholestasis and 2014). Various forms of inherited cholestasis
suggest an obstructive process such as biliary syndromes occur in 10–20% of cases.
atresia but may not be present with partial or Approximately 10% are caused by alpha1-anti-
evolving biliary obstruction. The presence of trypsin deficiency. Other inborn errors of metab-
deeply pigmented stools makes biliary atresia olism comprise about 20% of all cases. Congenital
unlikely. Parental reports of the stool color often infections, including the so-called “TORCH”
overestimate the degree of pigmentation; there- infections, account for only 5% of cases.

Diagnosis hypothyroidism) as well as those amenable to

surgical intervention (e.g. biliary atresia, chole-
The initial detection of neonatal cholestasis lies in dochal cyst) is crucial to avoid irreversible end-
the domain of the primary care provider and organ dysfunction. The quintessential example is
depends primarily on the recognition of prolonged the timing of hepatoportoenterostomy in patients
jaundice. A thorough physical examination and who have biliary atresia. In a recent report from
direct observation of urine color, and, most impor- the Japanese Biliary Atresia Registry, the likeli-
tantly, stool color, is an essential aspect of the pri- hood of success of the Kasai procedure and sur-
mary assessment of the jaundiced infant, as vival with native liver was highest in children
acholic stool and dark urine often indicate the who underwent the procedure in the first 30 days
presence of conjugated hyperbilirubinemia. of life (Nio et al. 2003). Even when specific ther-
To differentiate benign causes of jaundice from apy is not available, infants who have cholestasis
neonatal cholestasis, the American Academy of may benefit from early medical management to
Pediatrics and the North American Society for prevent long-term complications associated with
Pediatric Gastroenterology, Hepatology and chronic liver disease. Additionally, advanced
Nutrition recommend measurement of total and experience of the center in caring for complex
direct (conjugated) serum bilirubin levels if jaun- liver disease in neonates has been shown to cor-
dice is accompanied by dark urine or light stool or relate with improved outcomes (Kelly and
if it persists beyond 2 weeks of age (American Davenport 2007). Therefore it is imperative that
Academy of Pediatrics Subcommittee on primary care providers identify a center of excel-
Hyperbilirubinemia 2004; Fawaz et al. 2016). lence in order to refer patients in which complex
Breast-fed infants who can be reliably monitored neonatal liver disease is suspected.
and who have an otherwise normal history (i.e. no Malnutrition secondary to impaired absorp-
dark urine or light stools) and physical examination of fats, impaired metabolism of proteins and
tion may be asked to return at 3 weeks of age and, carbohydrates, and increased hepatic metabo-
if jaundice persists, have the serum bilirubin frac- lism is common in cholestatic infants and
tionated at that time. Considering the clinical adversely affects their outcome, and should be
complexity to determine whether or not a direct monitored by frequent anthropometric assess-
fraction exceeds a percentage of the total bilirubin ment. Nutritional support and supplementation
level, a direct bilirubin value greater than 1.0 mg/ with fat-soluble vitamins is recommended in all
dL, regardless of the total bilirubin level, should children with cholestasis. Caloric intake should
be considered abnormal (Rosenthal et al. 1986). be approximately 125% of the recommended
Any infant with cholestatic jaundice should be dietary allowance based on ideal body weight
immediately referred to a pediatric gastroenterol- (Suchy 2004). If breast feeding does not promote
ogist who can conduct a diagnostic evaluation to growth, cholestatic infants should receive a for-
identify a specific cause. mula containing medium-chain triglycerides
Of note, ultrasonography is useful to identify such as Pregestimil® or Alimentum®, because
anatomic abnormalities such as choledochal these triglycerides can be directly absorbed from
cysts. The diagnosis of biliary atresia cannot be the small intestine into the portal circulation
made reliably with an ultrasound scan, although without requiring modification by bile acids
the finding of an absent or atretic gallbladder is (Fawaz et al. 2016). Specialized infant formula
suggestive. and diets may have a role in select cases (e.g.
galactosemia, hereditary fructose intolerance,
and hereditary tyrosinemia). For infants with
Management continued poor growth, formulas can be concen-
trated or have additional carbohydrates or fats
Prompt identification of infants who have medi- added to increase caloric density (Fawaz et al.
cally treatable forms of cholestasis (e.g. UTI, 2016). Oral feeding is the preferred route of for-
galactosemia, hereditary tyrosinemia, congenital mula intake; however, if patients are unable to

ingest the needed calories, nasogastric tube feed- rise (2000). During the past 30 years, the percent-
ing should be initiated, generally continuous age of children in the United States (U.S.) aged
overnight feeding. Parenteral nutrition is rarely 6–11 years who were obese nearly tripled from
necessary; however, if there is severe protein- 6.5% in 1980 to 17.7% in 2012 (National Center
energy malnutrition, feeding intolerance, and/or for Health Statistics (US) 2012; Ogden et al.
malabsorption, provision of parenteral nutrition, 2014). Over the same time period, the percentage
in combination with enteral nutrition, improves of adolescents aged 12–19 years who were obese
nutrient delivery and does not invariably worsen quadrupled from 5% to 20.5%. Racial and ethnic
cholestasis (Fawaz et al. 2016). disparities exist, with higher rates observed
Infants with cholestasis require supplementa- among African-American and Hispanic children
tion with fat-soluble vitamins administered orally compared to Caucasian children and the highest
as water-soluble preparations (Suchy et al. 2002). rate for 6–11 year old Hispanic boys (48.7% are
Doses of at least 2–4 times the recommended overweight or obese).
daily allowance are typically required to produce Concurrent with the national epidemic of
therapeutic plasma concentrations. Serum levels childhood obesity, epidemiologic data collected
should be routinely monitored to guide dosing. from 1988 to 2010 demonstrate that the preva-
No single multivitamin preparation is adequate lence of nonalcoholic fatty liver disease (NAFLD)
for all cholestatic infants; most will need addi- among adolescents increased in parallel, becom-
tional vitamins K and E, and many will need vita- ing the most common cause of chronic liver dis-
mins D and A beyond a multivitamin preparation. ease in both adults and children in the past decade
Occasionally, intramuscular vitamin D is (Younossi et al. 2011; Welsh et al. 2013).
required. Vitamin supplementation should be Currently, NAFLD affects approximately 10% of
continued for at least 3 months after resolution of the pediatric population in the U.S., reaching
jaundice (Venigalla and Gourley 2004). rates as high as 38% among obese children and
Ursodeoxycholic acid (UDCA), a hydrophilic adolescents (Schwimmer et al. 2006). This repre-
bile acid, has been found to have beneficial sents an estimated seven million children with
effects on many forms of cholestasis. Although chronic liver disease who are at increased risk of
its mode of action is not completely understood. liver failure, cardiovascular disease, and liver
UDCA is generally used as first-line therapy for cancer in adulthood.
pruritus due to cholestasis, parenteral nutrition- According to the United Network for Organ
induced cholestasis, α1-antitrypsin deficiency, Sharing database, nonalcoholic steatohepatitis
and after successful surgery for biliary atresia (NASH)-related cirrhosis was the third most
(Dani et al. 2015). The most common side effect common indication for liver transplantation in
is diarrhea, which usually responds to dose reduc- patients younger than 65 years of age during the
tion. UDCA can be discontinued when cholesta- period from 2007 to 2010 (Kemmer et al. 2013).
sis has resolved. In infants with moderate to Although most liver transplants were not per-
severe pruritus due to cholestasis, cholestyramine formed before the age of 18 years, many of these
(240 mg/kg/day), a bile acid sequestrant, or cases were likely the consequence of childhood
rifampicin (5–10 mg/kg/day) may also be NAFLD. Due to the alarming trends in childhood
recommended. obesity and the improved management of chronic
viral hepatitis, NAFLD is expected to become the
most common indication for liver transplantation
Nonalcoholic Fatty Liver Disease in the near future (Charlton et al. 2011).
Improving our understanding of the etiopatho-
Background genesis of NAFLD, early identification of patients
through non-invasive diagnostic methods, and
With the rapidly increasing prevalence of child- the development of targeted therapies may reduce
hood obesity around the world, morbidity and the burden of disease and eliminate the need for
mortality related to its complications is on the liver transplantation.

Pathogenesis Presentation
NAFLD encompasses a broad histological spec- During the pre-cirrhotic stage, most children with
trum of disease activity ranging from simple steato- NAFLD are asymptomatic (Lewis and Mohanty
sis, which is mostly non-progressive, to NASH, a 2010). Typically, NAFLD is first suspected in a
state characterized by hepatic necroinflammation person found incidentally to have elevated serum
and/or fibrosis with variable risks for progression aminotransferases or abnormalities suggestive of
to cirrhosis and hepatocellular carcinoma (Adams hepatic steatosis on routine imaging while under-
et al. 2005; Vernon et al. 2011). While the patho- going evaluation for unrelated reasons such as
genesis of liver injury remains uncertain, a growing abdominal pain (Mofrad et al. 2003; Farrell and
body of literature suggests a role for genetic and Larter 2006). Rarely, patients may present with
epigenetic factors in the development and progres- fatigue, malaise, or vague abdominal discomfort
sion of NAFLD. In the majority of patients, due to hepatomegaly and stretching of the hepatic
NAFLD is also associated with metabolic risk fac- capsule (Choudhury and Sanyal 2004).
tors such as insulin resistance and atherogenic dys- Physical examination may reveal acantho-
lipidemia; it is thus considered the hepatic sis nigricans, which indicates the presence of
manifestation of the metabolic syndrome (Adams insulin resistance, or hepatomegaly, which is
et al. 2005). Although both excessive body mass often difficult to appreciate due to central obe-
index (BMI) and central obesity are common and sity (Schwimmer et al. 2003). Once a patient
well-documented risk factors for NAFLD, neither develops cirrhosis, they may display cutane-
is necessary for the development of ous stigmata of liver disease (e.g. palmar ery-
NAFLD. Familial clustering as well as racial and thema, spider nevi) or features of hepatic
ethnic differences in the prevalence of NAFLD decompensation, which include jaundice, pru-
indicates that genetic factors influence the develop- ritus, ascites, edema, variceal bleeding, and
ment and progression of NAFLD, but environmen- encephalopathy.
tal factors are also likely to influence development
and progression as well (Kitamoto et al. 2013).
Knowledge about the natural history and evolu- Diagnosis
tion of histologic changes in pediatric NAFLD is
still evolving. Based on the currently available evi- The diagnostic criteria for NAFLD include: (1)
dence from adult natural history studies, patients presence of hepatic steatosis detected either by
with simple steatosis exhibit very slow, if any, his- imaging or histology, (2) absence of significant
tologic progression, while approximately 20% of alcohol consumption, and (3) appropriate exclu-
patients with NASH ultimately develop cirrhosis, sion of other causes for hepatic steatosis and co-
usually over an average of 21.3 years (Singh et al. existing chronic liver disease (Chalasani et al.
2015). However, NAFLD in children may be more 2012). Competing etiologies for hepatic steatosis
severe compared to that in adulthood and a subset include viral hepatitis, particularly hepatitis C
of patients rapidly progress (Molleston et al. 2002; virus, severe malnutrition, provision of parenteral
Holterman et al. 2013). Children as young as nutrition, autoimmune hepatitis, and use of ste-
2 years of age have been reported with NAFLD, atogenic medications such as anabolic steroids.
and NASH-related cirrhosis has been reported as Given the relatively young age at diagnosis, con-
early as 8 years of age (Schwimmer et al. 2005). In sideration to the possibility of genetic disorders
addition to liver-related complications, NAFLD is such as alpha-1 antitrypsin deficiency, Wilson’s
associated with extrahepatic morbidity and mor- disease, cystic fibrosis, and various inborn errors
tality. Nonhepatic associations include cardiovas- of metabolism are more relevant for children. It is
cular, metabolic, pulmonary, and psychological important to recognize that, because of the high
disorders. Cardiovascular disease is the most com- prevalence of childhood obesity, NAFLD can co-
mon cause of death in NAFLD patients (Chacko exist with other chronic liver diseases
and Reinus 2016). (Nascimbeni et al. 2013).

Laboratory Evaluation 2004). Newer US-based methodologies such as

In clinical practice, serum alanine aminotransfer- transient elastography or FibroScan®, which
ase (ALT) concentration is most commonly used measure liver stiffness noninvasively, have shown
as the initial screening test for NAFLD, despite promising ability to stage liver fibrosis but are not
suboptimal sensitivity and specificity (Schwimmer available outside of large academic medical cen-
et al. 2013). Even in the presence of significant ters (Yoneda et al. 2008). Both MR spectroscopy
histological abnormalities, a substantial number of (MRS) and MRI-proton density fat fraction
NAFLD patients have normal transaminase levels (MRI-PDFF) accurately detect and quantify ste-
(Molleston et al. 2014), indicating that ALT alone atosis (Schwimmer et al. 2015). At this time,
is not an ideal screening test for NAFLD. Elevations MR-based methods are not widely used for
of aspartate aminotransferase (AST), alkaline screening because of the high cost, limited avail-
phosphatase, and gammaglutamyl transpeptidase ability, and lack of validated thresholds for diag-
(GGT) are common but not useful as screening nosis of NAFLD. CT is highly sensitive and
tools for NAFLD (Mofrad et al. 2003). specific, but its cost together with radiation expo-
In persons with suspected NAFLD, exclusion sure prevents its widespread application.
of other causes of chronic liver disease often
includes virological testing for hepatitis viruses A, Histologic Evaluation
B, and C, EBV, and CMV, a battery of serologic Despite its invasiveness, liver biopsy remains the
markers for autoimmune hepatitis (e.g. ANA, anti- gold standard for the diagnosis and staging of
LKM-1, anti-SMA, p-ANCA, and IgG), determi- NAFLD (Vos 2016). Histopathologic evaluation of
nation of alpha-1 antitrypsin phenotype and serum the liver is the only diagnostic test that reliably iden-
ceruloplasmin concentration in addition to other tifies and quantifies hepatic steatosis, steatohepati-
specific tests as directed by the clinical history and tis, and fibrosis, thereby distinguishing NAFLD
physical examination (Vajro et al. 2012). In the from NASH as well as other forms of liver disease.
absence of autoimmune hepatitis, autoantibodies While controversy remains about who should
are positive in a significant proportion of children have a liver biopsy and when in the diagnostic
with NAFLD (Patton et al. 2008). Although their evaluation liver biopsy should be used, there is
clinical significance is uncertain, their presence universal agreement that liver biopsy should not
requires liver biopsy to discriminate between the be performed in all patients. The clinical practice
two conditions. In patients with NAFLD, it is rea- guidelines on NAFLD from the American
sonable to assess for dyslipidemia and diabetes Association for the Study of Liver Diseases,
mellitus, because NAFLD may indicate the pres- North American Society for Pediatric
ence of these diseases. Gastroenterology, Hepatology and Nutrition
(NASPGHAN), and European Society for
Radiologic Evaluation Pediatric Gastroenterology, Hepatology and
Imaging studies including ultrasonography (US), Nutrition suggest that a liver biopsy be obtained
computed tomography (CT), and magnetic reso- when the diagnosis is uncertain, before pharma-
nance imaging (MRI) are useful in demonstrating cological or surgical treatment is undertaken, and
hepatic steatosis, at least when hepatic fat accu- in cases of clinically suspected advanced liver
mulation is moderate to severe (Saadeh et al. disease (Chalasani et al. 2012; Vos 2016).
2002). However, these tests cannot detect the
differences between NASH and NAFLD.

Transabdominal US is acceptable as the first-line Screening
imaging modality for NAFLD because of its uni-
versal availability, affordability, and lack of radi- Early diagnosis of NAFLD in children may help
ation exposure. However, its relatively low prevent the development of chronic liver disease
sensitivity for detecting mild steatosis, operator- during adulthood (Schwimmer et al. 2013). The
dependency, and poor image quality in obese American Academy of Pediatrics and
patients are major limitations (Mottin et al. NASPGHAN, in their most recent guidelines,

recommend screening for NAFLD with ALT Weight loss surgery (WLS) is a hot topic but is
levels beginning between ages 9–11 years for all not recommended as a primary treatment for
children whose BMI is ≥95th percentile and for NAFLD but is becoming more common for
those with a BMI between the 85th and 94th severely obese (BMI ≥35 kg/m2) adolescents
percentile with additional risk factors (e.g. cen- with non-cirrhotic NAFLD and other serious
tral adiposity, insulin resistance, diabetes, dys- obesity-related health conditions (Chalasani et al.
lipidemia, sleep apnea, or family history of 2012; Vos 2016). NAFLD has been proposed as a
NAFLD) (BarlowExpert Committee 2007; Vos criterion for WLS in several published adolescent
2016). Screening can be considered in younger bariatric surgery guidelines (Nobili et al. 2015).
patients with risk factors such as severe obesity However, no studies have examined the histolog-
or a family history of NAFLD or hypopituita- ical outcomes of WLS in the pediatric NAFLD
rism. When the initial screening test is normal, population, and only one has reported on the pro-
repeat screening should be performed every gression of liver disease post-operatively, using
2–3 years if risk factors remain unchanged or ALT as a surrogate marker (Holterman et al.
sooner if clinical risk factors increase in number 2012). Therefore, the impact of bariatric surgery
or severity. on NAFLD outcomes in children is difficult to
quantify. In addition, there is concern for sub-
acute liver failure secondary to massive steato-
Management hepatitis as a result of rapid weight loss after
bariatric surgery (D’Albuquerque et al. 2008).
The management of pediatric NAFLD is aimed at Therefore, bariatric surgery referral should never
preventing progression toward more advanced be considered without the direct input of an expe-
forms of disease, regression of steatosis, and rienced pediatric hepatologist.
improvement in any underlying metabolic risk
factors. Currently, the principal treatment for
NAFLD is lifestyle modification by diet (directed Viral Hepatitis
by a registered dietician) and exercise (Vos 2016).
Recommendations regarding pharmacological Viral hepatitis is a broad term that describes
therapy are limited by a small number of random- inflammation of the liver from any viral source.
ized controlled trials (RCTs) and insufficient Thousands of viruses may be implicated in induc-
information to assess the risk-benefit ratio. ing hepatic inflammation and likely represents an
Regardless of age, behavioral and/or pharmalogi- under diagnosed cause of nonspecific transami-
cal therapy should commence immediately after nase elevation. The mass majority of cases result
the diagnosis of NAFLD for all children. Taking in spontaneous, and often unrecognized, resolu-
into consideration the severity of NAFLD, the tion of hypertransaminemia but in rare cases may
degree of obesity, and the presence of comorbidi- progress to acute liver failure (ALF). In the larg-
ties, the clinician must individualize treatment est studied cohort of pediatric patients experienc-
accordingly. Comorbidities such as obesity, dia- ing ALF, Squires, et al. reported 20% of pediatric
betes mellitus type 2, hypertension, and dyslipid- patients presenting in ALF where ultimately
emia are managed concurrently as part of the diagnosed with a viral etiology. A further 49% of
therapy for NAFLD (Chalasani et al. 2012). It patients had an indeterminate cause of their ALF,
should be highlighted that the pharmacological many of which may have been secondary to an
treatment of metabolic risk factors, particularly undiagnosed viral causes (Squires et al. 2006).
with statins, is not contraindicated in NAFLD With the exception of Herpes simplex virus, ther-
(Chalasani 2005). If the patient becomes cir- apy is symptomatic with liver transplant reserved
rhotic, standard treatment of cirrhosis, including for the most severe cases in which hepatic syn-
liver transplantation in the decompensated state, thetic function appears to be irreversibly
is offered. compromised.

While a seemingly innumerable number of WHO Publication 2010). Breastfeeding has not
viruses may lead to an acute hepatitis, chronic been shown to be a significant risk in transmis-
viral hepatitis in children is almost exclusively sion of the virus from mother to newborn who
caused by either Hepatitis B or C. However, the have received proper immunoprophylaxis and in
landscape of these two diseases is rapidly and the absence cracked and/or bleeding nipples,
radically evolving as improved hygiene practices, should be encouraged to breastfeed (Shi et al.
blood supply monitoring and the widespread use 2011).
of vaccines has greatly impacted the prevalence
rates of Hepatitis B, while unprecedented success onitoring and Therapy
M
rates of Hepatitis C antiviral drugs is sure to lead The decision to start therapy for children with
to decreased chronic carrier rates as well as long- chronic hepatitis B is based on ALT levels,
term complications such as cirrhosis and hepato- HBeAg positivity, DNA levels, liver histology,
cellular carcinoma (HCC) (Corte et al. 2016). family history of HCC and a possible co-existing
liver disease (Sokal et al. 2013). Serum ALT,
viral DNA load and HBeAg/Anti-HBe levels
Hepatitis B should be obtained every 6 months and HCC sur-
veillance with hepatic ultrasound should be per-
The majority of cases of chronic Hepatitis B formed yearly. ALT levels (1.5× upper level or
(defined as positive Hepatitis B surface Antigen, normal or >60 IU/L, whichever is lower) for over
or HBsAg, for 6 months or longer) occur via 6 months, high DNA levels (>20,000 IU/ml),
maternal transmission as risk of chronicity is family history of HCC and/or evidence of cirrho-
highest among newborns who contract the virus sis should all prompt evaluation by an experi-
(90%) as compared to children less than 5 years enced pediatric hepatologist to determine the
of age (25–30%) and adolescents or adults (<5%) possible need for therapy (Sokal et al. 2013).
(McMahon et al. 1985; Tassopoulos et al. 1987). Given the evolving landscape of antiviral thera-
The disease course in children is typically asymp- pies with numerous ongoing clinical trials, treat-
tomatic with preserved growth and psychological ment strategies are beyond the scope of this
development, but close monitoring is required as review and should be determined by an experi-
3–5% of children will develop cirrhosis and enced hepatologist.
0.01–0.03% developing HCC during childhood
(Chang et al. 1995, 2005).
Hepatitis C
Prevention
Vaccination is the most effective measure to pre- There is an estimated 3.5 million people infected
vent the transmission and spread of Hepatitis B with hepatitis C (HCV) in the United States with
(Sokal et al. 2013). Administration of monova- nearly half of all infected people unaware
lent vaccine within the first 24 h of life followed (Holmberg et al. 2013; Denniston et al. 2014).
by 2 or 3 (preterm infants <2000 g) doses of mon- Higher incidence rates of disease during the
ovalent or combined vaccine with a minimum 1970s and 1980s has resulted in updated guide-
interval of 4 weeks results in about 95% seropro- lines from the Center for Disease Control and
tective response (anti-HBs ≥10 mIU/ml) (WHO Prevention (CDC) resulting in broader screening
Publication 2010). If mother is a chronic carrier, mechanisms to detect those patients with undiag-
vaccination alone is not sufficient to avoid verti- nosed, asymptomatic HCV infection (Mahajan
cal transmission and hepatitis B immunoglobulin et al. 2013). Given that the most common source
(HBIG) is recommended in addition to vaccine, of infection among children is via vertical trans-
resulting in 90% protection rate in newborns born mission, an increased recognition of disease bur-
to Hepatitis B e Antigen (HBeAg) positive moth- den among adults/parents has prompted an
ers (98% if HBeAg negative) (Lee et al. 2006; increase in screening of children of infected

mothers with early recognition of disease in (Bortolotti et al. 2008). In these instances routine
many instances (Corte et al. 2016). screening and anticipatory guidance become
imperative. Patients should undergo annual
Screening examination with a focus on education and
Any child born to a HCV positive mother, anticipatory guidance (see Table 10.12) and

regardless of the child’s age or clinical condi-
tion, should be screened for HCV infection. Table 10.12 General guidelines for patients with hepati-
While the mother’s viral load at time of delivery tis C
directly effects transmission rates, generally Topic Recommendations
speaking about 1 in 20 children born to a HCV Household Okay to share: sharing food,
positive mother will contract the virus (Corte contacts drink, utensils, clothes/towels,
et al. 2016). Although less common in children, toilet seats
Avoid sharing: toothbrush, nail
other populations in which to consider HCV
clippers, shaving supplies,
screening include; patients with prolonged ele- glucometers, any personal item
vation of their serum ALT levels, history of ille- that may be contaminated with
gal injected drug use, and needle stick, sharp blood
accident or mucosal exposure to a HCV positive Non-household No contraindication to attending
contacts day care, school, camps,
individual.
playgrounds, community pool or
Initial screening lab of choice is a serum HCV participating in contact and
antibody (IgG). There are some limitations to this non-contact sports
screening test though in that it does not become Casual contact No contraindication to kissing,
positive until 6–8 weeks after acquisition and hugging or holding-hands
thus not an appropriate choice in acute liver fail- Sexual contact Monogamous sexual contact is
non contraindicated while
ure screening, does not differentiate acute versus unprotected sexual activity with
chronic disease and is not useful in patients multiple partners is highly
<18 months of age when maternal antibodies are discouraged
still present in the blood (Mack et al. 2012). All Other activities Tattoos, body piercing, illicit drug
patients with a positive HCV antibody screen or use and use of alcohol should be
avoided
are being evaluated for acute liver failure should
Blood spills Gloves should be worn to clean
undergo testing with HCV RNA to confirm or all spills. Thoroughly clean with a
rule-out infection. In all patients with positive dilution of 1 part household
HCV RNA testing, referral to an experienced bleach to 10 parts water (refer to
hepatologist is indicated for further workup www.CDC.gov)
including determine virus genotype, consider- Minor cuts Universal precautions
Vaccines Should receive all age-appropriate
ation of possible of co-infections and decision on
vaccines including Hepatitis A &
whether therapy is indicated or not. B
Obesity Obesity may further burden
Monitoring hepatic health and affect response
The invention of direct-acting antiviral agents to HCV therapy
has revolutionized the therapy of HCV in both Pregnancy Universal screening is not
recommended and transmission
adults and children with multiple pediatric stud- rates similar between vaginal or
ies showing sustained viral remission rates >90%, cesarean deliveries. Prolonged
far superior and with less side effects than rupture of membranes and use of
previous interferon and ribavirin based therapies fetal scalp probes should be
avoided as they may increase
(Corte et al. 2016). However, given that 20% of transmission rates
patients will spontaneously clear the virus in the Breastfeeding Not contraindicated unless
first 3 years of life and only 2% of patients will mastitis or bleeding is present
progress to cirrhosis by the end of adolescents, General guidelines for parents of and children with hepa-
therapy may be delayed in many instances titis C (adapted from Mack et al. (2012)

laboratory evaluation of serum aminotransfer- Pathogenesis

ases, total and direct bilirubin, albumin, HCV
RNA level, complete blood count with platelets Acute liver failure (ALF) results from rapid death
and prothrombin time/international normalized or injury to a large proportion of hepatocytes,
ratio (Mack et al. 2012). Additionally, annual to leaving insufficient hepatic parenchymal mass to
biannual screening for HCC should be performed sustain liver function. The pathophysiological
via abdominal ultrasound or serum alpha- mechanisms that lead to ALF are yet to be fully
fetoprotein. Any abnormalities and/or concerns elucidated. However, acute hepatic necrosis is the
should be communicated with an experienced most common mechanistic pathway of a variety
hepatologist. of insults to the liver (Taylor and Whitington
2016). In 1999, the PALF Study Group was
formed to develop a database that would facilitate
Pediatric Acute Liver Failure an improved understanding of the etiopathogen-
esis, treatment and outcome of ALF in children.
The liver is the second-largest organ in the human A report of the first 348 patients enrolled in the
body and performs more than 500 vital functions PALF registry found that the etiologic categories
including gluconeogenesis, synthesis of plasma of non-acetaminophen-induced ALF in children
proteins and coagulation factors, drug metabo- were similar to adults and included metabolic,
lism, and conversion of ammonia into urea infectious, and immune-mediated conditions as
(Boyer et al. 2011). Specialized macrophages well as drug injury (Squires et al. 2006).
located in the hepatic sinusoids known as Kupffer Acute acetaminophen (APAP) toxicity was
cells are intimately involved in the liver’s the most common identifiable cause of ALF in
response to infection, toxins, ischemia, and other children ≥3 years (21%) (McGill et al. 2012).
stresses (Bilzer et al. 2006). The liver is also the Non-APAP drug-related ALF was recognized
body’s largest gland, responsible for the produc- primarily in older children. In most of these
tion and secretion of bile, an alkaline compound cases, the mechanism of injury leading to ALF is
that aids in digestion via the emulsification of lip- thought to be an idiosyncratic drug reaction. An
ids, and cholesterol, which serves as a precursor infectious etiology was identified in 6% of
for the biosynthesis of steroid hormones and bile patients, with herpes simplex virus (HSV) and
acids (Boyer et al. 2011). Epstein-Barr virus (EBV) the most common
Liver failure occurs when massive destruction identifiable infections in children <3 years and
of the hepatic parenchyma results in impairment ≥3 years, respectively (Squires et al. 2006).
of any one of these critical functions (Bucuvalas Autoimmune hepatitis (AIH) also accounted for
et al. 2006). Fortunately, a significant proportion 6% of patients and occurred in all age groups. A
of hepatocytes must be damaged before liver metabolic cause for ALF was established in 18%
failure occurs and spontaneous recovery is pos- of children <3 years of age. This group of dis-
sible, owing to the liver’s unique regenerative eases can lead to structural liver damage as a
ability. However, the outcome of pediatric acute result of acute or progressive accumulation of
liver failure (PALF) is generally poor, and one- toxic metabolites within the liver (Hansen and
half of patients die or require liver transplanta- Horslen 2008). Unfortunately, an indeterminate
tion (LT) (Squires et al. 2006). According to the cause of ALF was assigned to 54% of children
PALF Study Group, PALF is defined as coagu- <3 years of age and 49% overall (Taylor and
lopathy not corrected by the administration of Whitington 2016). Replacement of hepatic
vitamin K with an International Normalized parenchyma with nonfunctioning tissue is an
Ratio (INR) >1.5 in patients with hepatic occasional cause of PALF with hepatic heman-
encephalopathy, or >2.0 in patients without gioma, leukemia, and various other liver tumors
encephalopathy, within 8 weeks of onset of representing the most prominent etiologies.
symptoms in the absence of preexisting liver dis- Hypoxic-ischemic liver injury is an uncommon
ease (Squires et al. 2006). cause of ALF, but never in the absence of other

major organ dysfunction. Gestational alloim- result in gastrointestinal or mucocutaneous

mune liver disease (GALD), the most common bleeding (Kurtovic et al. 2005). The bleeding ten-
cause of neonatal ALF, is caused by transplacen- dency accounts for increased risk of morbidity
tal passage of maternal alloantibody that acti- and mortality in patients with ALF undergoing
vates fetal complement and leads to the formation diagnostic or therapeutic invasive procedures.
of a membrane attack complex, resulting in hepa- Multiple organ failure is a complication of ALF
tocyte injury (Whitington 2012). with substantial renal dysfunction occurring in
It is unclear why some individuals recover more than 50% of patients with ALF (Bernal and
from ALF spontaneously while others die or Wendon 2014). ALF often results in impaired
require LT. The final outcome is likely dependent glycogen storage and a diminished ability for
on the underlying etiology, modifying effects of gluconeogenesis. Therefore, ALF should be con-
host factors, and whether or not the massive sidered in children who are hypoglycemic and,
parenchymal loss can be compensated by liver likewise, children who are diagnosed with ALF
progenitor cell (LPC)-mediated regeneration. should be monitored closely for hypoglycemia
Due to the rapid and severe course of the disease, (Krasko et al. 2003). Findings on physical exami-
several factors may determine whether LPC- nation may include jaundice, hepatosplenomeg-
dependent liver regeneration can save the failing aly, ascites, dilated abdominal veins secondary to
liver, including the number of activated cells, portal hypertension, and cutaneous stigmata of
speed of cell proliferation, and direction of cell chronic liver disease (e.g. spider nevi, palmar
differentiation (Weng et al. 2015). These critical erythema, and leukonychia).
issues are awaiting further investigation.
Diagnosis
Presentation
Encephalopathy may be absent, late, or unrecog-
Jaundice is the presenting symptom in most chil- nized in children (Chen et al. 2003). Therefore,
dren with ALF. A prodromal phase indistinguish- the diagnostic emphasis in PALF is placed on the
able from that of acute viral hepatitis, associated presence of coagulopathy that is not correctable
with non-specific symptoms of malaise, nausea, by the administration of parenteral vitamin
vomiting, anorexia, and abdominal discomfort, K. The PALF Study Group used an INR > 2.0 as
may precede the appearance of jaundice. As the the primary defining feature of ALF in young
disease progresses, most patients develop hepatic children where hepatic encephalopathy cannot be
encephalopathy (HE), a complex neuropsychiat- reliably determined (Squires et al. 2006). Because
ric syndrome that encompasses a spectrum of ALF progresses rapidly, patients require prompt
disease ranging from excessive sleepiness or con- medical evaluation and treatment, preferably in a
fusion to severe psychomotor retardation or loss tertiary referral center that performs liver trans-
of consciousness. HE is classified into four plantation and is experienced in treating pediatric
grades based on the degree of impairment liver disease. The diagnostic evaluation of these
reflected by neurologic, psychiatric and physical critically ill patients is challenged by many fac-
findings (Ferenci et al. 2002). HE is particularly tors, including the lack of consensus on an age-
difficult to assess in young children and neonates. appropriate evaluation, the short time interval
Infants may present initially with poor feeding, between presentation and outcome, and limita-
irritability, inconsolable crying, and altered sleep tions on the maximum allowable blood draw
patterns, with frank features of HE manifesting volume.
late in the course of the disease. A wide range of laboratory studies is required
Coagulation abnormalities related to decreased to determine the etiology, severity, and prognosis
synthesis of clotting factors as well as qualitative in pediatric patients with ALF. The initial labora-
platelet abnormalities are seen in ALF and may tory evaluation can be divided into three areas:

(1) basic screening tests to assess hematological, lead to a specific diagnosis. Despite recent
renal, and electrolyte abnormalities; (2) liver- improvements, current practice indicates that the
specific biochemical and function tests; and (3) diagnostic evaluation in children with ALF is
diagnostic tests indicated for signs and symptoms often insufficient and the precise etiology remains
suggestive of a specific pathology. Proactive unidentified in approximately 50% of cases
coordination of these tests is necessary to ensure (Narkewicz et al. 2009).
that high-priority tests are performed
expeditiously.
Serum aminotransferase levels do not corre- Management
late with the severity of the disease (Giannini
et al. 2005). Their degree of elevation varies dur- In the absence of a condition known to respond to
ing the course of injury and may depend on the specific therapy (e.g. acute APAP toxicity, HSV,
mechanism. It is important to note that a decrease GALD, tyrosinemia, galactosemia, AIH), the
in aminotransferase levels alone does not have medical management of PALF is largely support-
prognostic value, since both resolution and mas- ive (Squires et al. 2006). Medical treatment is
sive hepatic necrosis may cause a similar bio- focused on monitoring and supporting the physi-
chemical picture. Both direct and indirect serum ological functions of the liver as well as prompt
bilirubin levels are usually elevated. Typically, identification and treatment of complications as a
conjugated hyperbilirubinemia is present. bridge to spontaneous recovery or LT. A multi-
Hypoalbuminemia, prolongation of the pro- disciplinary approach and early referral to a pedi-
thrombin time, and hypoglycemia are markers of atric liver transplantation center with an
synthetic liver dysfunction. Serum creatinine lev- experienced hepatologist, transplant surgeon, and
els have been recognized as strong predictors of intensivist are essential.
survival and the need for LT. The correlation Vital signs, including continuous blood oxy-
between ammonia levels and the severity of HE gen saturation, should be carefully monitored.
remains controversial (Ong et al. 2003). Metabolic, hematologic, and coagulation param-
A comprehensive summary of the specific eters should be monitored daily, or more fre-
diagnostic tests for the cause of ALF is beyond quently in an unstable child, until the patient
the scope of this review. Unfortunately, the ten- becomes stable. Serial neurologic examinations
dency is to attempt to rule out every known cause performed at regular intervals are essential to
of liver disease with exhaustive and expensive characterize the degree and progression of
testing. A well-thought workup is far more use- HE. The use of benzodiazepines and other seda-
ful. Priority should be guided by the age of the tive medications must be avoided in non-
patient and those conditions amenable to specific intubated patients to prevent worsening or
therapies. Even if no specific therapy exists, interference with assessment of the neurological
establishing a diagnosis may have important status. If sedation is required, agents with a short
implications regarding the decision to proceed half-life such as midazolam, propofol, or dexme-
with LT and/or offer genetic counseling for heri- detomidine are preferred. Placement of a central
table diseases that predispose to early cirrhosis venous catheter allows for measurement of cen-
(Whitington and Hibbard 2004). While some dis- tral venous pressure, administration of fluids,
orders such as GALD and galactosemia have medications, and blood products, and frequent
characteristic clinical presentations, a detailed laboratory monitoring. Any child who has grade
history and physical examination cannot be over- III or IV encephalopathy should be intubated
looked or abbreviated. Exposure to contacts with (Pediatric Gastroenterology Chapter of Indian
infectious hepatitis, accurate medication recon- Academy of Pediatrics et al. 2013).
ciliation, or a family history of Wilson’s disease, General supportive care includes correction of
α-1 antitrypsin deficiency, infectious hepatitis, any fluid, electrolyte, and acid-base disturbances.
infant deaths, or autoimmune conditions might Intravenous fluids should be tailored to the

clinical status of the patient and restricted to products such as recombinant factor VIIa is not
85–90% of maintenance volumes to avoid fluid recommended, as they often obscure the trend of
overload (Squires 2008). The classic signs and INR as a prognostic marker and impair medical
symptoms of hypoglycemia are often obscured, decision making regarding LT. However, replace-
especially in the presence of encephalopathy; ment is indicated in patients with clinically sig-
therefore, blood glucose levels should be moni- nificant bleeding or prior to invasive procedures
tored regularly. Oral or enteral nutrition is pre- (Rahman and Hodgson 2001). Risks associated
ferred to parenteral nutrition if it can be done in a with FFP include volume overload and transmis-
safe manner and there is a functional gastrointes- sion of infectious agents via large donor pools.
tinal tract. Protein restriction is not recommended Cryoprecipitate may be helpful in patients with
for children with HE. If a metabolic condition is significant hypofibrinogenemia (<100 mg/dL).
suspected, all nutrition should be discontinued Platelet transfusion is not recommended unless a
for 24 h and then restarted keeping the specific threshold platelet count of 10–20 × 109 L−1 is
condition in mind (Pediatric Gastroenterology reached or there is significant bleeding and plate-
Chapter of Indian Academy of Pediatrics et al. let count <50 × 109 L−1 (Drews and Weinberger
2013). 2000). Prophylactic use of proton pump inhibi-
One of the most serious complications of ALF tors aid in the prevention of gastrointestinal
is intracranial hypertension as a result of cerebral bleeding (Polson et al. 2005).
edema and HE, which can cause irreversible neu- Due to impaired immune function, bacterial
rologic damage, and death (Cochran and Losek and fungal infections are common and a leading
2007). Classic signs of intracranial hypertension, cause of mortality (Wade et al. 2003). An active
such as papilledema and loss of pupillary reflexes uncontrolled infection is also a relative contrain-
are not always clinically apparent and radio- dication for LT. Surveillance cultures should be
graphic evidence of cerebral edema frequently obtained upon admission and with any unex-
occurs late and does not reliably detect intracra- plained deterioration in clinical status. Empiric
nial hypertension (Hirsch et al. 2000). Direct administration of broad-spectrum antibiotics is
intracranial pressure (ICP) monitoring is the recommended when the likelihood of impending
most accurate method to monitor changes in sepsis is high (Stravitz et al. 2007). Empiric anti-
intracranial pressure in ALF patients. However, biotics are also recommended for patients with
ICP monitoring is not routinely recommended ALF listed for LT, since immunosuppression
due to the risk of local complications and lack of after liver transplant is imminent. Fluconazole or
survival benefit (Vaquero et al. 2005). amphotericin should be added for suspected or
Management of intracranial hypertension often proven fungal infection.
reflects the preferences of individual centers and Renal dysfunction occurs in many patients
may include positioning the head of the patient at with ALF and is usually multifactorial with com-
>30° from horizontal, hyperventilation of intu- ponents of acute tubular necrosis, hypovolemia
bated patients to a PCO2 of <35 mmHg, infusion and even hepatorenal syndrome. Avoidance of
of hypertonic saline to maintain serum sodium at nephrotoxic agents, including aminoglycosides
145–155 mmol/L, mannitol infusions for surges and non-steroidal anti-inflammatory drugs is crit-
of ICP exceeding 20 mmHg, maintenance of ical. If progressive renal failure ensues, continu-
mild-moderate hypothermia, and bowel decon- ous venovenous hemofiltration is preferred over
tamination with lactulose or neomycin to reduce standard hemodialysis due to less dramatic fluid
ammonia levels. If lactulose is administered, care shifts. Use of plasmapheresis and therapeutic
should be taken to avoid over distension of the plasma exchange have been advocated in chil-
abdomen, which can interfere with a liver trans- dren with ALF to improve coagulopathy and pre-
plant procedure, if required. vent bleeding complications while allowing for
Routine correction of coagulopathy with fresh adjustments of fluid, electrolyte, and acid-base
frozen plasma (FFP) and other procoagulation balance (Singer et al. 2001).

Because ALF in children can progress rapidly, approximately 13.2 cases per 100,000 children in
a timely decision to proceed to LT is needed to the United States (Morinville et al. 2010).
prevent sequelae. Unfortunately, existing prog- Although the increase in disease burden is
nostic scoring systems based on biochemical well recognized for pediatric pancreatitis, data on
markers and/or clinical features, including the pathophysiology, etiologies, management and
King’s College Criteria, have not been shown to clinical outcomes is continuing to take shape.
be useful for predicting survival or death in PALF The majority of available data is based almost
(Shanmugam and Dhawan 2011). exclusively from the adult literature, yet pancre-
Approximately 10–15% of pediatric liver atitis among adults is likely a very different dis-
transplants are performed for ALF (Squires et al. ease than that seen in children given the
2006). Although post-transplant survival in PALF differences in etiological backgrounds (Abu-El-
remains lower than that observed for children Haija et al. 2014). Among adult patients with AP,
who receive liver transplants for other causes, alcohol and biliary etiologies predominate while
pediatric liver transplant recipients have the high- genetic, anatomic, metabolic and toxic causes are
est survival rate for any solid organ (Baliga et al. much more prevalent amongst pediatric patients
2004). Contraindications to LT are active uncon- (Husain et al. 2016). Fortunately, a greater
trollable sepsis, severe cardiopulmonary disease, amount of attention has been focused recently on
multisystem organ failure, extrahepatic malig- addressing pediatric specific pancreatitis con-
nancy, and severe neurological impairment. cerns with large, pediatric-centered consortium
Artificial and bioartificial liver support devices such as INSPPIRE (International Study Group of
such as the Molecular Absorbent Recirculating Pediatric Pancreatitis: In Search for a Cure) and
System (MARS) and Extracorporeal Liver Assist PINEAPPLE (Pain in Early Phase of Pediatric
Device (ELAD), which temporarily perform nor- Pancreatitis) already significantly increasing our
mal hepatocyte functions, are currently undergo- understanding of the disease process and burden.
ing development for PALF as a means of bridging
patients to either transplantation or spontaneous
recovery during native liver regeneration. Presentation
Abdominal pain is the most common initial pre-

Pancreatitis sentation of AP affecting 80–95% of patients,
with nausea or vomiting noted in up to 80% of
Over the last two decades the incidence of pan- cases (Bai et al. 2011). Importantly though,
creatitis among children has been on the rise. A infants and toddlers are less likely to present with
lack of historical pediatric data represents a major abdominal pain (43–93%) and/or emesis (29–
limitation in determining the degree of this 76%), but have a higher likelihood of presenting
increase but several studies out of the United with abdominal distention (16%) or fever (40%),
States, Mexico and Australia have all shown a both of which are rare in older patients (Kandula
significant increase in the number of hospital and Lowe 2008; Park et al. 2010). Biochemical
admission for pediatric pancreatitis (Bai et al. presentation may also differ by age. In older
2011). Establishing the true incidence of pediat- patients the sensitivity of amylase to detect AP
ric pancreatitis is further complicated by a vast ranges from 50% to 85% with lipase felt to be
difference in incidence reports amongst hospitals approximately 75% more sensitive (Park et al.
which is felt to be due to variations in institu- 2010). However, among infants and toddlers,
tional management of acute abdominal pain, par- studies suggest 100% of patients will have ele-
ticularly in emergency units (Zsoldos et al. 2016). vated lipase levels with only approximately 50%
Despite the likely under reporting of acute pan- having elevated amylase levels (Kandula and
creatitis (AP) in children, retrospective analysis Lowe 2008). Amylase remains an important
suggests the true incidence of disease to be marker in the detection of AP though as several

reports exist of patients with radiographic evi- sent a small proportion of all pancreatitis cases
dence of pancreatitis with isolated elevation of (0.3–2%) but is an important consideration for
their amylase seen (Werlin et al. 2003; Bai et al. patients on certain medications which include
2011). certain antibiotics, nonsteroidal anti-
inflammatory agents, immunomudulators, cer-
tain chemotherapeutic agents, antiepileptic drugs,
Etiologies antihypertensives, antihyperglycemics and anti-
viral therapies (Nitsche et al. 2012). Directly
While the pathophysiology remains obscure and establishing drug-induced pancreatitis is often
largely theoretical, several risk factors are known difficult requiring a withdrawal and monitor
to increase a patient’s risk of developing AP. Risk approach. Utilization of drug-induced pancreati-
factors typically fit into one of the following four tis algorithms, such as that proposed by Trivedi,
categories: (1) Metabolic, (2) Environmental, (3) may be of use to the clinician to more accurately
Genetic, or (4) Anatomical/Obstructive. recognize drug-induced pancreatitis (Trivedi and
Pitchumoni 2005).
Metabolic
Hypertriglyceridemia, hypercalcemia and Genetic
chronic renal failure are all considered significant Cystic fibrosis transmembrane conductance regu-
risk factors for the development of AP and acute lator (CFTR), pancreatic secretory trypsin inhibi-
recurrent pancreatitis (ARP). Triglyceride levels tor (SPINK1), cationic trypsinogen (PRSS1) and
>1000 mg/dL represent an absolute risk, while chymotrypsin C (CTRC) represent the major
levels >500 mg/dL represent an absolute risk for genetic causes of ARP and chronic pancreatitis
the development of AP (Bălănescu et al. 2013; (CP) in children. A recent review of the INSPPIRE
Christian et al. 2014). A threshold for hypercal- database showed 48% of patients with ARP and
cemia imparting a risk for AP has yet to be estab- 73% of patients with CP had at least one mutation
lished but hypercalcemia associated with primary on one of these pancreatitis-associated genes. The
hyperparathyroidism, high IV calcium during most common mutation associated with ARP was
cardiac surgery or parenternal nutrition adminis- CFTR (34% of patients) while PRSS1 was the
tration, and ectopic secretion of calcium- most commonly seen mutation among patients
mobilizing hormones such as seen acute with CP (46%) (Kumar et al. 2016).
lymphoblastic leukemia have all been associated
with the development of pancreatitis (Husain Anatomic/Obstructive
et al. 2016). Autopsy studies have shown signifi- Approximately 1/3 of patients with ARP or CP
cant pancreatic disease among patients with end are felt to have an anatomic or obstructive etiol-
stage renal disease. However, determining the ogy (Kumar et al. 2016). Although surgical inter-
diagnosis of pancreatitis in patients with chronic vention is required in certain anatomical
renal failure may difficult due to the impaired conditions, many obstructive etiologies may
clearance of amylase and lipase leading to the safely be managed by ERCP, which has been
recommendation that levels 3× ULN are needed shown to be safe and effective in pediatric
in order to the make diagnosis in this specific patients (Enestvedt et al. 2013; Halvorson et al.
patient population (Husain et al. 2016). 2013; Saito et al. 2014).
Environmental
To date no studies have shown a clear association Management
between smoking and/or alcohol use and the
development of pancreatitis among children, Historically, management of pancreatitis has
although as one might imagine data on the sub- been based on adult recommendations but more
ject is scarce (Husain et al. 2016; Kumar et al. recently pediatric driven data is emerging sug-
2016). Drug-induced pancreatitis is felt to repre- gesting new approaches may be warranted.

Acute Pancreatitis and/or anesthesia while simultaneously improv-

Pain management is an integral part of AP man- ing diagnostic and therapeutic efficacy.
agement with narcotics often considered the drug
of choice. However, determining when to intro-
duce enteral nutrition and how aggressive to be Esophagogastroduodenoscopy
with IV hydration have been highly debated top-
ics in pediatric AP research. Recent pediatric From 1985 to 2005 there was over a 12-fold
studies have shown that aggressive IV hydration increase in the number of pediatric EGD’s per-
(1.5–2× maintenance) over the first 48 hours and formed (Franciosi et al. 2010). Expanding diag-
early enteral nutrition (within 48 h) were not only nostic and therapeutic indications for EGD has
safe but also resulted in shorted hospital stays resulting in further growth of the field with EGD
and decreased risk of developing severe AP becoming viewed as a routine procedure in
(Szabo et al. 2015). Additionally, those patients many larger institutions (see Table 10.13 for
who consumed a high fat intake experienced common indications for EGD). Growth in inter-
lower pain scores as compared to those place on ventional technologies has been particularly
a fat restricted diet (Abu-El-Haija et al. 2016). influential in changing the way we treat a num-
ber of conditions including, but not limited to,
Chronic foreign body ingestions and acute gastrointesti-
Pain control is the mainstay of therapy for patients nal bleeding.
with CP and without proper oversight may result
in narcotic addiction. Therefore, neuropathic pain oreign Body Ingestion
F
control with tricyclic antidepressants, gabapentin Although patients with a retained foreign body
or pregabalin are preferred (Pohl and Uc 2015). may present with drooling, pain, stridor, refusal
The use of proton-pump inhibitors, antioxidants to eat, dysphasia, stridor, wheezing or respiratory
and pancreatic enzymes for pain control have distress, approximately 50% of pediatric foreign
been proposed but none have been thoroughly body ingestions will present without symptoms
studied or shown to be of benefit in pediatric pan- (Temiz 2015). Coins represent the most common
creatitis. In severe cases of ARP and CP in which accidental ingestion in children in the western
pain becomes unmanageable, total pancreatec- hemisphere, accounting for ~70% of ingestions
tomy with islet autotransplantation may be a via- (Peters et al. 2015). While a number of other
ble option (Bellin et al. 2016). toys, jewelry, food products (e.g. bones) and
other common objects can be ingested, special
attention much be shown to any object stuck in
Endoscopy the esophagus for over 24 h, button batteries and
high-powered Neodymium magnets (e.g.
Pediatric esophagogastroduodenoscopy (EGD) Buckyballs®) given the potential risk of bowel
was first described in the 1970’s and has trans- perforation and should prompt immediate refer-
formed from an infrequently performed proce- ral to a pediatric center with advanced endoscopy
dure with significant risk to the routine, often capabilities (see Fig.10.7).
outpatient procedure that it is viewed as today
(Friedt and Welsch 2013). The majority of pper Gastrointestinal Bleeding
U
Advances in pediatric endoscopy have resulted in Life threatening gastrointestinal bleeding is a
physicians becoming less reliant on invasive sur- rare occurrence in pediatrics and is best treated
gical measures and advancing imaging tech- by an advanced endoscopist at a pediatric tertiary
niques such CT and MRI, which are frequently care center. Interventions are dependent upon the
less sensitive and specific, to diagnose and treat a size of the child, the site of the bleed and the
variety of gastrointestinal disorders. Future judgment of the endoscopist (Rahman et al.
advancements promise to further decrease the 2015). Bleeding is typically characterized as var-
need of invasive procedures requiring sedation iceal or non-variceral. Variceal bleeding is

Table 10.13 Common indications for pediatric EGD

Diagnostic Therapeutic
Abdominal pain/functional disorders Foreign body/Bezoar removal
Weight loss/failure to thrive Enteral tube placement
Dysphasia/odynophagia Dilation
Diarrhea/malabsorption Banding/injection of varices
Emesis/hematemesis Non-variceal bleeding control
Iron deficiency anemia Polypectomy
Enteropathy/suspected celiac disease Botox/other injections
Suspected/surveillance inflammatory bowel disease
Common diagnostic and therapeutic indications for performing an EGD in pediatric patients (Adapted from Rahman
et al. (2015))
a c
Fig. 10.7 Coin and neodymium magnet ingestions. (a) nal x-ray of a neodymium magnet ingestion in a 5 year old
EGD image of penny ingested in a 2 year old >30 h before with free air seen below the diaphragm (green arrows)
presentation to the emergency room with resulting linear from resulting intestinal perforation
ulcer (B-blue asterix) after extraction. (c) Shows abdomi-
typically managed with IV octreotide and endo- ventions; (1) injection therapy (e.g. adrenaline,
scopic banding or sclerotherapy (Thomson and sclerosing agents, fibrin glue or normal saline),
Belsha 2016). Non-variceal bleeding is typically (2) Mechanical therapy (e.g. endoscopic hemo-
treated with two of the following classes of inter- clips) or (3) Thermo-coagulation (e.g. hot biopsy

forceps, gold probe or argon plasma coagulation) capable with EGD. Investigation of obscure GI
(Thomson and Belsha 2016). bleeds or unexplained anemia, investigation of
IBD and surveillance of polyposis syndromes are
Future Directions the main indications for both modalities (Zevit
A specific focus of endoscopic research has been and Shamir 2015). Like many of the other inter-
to decrease the need for surgical intervention in ventions outlined in this section, VCE and bal-
patients with severe gastroesohpageal reflux dis- loon enteroscopy are best performed at pediatric
ease (GERD). Two exciting techniques that have tertiary centers by pediatric gastrointestinal pro-
been developed are endoluminal gastroplication viders with experience utilizing these modalities.
and iatrogenic stricture formation through radio- Future directions include VCE dedicated to eval-
frequency energy as replacements for surgical uate the esophagus and colon in order to decrease
fundoplications (Rahman et al. 2015). While ini- the number of endoscopy procedures that require
tial results are promising, years more research is anesthesia.
required before these modalities will be deter-
mined to have any potential use in pediatric reflux
therapy. Colonoscopy
While a number of advancements have occurred

Endoscopic Retrograde in upper endoscopy and small bowel imaging,
Cholangiopancreatography (ERCP) colonoscopy has remained essentially unchanged
and continues to serve more as a diagnostic tool.
ERCP has been established as an effective diag- The main pediatric indications for colonoscopy
nostic and therapeutic tool for pancreaticobiliary remain: (1) Hematochezia, (2) Abdominal pain,
disorders in pediatrics. The invention of smaller (3) Diarrhea and (4) Polypectomy/polyp screen-
diameter duodenoscopes in the late 1980s ing (Park 2010).
allowed for ERCP use in the pediatric population
with several studies reporting outcomes in pedi-
atrics is not statistically different than that seen in
the adult population (Enestvedt et al. 2013;
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joint recommendations of the North American Society scopes: does size really matter? Spring. 2016;5:128.
for Pediatric Gastroenterology, Hepatology, and https://doi.org/10.1186/s40064-016-1749-9.
Nutrition (NASPGHAN) and the European Society Yoneda M, Mawatari H, Fujita K, et al. Noninvasive
for Pediatric Gastroenterology, Hepatology, and assessment of liver fibrosis by measurement of stiff-
Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. ness in patients with nonalcoholic fatty liver disease
2009;49:498–547. (NAFLD). Dig Liver Dis. 2008;40:371–8. https://doi.
Vaquero J, Fontana RJ, Larson AM, et al. Complications org/10.1016/j.dld.2007.10.019.
and use of intracranial pressure monitoring in Younossi ZM, Stepanova M, Afendy M, et al. Changes in
patients with acute liver failure and severe encepha- the prevalence of the most common causes of chronic
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org/10.1002/lt.20625. Clin Gastroenterol Hepatol. 2011;9:524–530.e1-quiz
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Perinatol. 2004;28:348–55. Zevit N, Shamir R. Wireless capsule endoscopy of the
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in adults. Aliment Pharmacol Ther. 2011;34:274–85. Zhang Y, Li L, Guo C, et al. Effects of probiotic type, dose
https://doi.org/10.1111/j.1365-2036.2011.04724.x. and treatment duration on irritable bowel syndrome
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adolescents, 1988–1994 to 2007–2010. J Pediatr.

Update in Pediatric Hematology
11
Ziad Solh, Anthony K.C. Chan, and Mihir D. Bhatt
Introduction (Table 11.1). It is the most common hematologic

abnormality encountered by pediatricians. Anemia
Blood is composed of multiple cellular and can be classified based on mean corpuscular vol-
non-cellular components, each deserving of ume into microcytic, normocytic, and macrocytic
special consideration for a full understanding anemias (Janus and Moerschel 2010). It can fur-
of human blood physiology and disease. In this ther be classified based on pathophysiology into
chapter, we discuss the current understanding anemia resulting from decreased production in the
of blood physiology and recent advances in the bone marrow, increased red cell destruction, and
treatment of disorders in red cells, platelets, blood loss. In this chapter, we focus on the most
white cells, and plasma components. The field common type of anemia: iron-deficiency anemia.
of pediatric hematology has witnessed signifi- It is a microcytic anemia related to decreased pro-
cant advances in the past decade. Novel thera- duction of hemoglobin due to reduced availability
peutic options for blood disorders such as sickle of iron - an essential component of the hemoglobin
cell disease and immune thrombocytopenia are structure (Jimenez et al. 2015).
being investigated and implemented. Cutting
edge therapies such as gene therapy for hemo-
philia herald a new dawn of therapies and Diagnosis of Iron Deficiency
potential cure.
Iron deficiency is diagnosed based on clinical
suspicion leading to laboratory evaluation with
Iron-deficiency Anemia iron studies. Clinical symptoms in children may
include mood changes, neurocognitive/develop-
Anemia is defined as a hemoglobin concentration, mental delay, growth retardation, epithelial
hematocrit, or red blood cell number below two changes, and pica. Hemoglobin value may be
standard deviations from the age-specific mean used as a screening test, but because the hemo-
Z. Solh, M.D., M.Sc., F.R.C.P.C., (*)

Department of Pathology and Molecular Medicine,
A.K.C. Chan, F.R.C.P.C., F.R.C.Path
McMaster University,
M.D. Bhatt, B.H.Sc., M.D., F.R.C.P.C.
Room 3N27, 1280 Main Street West, Hamilton, ON,
Division of Hematology/Oncology, Department of
Canada, L8S 4K1
Pediatrics, McMaster University,
Medical Services and Innovation, Canadian Blood Room 3N27, 1280 Main Street West, Hamilton, ON,
Services, Hamilton, ON, Canada Canada, L8S 4K1
e-mail: ziad.solh@medportal.ca e-mail: akchan@mcmaster.ca; bhattm2@mcmaster.ca


314 Z. Solh et al.
Table 11.1 Normal ranges of red blood cell laboratory result in false negative hemoglobin electropho-
indices by age
resis results.
Mean hct
[−2SD] MCV
Mean Hb (proportion [−2SD]
Age [−2SD] (g/L) of 1.0) (fL) evelopment of Iron Deficiency
D
Birth 165 [135] 0.51 [0.42] 108 [98] in Children
1–3 days 185 [145] 0.56 [0.45] 108 [95]
1 month 140 [100] 0.43 [0.31] 104 [85] At birth, newborns experience an increase in oxy-
2 months 115 [90] 0.35 [0.28] 96 [77] gen availability which leads to the downregula-
3–6 months 115 [95] 0.35 [0.29] 91 [74] tion of erythropoietin and a subsequent gradual
6 months to 120 [105] 0.36 [0.33] 78 [70] decline in hemoglobin. The physiologic hemo-
2 years globin nadir in term infants (90–110 g/L) occurs
2–6 years 125 [115] 0.37 [0.34] 81 [75] at 8–12 weeks of life. When oxygen delivery no
6–12 years 135 [115] 0.40 [0.35] 86 [77] longer meets metabolic needs, erythropoietin is
12–18 years upregulated again leading to a physiologic hemo-
Females 140 [120] 0.41 [0.36] 90 [78] globin recovery.
Males 145 [130] 0.43 [0.37] 88 [78] In preterm infants, the hemoglobin nadir is
Adapted from Richardson (2007) more profound (70–90 g/L), and it occurs earlier
Hb hemoglobin, hct hematocrit, MCV mean corpuscular at 3–6 weeks of life. This anemia of prematurity
volume
ensues from a variety of reasons. Most preterm
infants do not get the benefit of the maternal
globin declines only in the later stages of iron transfer of iron which occurs in the third trimes-
deficiency, this test may miss the earlier stages of ter, resulting in lower hemoglobin at birth.
iron deficiency. Iatrogenic causes from frequent blood draws also
Complete iron studies are more reliable and contribute to the hemoglobin drop. A poor eryth-
include: hemoglobin, blood smear, reticulocyte ropoietin response in preterm infants is also pos-
count, ferritin, and transferrin saturation (TS). TS tulated to exacerbate and prolong anemia.
is the most useful test to evaluate iron deficiency. In toddlers, the most common cause of iron-
Although total iron is low and total iron binding deficiency anemia is nutritional and marked by
capacity (TIBC) is high in iron deficiency, these excessive cow’s milk consumption beyond an aver-
two tests are not accurate or useful in isolation; age of 500 mL a day. The reasons cow’s milk leads
instead, they are best used together to calculate to iron deficiency are threefold: (1) milk is filling and
TS. Most laboratories calculate and report the TS causes slow gastric emptying, which in turn leads to
so that the clinical team does not have to do this. decreased appetite for other iron-rich foods; (2) cal-
In a normal individual, 20–40% of transferrin cium found in milk inhibits iron absorption; and (3)
sites are used to transport iron. In an iron deficient cow’s milk protein may cause an allergy with micro-
patient, less than 20% are used, which is reflected scopic or gross gastrointestinal bleeding.
in a TS < 20%. In the absence of inflammatory Post-pubertal females are at an increased risk
conditions that result in an elevated ferritin, a fer- of iron deficiency due to menstrual blood loss.
ritin value <30 ng/mL supports the diagnosis of Referral to a gynecologist should be considered
iron deficiency (McDonagh et al. 2015). for hormonal or non-hormonal options to control
It is important to note that the differential chronic menstrual bleeding.
diagnosis of microcytic anemia includes thalas-
semia. Because thalassemia patients are not
immune to iron deficiency, a thorough iron Treatment of Iron Deficiency Anemia
work up is necessary to exclude iron deficiency
(or treat it) before a diagnosis of hemoglobin- The treatment of iron deficiency anemia requires
opathy can be excluded because low iron may a combination of dietary changes and iron supple-

11 Update in Pediatric Hematology 315
mentation (Siu 2015). Dietary changes may controlled trial which included infants aged
include the reduction of milk consumption and 9–18 months with Hb SS or Sβ0 thalassaemia
increasing the intake of iron-rich foods. Iron from (Wang et al. 2011). Hydroxyurea was given as a
animal sources is better absorbed by the human health maintenance drug to 96 study group sub-
gut than plant-based iron. Dietary iron is also bet- jects at a dose of 20 mg/kg/day for 2 years, and
ter absorbed in the presence of vitamin C (i.e. in a placebo was given to 97 subjects in the control
combination with foods rich in ascorbic acid). group. The results of the trial showed that
Iron supplementation may be in the form of hydroxyurea decreased the frequency of pain
oral or intravenous iron. Oral iron is available crises and dactylitis significantly. There was
in a variety of affordable formulations and is also a trend suggestive of decreased acute chest
recommended at a dose of 6 mg/kg/day of ele- syndrome, hospitalisation and transfusion.
mental iron for 1 month; once the iron indices Hydroxyurea also increased the level of Hb
have been corrected this is followed by 3 mg/ (improved anemia), Hb F and decreased white
kg/day for 2 months of maintenance. If oral blood cell (WBC) count (leukocytosis is
iron is poorly tolerated, intravenous iron may involved in the pathophysiology of SCD mor-
be better tolerated and lead to more rapid bidities). Mild-moderate neutropenia was the
replacement of iron stores. Intravenous iron only toxicity noted.
may also be used in patients who fail oral iron Unfortunately, a major challenge in SCD clin-
therapy due to iron refractory iron deficiency ical practice is overcoming a parent’s reluctance
anemia (IRIDA) which is a disorder of iron to consent to treating their child with a drug that
metabolism due to the TMPRSS6 gene muta- is historically associated with cancer treatment.
tion leading to the upregulation of hepcidin and In such cases, it is paramount to devote time to
decreased absorption of iron from the duode- counselling the parents about the history of
num (De Falco et al. 2013). hydroxyurea, its pathophysiology, its significant
benefits, and the limited side effect profile. This
is coupled with reassuring a parent that hydroxy-
Hydroxyurea in Sickle Cell Disease urea maintenance therapy would not occur with-
out close monitoring of bloodwork and clinical
Sickle cell disease (SCD) is a group of qualitative status at follow-up visits.
hemoglobin (Hb) disorders which can be caused Prior to starting hydroxyurea, the following
by a number of hemoglobin variants: Hb SS, SC, baseline tests should be ordered: complete blood
S-beta thalassemia, SO Arab, SD, and other rare count (CBC), reticulocyte count, Hb F level,
S hemoglobins. Hb S polymerizes in the deoxy- renal function, and liver function. The pediatric
genated state leading to crescent-shaped red cells starting dose is 20 mg/kg unless creatinine
that are poorly deformable when passing through clearance is low. After ensuring adherence to
capillary microcirculation. This leads to chronic daily therapy for 2–4 weeks, a CBC may be
hemolysis, vascular occlusion, and end-organ done to confirm the expected decrease in WBC
damage (Solh et al. 2016). and platelet count and a rise in mean corpuscu-
Significant advances in SCD therapy have lar volume (MCV). If these indices are
taken place over the past decade. Most notable unchanged from baseline, verify the dose calcu-
is the role of hydroxyurea, which was initially lation, and review adherence with the patient.
introduced as a chemotherapeutic drug for the The hydroxyurea dose can be adjusted based on
treatment of leukemia and myeloproliferative CBC and reticulocyte count (every 2–4 weeks)
disease, but gained recognition in SCD clinical until the maximum tolerated dose is reached. If
practice as an agent that increases Hb F levels. the patient develops one or more abnormal
Hb F overexpression leads to a relative decrease hematological index (e.g., neutropenia, throm-
in Hb S levels and improved red cell deform- bocytopenia, Hb < 50 g/L, or reticulocytopenia,
ability. The BABY HUG study is a randomized the hydroxyurea can be held until recovery, then

316 Z. Solh et al.
resumed at a reduced dose. When a tolerated Desferrioxamine (Desferal® or deferox-

dose is reached, less frequent monitoring is amine; DFO) is a hexadentate chelator which is
appropriate (e.g., every 3 months). Pregnancy licensed for children over the age of 2 years. It
planning is an important counselling point due requires slow subcutaneous infusion for 8–12 h
to the known teratogenicity of hydroxyurea daily or at least five nights a week. Subcutaneous
(Platt 2008; Canadian Haemoglobinopathy infusion can be costly, cumbersome and time-
Association 2014). consuming for patients. It has a very short half-
life whereby it only chelates iron during
infusion, and it is excreted via the colon and
Iron Chelation in Thalassemia kidney. To increase the availability of chelatable
iron in the gut, vitamin C can be started (after
The thalassemias are a group of quantitative several weeks of deferoxamine infusion) at a
hemoglobinopathies caused by insufficiencies in dose no more than 2–3 mg/kg/day and taken just
globin chain synthesis. This leads to hypochro- before the deferoxamine infusions (Guidelines
mic microcytic anemia and an imbalance in glo- for the Management of Transfusion Dependent
bin chains leading to unstable globin tetramer Thalassaemia, 3rd Edition 2014). Due to its side
deposition within red cells, impaired erythropoi- effect profile (auditory, visual, and renal distur-
esis and hemolysis (Kelly 2012). bances), deferoxamine is only recommended for
The two major thalassemia syndromes are use if the serum ferritin is above 1000 μg/L or
alpha-thalassemia (disorder in α-chain) and beta- after the first 10–20 transfusions at a dose of
thalassemia (disorder in β-chain), which affect 20–40 mg/kg/day for children (50–60 mg/kg/
the synthesis of the most prevalent adult hemo- day for adults).
globin (Hb A: α2β2). Four genes control α-chain Deferiprone (Ferriprox®, Kelfer®, GPO-L-
synthesis while two control β-chain synthesis. ONE®; DFP) is a bidentate chelator which is
The severity of thalassemia syndromes varies administered orally as a liquid or a tablet, which
based on the genetic mutation and the number of improves compliance (95%) compared to subcu-
globin genes affected (Kelly 2012). The genetics, taneous deferoxamine (72%) (Olivieri and
pathophysiology and investigation of thalassemia Brittenham 1997). There is insufficient safety
syndromes are beyond the scope of this section data for licensing in children 2–6 years of age,
which will focus on chelation therapy. but it is used in children >6 years if deferox-
A therapeutic cornerstone for severe thalas- amine is not tolerated or ineffective (Guidelines
semia (e.g. β-thalassemia major) is regular life- for the Management of Transfusion Dependent
long red cell transfusion to suppress Thalassaemia, 3rd Edition 2014). Side effects
dyserythropoiesis. Transfusions are usually include agranulocytosis, nausea, liver dysfunc-
administered every 2–5 weeks, to maintain a pre- tion, and arthropathy. The recommended dose
transfusion Hb value above 90–105 g/L. However, is 75 mg/kg/day three times a day. Vitamin C
without iron chelation, patients may only be co-therapy with deferiprone is of unclear benefit
expected to survive until 10–25 years of age suc- and therefore not recommended. Deferiprone
cumbing to cardiac iron overload. With iron che- may be used in combination with deferoxamine
lation as the other cornerstone of therapy, patient to treat severe cardiac iron overload (Galanello
survival may be extended to over 40 years of age et al. 2010).
(Modell et al. 2000). The third cornerstone of Deferasirox (Exjade®, Asunra®; DFX) is an
therapy is multidisciplinary care, which high- oral once daily tridentate iron chelator. It is dis-
lights the prevention of multi-organ deterioration persed (not dissolved) in water or juice and rec-
and the management of medical and psychoso- ommended to be taken before a meal. Its long
cial aspects of thalassemia (Guidelines for the half-life and daily dosing make it an attractive
Management of Transfusion Dependent option for patients. Studies have shown that the
Thalassaemia, 3rd Edition 2014). dose can be adjusted between 20 and 40 mg/kg/

day depending on the degree of iron overload liberal transfusion strategy. The TRIPICU trial
(Guidelines for the Management of Transfusion was done in stable critically ill children (Lacroix
Dependent Thalassaemia, 3rd Edition 2014; et al. 2007). The results showed that a restrictive
Porter et al. 2013). It is licensed in most countries Hb threshold (70 g/L) was as safe as a liberal one
as first line therapy in children over 2 years of (95 g/L). The results were not applicable to
age, similarly to deferoxamine. Side effects unstable pediatric patients.
include gastrointestinal upset, renal impairment In general, no universal transfusion “trigger”
and proteinuria, and hepatic dysfunction. exists. Instead, the decision to transfuse varies
depending on the individual clinical scenario tak-
ing into account both the overall clinical picture
Transfusion Medicine and the Hb value. Higher thresholds can be con-
Controversies: Transfusion Triggers sidered if there is symptomatic anemia or cardio-
and Age of Blood respiratory compromise. It is important to restrict
iatrogenic blood loss due to blood sampling,
Transfusion medicine specialists have recently especially in the neonate, to minimize transfusion
confronted two important controversies which needs.
affect both the clinical care and the blood bank-
ing needs of transfused patients. The first contro-
versy is that of red blood cell transfusion Age of Blood
thresholds with the second being the optimal
storage age of red cells as they relate to patient During storage, red blood cells undergo struc-
outcomes. The neonatal and pediatric popula- tural and biochemical changes which have been
tions have received special attention during the hypothesized to result in clinical effects post-
resolution of these controversies. transfusion. The hypothesis has been the basis of
several randomized trials exploring the effect of
storage age on patient outcomes. The ABLE trial
Red Cell Transfusion Triggers (in critically ill adults) and the RECSS trial (in
cardiac surgery patients over 12 years of age)
Since the TRICC trial was published in 1999, it both showed no difference in outcomes between
has been accepted that critically ill adults (except fresh and older blood (Lacroix et al. 2015; Steiner
those with myocardial infarction and unstable et al. 2015). Subsequently, the INFORM trial—a
angina) do not have a 30-day survival benefit much larger and pragmatic trial including a gen-
from liberal transfusions (keeping Hb > 100 g/L) eral adult population—was performed showing
compared to a restrictive strategy (keeping no difference in mortality (Heddle et al. 2016).
Hb > 70 g/L). In fact, a restrictive strategy was The ARIPI trial focussed on premature neo-
shown to result in less in-hospital mortality in nates and found no difference in the composite
this adult population (Hebert et al. 1999). Similar outcome of death and neonatal morbidities when
neonatal and pediatric data were not available fresh (mean of 5 days) and standard/older blood
until several years later when the PINT and (mean 14 days) were used (Fergusson et al.
TRIPICU trials were published in 2006 and 2007, 2012). This evidence points to the general safety
respectively. PINT showed that maintaining a of storing and using red blood cells up to their
higher Hb threshold in extremely low birth time of expiration in these patient populations.
weight neonates did not confer any mortality or The Age of Blood in Children in Pediatric
morbidity advantage (Kirpalani et al. 2006). The Intensive Care Units (ABC PICU) trial is ongo-
Hb threshold took into account physiological ing (NCT01977547).
changes in Hb values with post-natal age i.e. the Other aspects of the blood supply being inves-
tested thresholds decreased with age. Ventilatory tigated are the recently found association
support also raised the tested threshold to a more between blood donor characteristics and recipi-

318 Z. Solh et al.
ent mortality. A study of adult red cell transfu- between 100 and 150 × 109 L−1 is common in
sion recipients found a higher mortality rate some populations with a low probability of
when the donors were female; mortality rate was developing severe thrombocytopenia. ITP is
also inversely related to donor age (Chasse et al. now classified as newly diagnosed (within
2016). This hypothesis has yet to be tested pro- 3 months of diagnosis), persistent (3–12 months
spectively and in pediatric recipients of from diagnosis), and chronic (>12 months from
transfusion. diagnosis).
Although transfusion is an important life- First-line management of ITP in non-bleed-
saving therapy, there is a possibility that its over- ing children is observation of symptoms with
use may be associated with transfusion-transmitted reassessment of platelet count. If a rapid (24–
non-infectious harm to patients. This is difficult 48 h) increase in platelet count is desired to pre-
to ascertain because transfusions are usually vent the low (<3%) risk of hemorrhage
given to individuals with underlying disease who (including intracranial hemorrhage), prophy-
have higher morbidity and mortality rates (i.e. laxis can be offered with intravenous immuno-
transfusion is a confounding factor). For exam- globulin (IVIG) (0.8–1 g/kg/day for 1–2 days),
ple, the neonatal entity of transfusion associated or anti-D for Rh-positive non-splenectomized
necrotizing enterocolitis (TA-NEC) remains patients (50–75 μg/kg for 1 dose) (Neunert
problematic due to the underlying neonatal ane- 2013; Cooper 2014). Anti-D is not recom-
mia which has also been associated with NEC mended for children with low hemoglobin due
(Patel et al. 2016). As a result, the controversy of to bleeding or autoimmune hemolysis. A short
transfusion-transmitted harm may remain unre- course of high-dose steroids (for example pred-
solved for some time. nisone 4 mg/kg/day for 4 days) is also an option
for first-line prophylaxis bearing in mind that
the onset of platelet response is not immediate
anagement of Immune
M and can occur 1 week later (Blanchette and
Thrombocytopenia Carcao 2000). Platelet transfusion is generally
not useful in ITP but may have a role in the
Before discussing the treatment of immune throm- actively bleeding patient while awaiting the
bocytopenia (ITP) in children, it is important to effects of other treatments (Cooper 2014).
describe the latest standardized terminology which Splenectomy is the only known long lasting
was agreed upon in 2009 by the International treatment for chronic immune thrombocytope-
Working Group of ITP experts (Rodeghiero et al. nia, but it has to be weighed against the risk of
2009). The group published a standardization sepsis. Rituximab offers the benefit of a rela-
document outlining their recommendations: the tively long lasting response (6–12 months) but
term “idiopathic thrombocytopenic purpura” is complete remission is rare. There is currently
considered inaccurate, and “immune thrombocy- not enough evidence to support the use of
topenia” is preferred; ITP is primary if there is no tranexamic acid, recombinant factor (F) VIIa, or
inciting cause, and secondary if there is an under- immunosuppressive agents like azathioprine or
lying autoimmune or other medical disorder. This mycophenolate mofetil (these agents have been
new terminology emphasizes the immune-medi- used off-label).
ated pathophysiology of ITP, the absence of pur- Thrombopoietin (TPO) receptor agonists are
pura in the majority of cases, and the importance novel agents that are licensed for use in adult and
of ruling out an underlying cause. with very recent published data in children with
In addition, a platelet count below persistent ITP. Romiplostim (AMG 53, Nplate;
100 × 109 L−1 (instead of 150 × 109 L−1) was Amgen, Thousand Oaks, CA) is a subcutane-
established as the new threshold for diagnosis ously administered recombinant protein. A phase
owing to the observation that a platelet count 3 placebo-controlled double-blinded study ran-

domized 42 children to romiplostim and 20 chil- Evans syndrome is much more difficult to
dren to placebo. A platelet response to a count treat compared to ITP, AIHA or autoimmune
over 50 × 109 L−1 was achieved in 22 (52%) neutropenia alone. It is frequently chronic,
patients in the study group and 2 (10%) in the relapsing and refractory. Many patients do not
placebo group; p = 0.002, odds ratio 9.1 [95% CI: respond fully to steroid therapy and require mul-
1.9–43.2] (Tarantino et al. 2016). Eltrombopag tiple agents. A study showed that almost two-
(SB-497115; GSK, Brentford, UK) is a small thirds of patients with Evans syndrome required
molecule TPO receptor agonist agent dosed once multiple agents compared with only one-third of
a day orally. The PETIT trial randomized 45 chil- patients with isolated AIHA (Aladjidi et al.
dren to receive eltrombopag, and 22 children to 2011). Most commonly used treatments are ste-
the placebo group. A platelet response to a count roids and IVIG. IVIG is used more commonly in
over 50 × 109 L−1 was achieved in 28 (62%) study patients with ITP.
group patients and 7 (32%) placebo patients; Other treatment options include rituximab,
p = 0.011, odds ratio 4.31 [95% CI: 1.39–13.34] mycophenolate mofetil and sirolimus. Rituximab
(Bussel et al. 2015). is an effective second-line treatment for patients
with Evans syndrome. In a retrospective study by
Bader-Meunier et al. (2007), rituximab therapy
Evans Syndrome was administered in combination with predni-
sone (14 patients) or other immunosuppressive
Evans syndrome is characterized by ITP, autoim- drugs (three patients) in 17 patients. Thirteen of
mune hemolytic anemia (AIHA) and/or autoim- the 17 patients (76%) experienced partial or com-
mune neutropenia. Some children may present plete remission in cytopenias. Three patients
with isolated cytopenia, commonly ITP or relapsed at a median follow-up of 2.4 years. In
AIHA, and then develop additional cytopenias the ten long-term responders, they were able to
months or even years later. Of the children diag- discontinue completely or taper steroid therapy
nosed with pediatric AIHA, up to one-third may to less than 50% of initial dosing.
have Evans syndrome (Aladjidi et al. 2011; Splenectomy is another mode of second-line
Vaglio et al. 2007). treatment that has been shown to reverse
The underlying immune defect in Evans cytopenias in patients with Evans syndrome.

syndrome has not been identified yet despite However, the response rate if lower than for
many suggested immunoregulatory abnormali- patients with isolated ITP or AIHA (Chou and
ties. There is evidence of auto-antibody forma- Schreiber 2015). In patients who respond ini-
tion against antigens on the blood cells without tially, relapse is not uncommon. Splenectomy is
obvious cross reactivity (Pegels et al. 1982). generally reserved for patients who fail all med-
The patients with Evans syndrome are more ical treatments.
likely to develop systemic autoimmunity.
Many patients presenting with Evans syndrome
have autoimmune lymphoproliferative syn- Diagnosis and Management of DIC
drome (ALPS) as the underlying cause of their
immune dysregulation, while some may have Disseminated intravascular coagulation (DIC) is
common variable immunodeficiency (CVID) a syndrome of systemic activation of blood coag-
or other immunodeficiencies (Teachey et al. ulation, characterized by intravascular thrombin-
2005). It is thus important to check for ALPS induced fibrin generation which leads to
in all patients with two cytopenias. In a study thrombosis of small and medium-sized vessels,
by Seif et al. (2010), almost half of 45 patients and organ dysfunction. Platelet and coagulation
with Evans syndrome were eventually diag- factor consumption also leads to a bleeding
nosed with ALPS. diathesis.

320 Z. Solh et al.
The causes of DIC vary from infection and committees including: the British Committee for
cancer, to trauma and liver disease among other Standards in Haematology (BCSH), the Japanese
etiologies (Wada et al. 2013). In neonates, sepsis Society of Thrombosis and Hemostasis (JSTH),
from Group B streptococcus and perinatal stress the Italian Society for Thrombosis and Hemostasis
(asphyxia, respiratory distress syndrome, meco- (SISET), and the International Society on
nium aspiration) are the most common causes of Thrombosis and Hemostasis (ISTH). For pediat-
DIC, whereas in older children bacterial sepsis ric patients, there is controversy regarding the
and injury (trauma, burn, drowning) are the top applicability of these scoring systems due to age-
causes followed by malignancy, toxins (snake related differences in laboratory values and due to
bites, recreational drugs), liver disease and the low sensitivity of some coagulation tests in
immunological reactions such as acute hemolytic diagnosing early DIC in pediatrics (Soundar et al.
transfusion reactions and transplant rejection 2013; Rajagopal et al. 2017). See Table 11.2
(Rajagopal et al. 2017). regarding pediatric considerations in the investi-
These etiologies have in common the ability to gation of DIC.
release tissue factor from endothelial cells and The ISTH DIC scoring system uses four steps:
mononuclear cells. Tissue factor activates the (1) Risk assessment based on underlying disorder
extrinsic coagulation pathway by forming a com- associated with DIC; (2) Obtaining global coagu-
plex with coagulation FVII, which then leads to lation tests (platelet count, prothrombin time
thrombin generation and clot formation. Thrombin [PT], fibrinogen, fibrin-related marker such as
also activates the intrinsic and common pathways, D-dimer or fibrinogen degradation product); (3)
which propagates further coagulation. Evaluating or scoring each laboratory value; (4)
Consumptive coagulopathy ensues which leads to Calculating a total score (≥5 is compatible with
the thrombo-hemorrhagic syndrome of overt DIC). Other scoring systems (Soundar et al.
DIC. Fibrin degradation products and D-dimers 2013) have found that serial laboratory tests
may form due to the action of plasmin on fibrin. which show a trend are significantly more sensi-
The diagnosis of DIC is challenging due to the tive in detecting pediatric DIC (though this
differences in presentation and laboratory abnor- approach is less specific for DIC).
malities present in each case. To simplify the The management of DIC in pediatrics is pri-
diagnostic approach, several scoring systems have marily aimed at treating the underlying condi-
been developed in adult patients by guidelines tion (infection, malignancy) and replacing
Table 11.2 Pediatric considerations for DIC laboratory testing

Sampling and analysis
Laboratory test Age considerations considerations
Low platelet count – Platelet clumping due to
difficult venous access
Prolonged prothrombin time (PT), – Vary with age – Heparin contamination from
activated partial thromboplastin – Neonatal polycythemia leads to excess central lines
time (aPTT) citrate in tube – Insufficient sampling leads to
excess citrate in tube
Prolonged international – Vary with age – Laboratory should develop
normalized ratio – INR control values use adult plasma, locally derived ranges using local
(INR) so pediatric results appear abnormal reagents and analysers
Low fibrinogen – Congenital hypofibrinogenemia must – Acute-phase reactant
be considered – The functional Clauss
fibrinogen assay is more accurate
in DIC
Elevated D-dimer – No reference range available in –
pediatrics

deficient coagulation factor using plasma protein FIX products as well as employment of gene
products. Equally essential management strate- therapy in the treatment of hemophilia.
gies are the serial monitoring of laboratory val- Over the last decade, longer acting factor
ues and the regulation of excess thrombin using replacement products have been engineered to
heparin. Continuous infusion of unfractionated allow for longer dosing intervals. Long-acting
heparin is the preferable pediatric option, in the FVIII and FIX products are available and
non-bleeding patient, due to its short half-life approved for older children and adults in Canada.
and its reversibility with protamine sulfate. Some of the ways that FVIII half-life has been
Platelet transfusion should be reserved for the increased include pegylation, fusion to immuno-
bleeding patient or those undergoing invasive globulin Fc domain and reconstitution with
procedures with a platelet count below pegylated liposomes. FIX half-life has been
50 × 109 L−1. Plasma transfusion is only indi- extended by pegylation, fusion to Fc domain and
cated in bleeding patients whose PT or activated fusion to albumin. With adequate control of
partial thromboplastin time (aPTT) are over 1.5 bleeding episodes and less frequent infusions, it
times the upper age-based limit. Cryoprecipitate is expected that the extended half-life factors
may be used in bleeding patients if the fibrino- would lead to an improvement in quality of life in
gen is below <1.5 g/L. Fibrinogen concentrates children and caregivers. A preliminary analysis
are not currently licensed for DIC management; of Haem-A-QoL, a quality of life measurement
they are only licensed for congenital afibrino- tool, has shown numerical improvements in total
genemia and congenital hypofibrinogenemia. scores from baseline for adult hemophilia patients
The use of antithrombin and recombinant acti- taking Eloctate and Alprolix. Final analyses are
vated protein C (rAPC) are not widely accepted pending.
in pediatrics due to the lack of sufficient evi-
dence. Due to the risk of thrombosis, recombi-
nant FVIIa and antifibrinolytics are not Long-Acting FVIII Products
recommended (Rajagopal et al. 2017).
FVIII-Fc Fusion
Eloctate® is a recombinant product, rFVIIIFc,
evelopments in Hemophilia
D made of FVIII fused with a human immunoglob-
Treatment ulin Fc domain (Dumont et al. 2012). The Fc
domain binds the neonatal Fc receptor and pro-
Hemophilia is a bleeding disorder caused by defi- tects the factor from degradation. The half-life is
ciency of FVIII (Hemophilia A) or FIX extended 1.5–2 times in studies. The pilot study
(Hemophilia B). The management of children as well as the dosing study were published in
with hemophilia requires a multi-disciplinary 2012 and 2014, respectively (Powell et al. 2012;
team and multi-dimensional approach. It includes Mahlangu et al. 2014). The pilot study, consisting
provision of replacement therapy with coagula- of 16 patients, and dosing study, consisting of
tion factors that the patients are missing. The 165 patients, showed that rFVIIIFc was well
factor treatment is provided during acute bleed- tolerated and patients did not develop inhibitors
ing and for prophylaxis. There are two major to the fusion protein during 28 days of observa-
classes of factor replacement therapies, namely tion and 50 exposure days, respectively. The half-
plasma- derived and recombinant products. life of rFVIIIFc in the pilot study was 18.8 h
Plasma-derived products are extracted and puri- compared to 11 h for rFVIII and the trough levels
fied from human plasma, while recombinant fac- with twice weekly dosing were 1–3 units/
tors are produced from cell lines (human or dL. There is wide variation in the pharmacokinet-
animal) which are engineered to express large ics of FVIII among different individuals.
amounts of factor. This section will address the Eloctate® was approved by the US FDA in June
development and use of longer-acting FVIII and of 2014 for patients with hemophilia A.

322 Z. Solh et al.
VIII with Pegylated Liposomes

F until the link is cleaved during FIX activation. The
One strategy used to prolong FVIII half-life was half-life of Idelvion® this product is 102 h
reconstitution with pegylated liposomes. It seemed (Santagostino et al. 2016). In addition to increased
effective in preclinical studies, wherein it not only half-life, Idelvion® also has the potential for higher
prolonged the half-life FVIII, but also reduced trough levels. Idelvion® was approved by the US
bleeding complications (Baru et al. 2005). However, FDA in 2016 for prophylaxis or treatment of
in randomized controlled trials in humans, the phar- bleeding.
macokinetic profile was comparable to native
FVIII. Hence, this strategy was not further pursued. Pegylated FIX
Then, it was thought that reconstitution with liposo- N9-GP® is a pegylated long-acting FIX product.
mal carriers may do the trick. There is a molecule The PEG moiety is removed during the proteo-
wherein plasma-derived FVIII is reconstituted with lytic activation of FIX in the coagulation cas-
a liposomal diluent immediately prior to infusion, cade. The half-life of N9-GP® was measured at
which is under study (Spira et al. 2012). 93 h in the initial study (Negrier et al. 2011).
Collins et al. (2014) published the first N9-GP
trial in humans, in which they had 74 patients
Long-Acting FIX Products with hemophilia B who were treated with pro-
phylaxis or on-demand treatment. The annual
FIX-Fc Fusion bleeding rates were 1.04, 2.93, and 15.58 with
Alprolix® is a recombinant molecule, rFIXFc, 40 IU/kg weekly, 10 IU/kg weekly, and on-
made of FVIII fused with a human immunoglobu- demand dosing, respectively. Fourty-five percent
lin Fc domain. The Fc domain causes the protein of patients receiving prophylaxis had no bleed-
to be recycled to the circulation through its binding, while 17% of patients receiving 10 IU/kg
ing to the neonatal Fc receptor, which extends the had no bleeding. No inhibitors developed and
half-life 3–5 times. The half-life of the rFIXFc is there were no other safety concerns during the
measured at 54–90 h, compared with 18 h for trial.
unmodified FIX products (Peters et al. 2010).
Powell et al. (2013) published the first observa-
tional study of rFIXFc, where its efficacy was Gene Therapy
examined in prevention of bleeding using prophy-
lactic as well as on-demand dosing. The annual Gene therapy is a curative option for patients with
bleeding rates were 3, 1.4, and 17.7 with once- hemophilia as it has the potential to replace the
weekly dose-adjusted prophylaxis, interval- deficient factor. With gene therapy, achieving
adjusted prophylaxis, and on-demand dosing, fully normal factor levels is not the aim. It is suf-
respectively. There were no inhibitors, thrombo- ficient to convert severe hemophilia patients (<1%
embolic events, or anaphylactic reactions in two factor level) to moderate (1–5%) or mild factor
other open label studies of 138 patients (Shapiro levels (>5%) to improve their clinical phenotype.
et al. 2012). Alprolix® was approved by the US There are two important technologies being
Food and Drug Administration (FDA) in 2014 for explored: (1) Injection of FVIII or FIX encoding
prophylaxis and treatment (http://www.alprolix. vectors into the recipient, and (2) Ex vivo gene
com/pdfs/PrescribingInformation.pdf [Accessed therapy in which cells from the intended recipients
on April 01, 2014]). are explanted and genetically modified to secrete
the factor.
FIX-Albumin Fusion There have been two studies in Hemophilia
Idelvion® is a recombinant FIX product which is A. In the study by Roth et al. (2001), dermal
produced by fused human FIX and human albumin fibroblasts from six patients were explanted,
genes. The protein circulates as a fused protein transfected with a plasmid for FVIII and then

injected into the omentum. The FVIII activity delivery, neutralizing antibody response cost and
increased in 4/6 patients, with decreased in bleed- safety (Scott and Lozier 2012).
ing and factor requirement. No serious side
effects were reported. Powell et al. (2003) used a
retroviral vector for expression of a B-domain- Oral Anticoagulants in Children
deleted human FVIII. Out of 13 patients treated,
FVIII requirement decreased in five patients. No The mainstay of anticoagulation therapy in neo-
major adverse events were reported. nates and children with thrombosis comprises of
There have been multiple studies examining unfractionated heparin, low molecular weight
the utility of gene therapy in Hemophilia B heparin and warfarin. Warfarin is the only oral
patients. These studies have all evaluated adeno- anticoagulant approved for use in children; how-
viral gene transduction of FIX constructs. ever, its therapeutic effect is significantly influ-
Nathwani et al. (2011, 2014) treated ten patients enced by changes in diet and medications (Ansell
with intravenous infusion of adeno- associated et al. 2008). Secondly, it requires rigorous moni-
virus serotype 8 (AAV8) vector expressing a toring with international normalized ratio (INR)
codon-optimized FIX. These patients experienced to ensure appropriate therapeutic effect. Given
a dose dependent increase in FIX levels. A follow- these reasons, it is not very practical to use war-
up study showed that the increase in FIX level was farin in children for shorter treatment durations
persistent over a median of 3.2 years. The annual of 3–6 months.
bleeding rates in these patient groups decreased New oral anticoagulants such as FXa inhibitors
from 16% to 2%. Four out of seven patients were (rivaroxaban, apixaban, and edoxaban) and direct
able to discontinue prophylaxis. In terms of side thrombin inhibitors (argatroban, dabigatran, and
effects, temporary asymptomatic elevations in bivalirudin), have been tested and approved for use
transaminases were reported. There were no other in adults. However, there is limited data for use in
major adverse events. children. Many of these agents are in the clinical
Gene therapy is promising, but challenging. trial phase in pediatric patients (Table 11.3). In the
There are many unresolved issues including T meantime, it is not recommended to use these
cell response to viral insertion vector, factor agents outside of clinical studies.
Table 11.3 Drug and research study information for oral anticoagulant use in pediatrics
Anticoagulant General information Published studies Ongoing studies
Rivaroxaban Direct Xa inhibitor, once daily PK/PD studies in children PK/PD study in <6 months
dosing ages 6 months to 18 years children; phase II and III studies
comparing dose equivalent in all children >6 months
to adult 20 mg dose
Apixaban Direct Xa inhibitor, twice daily None Phase I PK/PD study in all
dosing children; phase III study in
1–18 years (phase III open only
once phase I completed in each
age cohort)
Edoxaban Direct Xa inhibitor, once daily None Phase I PK/PD study in
dosing, useful for patients with 0–18 years
renal impairement
Dabigatran Direct thrombin inhibitor, twice Phase II study in Phase II and III studies in
daily dosing adolescents different cohorts for prophylaxis
and treatment
From von Vajna et al. 2016
PK pharmacokinetics, PD pharmacodynamics

324 Z. Solh et al.
The new oral anticoagulants, including apixa- FAS gene (classified as ALPS-FAS, MIM
ban, dabigatran, rivaroxaban, have been studied #601859) (Madkaikar et al. 2011). ALPS-FAS is
and approved in adults for thromboprophylaxis inherited in an autosomal dominant manner. In
after hip and knee arthroplasty, treatment of rare cases, ALPS is caused by mutations in the
venous thromboembolism and stroke prevention genes encoding Fas ligand (ALPS-FASLG) or
in atrial fibrillation. They are currently being caspase 10 (ALPS-CASP10) (Magerus-Chatinet
evaluated in children in international studies. et al. 2013; Zhu et al. 2006). The Fas/Fas ligand
Pediatric studies are required before usage (FasL) pathway in implicated in the defective
because of uncertainties about dosing, effective- lymphocyte apoptosis, leading to expansion of
ness and safety related to differences in children antigen-specific lymphocyte populations.
compared to adults. Children are different from The diagnostic criteria for ALPS has been
adults for many reasons, including developmen- revised multiple times, with the most recent
tal hemostasis, pharmacokinetics/pharmocody- being published in 2010 (Table 11.4) (Oliveira
namics, renal function, and hepatic function. et al. 2010). The main laboratory abnormalities
include the expansion of CD4 and CD8 negative
T cells (or double-negative T [DNT] cells) in
Autoimmune Lymphoproliferative blood and tissue, elevated interleukin-10 (IL-10)
Syndrome (ALPS) in blood, elevated vitamin B12, and defective Fas-
mediated apoptosis in vitro. A definitive diagno-
ALPS is caused by dysregulation of the immune sis of ALPS is based upon the presence of both
system, specifically due to an inability to regulate required criteria and one primary accessory crite-
lymphocyte apoptosis (Rao and Oliveira 2011). rion. A probable diagnosis is based upon the
Such deregulation leads most commonly to lympho- presence of both required criteria plus one sec-
proliferative disease and less often autoimmune dis- ondary accessory criterion. Important differential
ease. Manifestations of lymphoproliferative disease, diagnoses include lymphoma, immunodeficiency
such as lymphadenopathy, hepatomegaly, spleno- disorders, and autoimmune disorders.
megaly, occur most commonly in children with a The management of ALPS should focus on
median age of onset being 2.7–3 years (Neven et al. three domains: management of clinical manifes-
2011; Price et al. 2014). Autoimmune disease is tations, preventing complications and curative
more common in adult onset ALPS. The exact inci- therapy. The treatment of lymphoproliferation
dence and prevalence of ALPS are unknown. There and autoimmune disease, the two main manifes-
is a proven male predominance, with male to female tations, is based mostly on clinical experience
ratio being 2.2 in the French cohort and 1.6 in NIH and observational studies. Immunosuppressants
cohort (Neven et al. 2011; Price et al. 2014). such as steroids, sirolimus, tacrolimus, cyclospo-
The majority of patients with ALPS (approxi- rine, and mycophenolate mofetil have been used
mately 67%) have a confirmed genetic defect, with some success. The benefits, however, need
with majority having a germline mutation in the to be weighed with side effects (Bleesing 2003;
Table 11.4 Diagnostic criteria for ALPS

Required Primary accessory Secondary accessory
– Chronic (>6 months) – Defective lymphocyte – Positive family history
nonmalignant, noninfectious apoptosis (assay repeated – Elevated plasma levels of soluble Fas ligand
lymphadenopathy, at least once) (FasL), interleukin-10 (IL-10), vitamin B12, or
splenomegaly, or both – Somatic or germline interleukin-18 (IL-18)
– Elevated CD4−/CD8− T cells pathogenic mutations in – Autoimmune cytopenias with elevated
with normal or elevated FAS, FASLG, or CASP10 (polyclonal) immunoglobulin G (IgG) levels
lymphocyte counts – Typical immunohistologic findings as determined
by an experienced hematopathologist (see
‘Laboratory findings’ above)

Rao et al. 2005; Teachey et al. 2010). Due to side Table 11.5 Inherited and acquired causes of aplastic
effects and return of symptoms post-anemia
discontinuation, immunosuppression is reserved Inherited Fanconi anemia
for severe and life-threatening complications Dyskeratosis congenita
(Bleesing 2003). Patients with autoimmune man- Schwachman Diamond syndrome
ifestations (such as autoimmune cytopenias) have Congenital amegakaryocytic
thrombocytopenia
a harder time discontinuing immunosuppression
Diamond Blackfan anemia
than those with only lymphoproliferation. Of
Reticular dysgenesis
note, IVIG monotherapy has been successful in
GATA-2 syndromes
some patients to manage cytopenias (Bleesing
Acquired Viruses: Hepatitis, Parvo, EBV, CMV,
2003). The most frequent complication of ALPS VZV, HSV, HIV
and its therapies is infection. Prophylactic anti- Drugs/chemicals: chemo, benzenes,
microbials to prevent opportunistic, fungal and chloramphenicol, anti-epileptics,
viral infections are warranted in some cases. anti-inflammatory, sulfonamides,
Patients with signs or symptoms of infection quinine, anti-histamines, lindane
should be worked up and treated aggressively. Radiation
Paroxysmal nocturnal hematuria
The only curative therapy for ALPS is hema-
Immune: eosinophilic fasciitis, systemic
topoietic stem cell transplantation (HSCT), and
lupus erythematous, graft versus host
it is generally done with reduced-intensity con- disease
ditioning regimens to minimize morbidity and Myelodysplasia
mortality (Sleight et al. 1998). It is offered after Pregnancy
careful discussion of risks versus chance of CMV cytomegalovirus, EBV Epstein-Barr virus, HIV
success in each patient. Some transplant indica- human immunodeficiency virus, HSV herpes simplex
tions include development of lymphoma, severe virus, VZV varicella zoster virus
recurrent infections, severe refractory autoim-
mune cytopenias, or severe disease type at immune response, oligoconal T-cell expansion,
diagnosis. and cytotoxic T-cell mediated suppression of
hematopoietic progenitors. In acquired aplastic
anemia, there is absence of abnormal infiltrates
Acquired Aplastic Anemia and normal reticulin.
in Children Aplastic anemia patients usually present with
signs and symptoms from cytopenias: bruising
Aplastic anemia is a disorder of abnormal bone and bleeding secondary to thrombocytopenia;
marrow function, which leads to pancytopenia. fatigure and pallor due to anemia; and fever,
Inherited and acquired causes of aplastic anemia infection and ulcerations because of neutrope-
are listed in Table 11.5. Acquired aplastic anemia nia. Complete blood count will help to identify
is most common, and within acquired 70–80% of cytopenias, but the definitive diagnosis of aplas-
children have idiopathic aplastic anemia and no tic anemia is made by bone marrow aspiration
identifiable risk factor (Guinan 2009). The inci- and biopsy. Some features on bone marrow
dence of aplastic anemia in children is estimated examination include decreased cellularity, mar-
to be 2 per million, with an equal incidence in row invasion by fat and stroma cells, and
boys and girls. reduced but morphologically normal hemato-
The pathophysiology of aplastic anemia is poietic cells.
thought to be loss of pluripotent hematopoietic Aplastic anemia is classified as moderate,
stem cells due to injury from autoimmunity or severe or very severe. Moderate aplastic anemia
external toxins (Young et al. 2010). Some possi- is defined by decreased bone marrow cellularity
ble theories behind immune-mediated attack of (<50%), depressed two out of three cell lines
hematopoietic stem cells include aberrant (anemia with absolute reticulocyte counts [ARC]

326 Z. Solh et al.
<60,000 μL−1, absolute neutrophil count [ANC] actors That Affect the Neutrophil

F
<1500 μL−1, platelet counts <100,000 μL−1), and Count
not meeting criteria for severe aplastic anemia
(SAA). SAA is defined as <25% bone marrow Normal values for absolute neutrophil count are
cellularity or 25–50% bone marrow cellularity age-dependent. At birth, neutrophils can consti-
with <30% hematopoietic cells and severe tute up to 70% of white blood cells (minimum
depression of two out of three cells lines defined 6000 μL−1), and at 1 week to 1 month of age they
by ARC <40,000 μL−1, ANC <500 μL−1, platelets range from 30% to 45% (minimum 1000 μL−1)
<20,000 μL−1. Very severe aplastic anemia is rising again at 6–8 years of age to over 50%
defined by the same criteria as SAA, but having (minimum 1500 μL−1). Adult levels can approach
an ANC <200 μL−1 (Hartung et al. 2013). 60% (Segel and Halterman 2008).
The management of aplastic anemia consists Normal neutrophil values are also race-
of two potential therapies: (1) immunosuppres- dependent. At least 3–5% of children of African
sive therapy (IST) or HSCT (Davies and Guinan descent have a neutrophil count below 1500 μL−1
2007; Young et al. 2006). For those children who without any underlying pathology.
have a matched sibling donor, the preferred The neutrophil count may be affected by med-
option for treatment is HSCT. For the rest of ications. Steroid medications demarginate neu-
children, IST is the preferred treatment modality. trophils from the vascular wall raising the
IST regimens consist of combination of antithy- neutrophil count. Hormonal therapy with granu-
mocyte globulin ATG, clyclosporine, steroids locyte colony stimulating factor drives stem cells
and sometimes growth factors (Davies and to produce neutrophils.
Guinan 2007). The response rate for IST is
around 70–75% at 3–6 months, but the long-
term event free survival is 40–50% at 10 years. igns and Symptoms
S
HSCT on the other hand has a much better long- of a Neutropenic Child
term event free survival up to 90%, however
there are important side effects such as graft ver- The clinical manifestations of neutropenia
sus host disease, infertility, and secondary malig- include: oral ulceration, gingival inflammation,
nancy that need to be considered. HSCT is otitis media, cellulitis, pustules, adenitis, pneu-
offered to patients without matched sibling monia, perianal infection, ischio-rectal fossa
donors at relapse post-IST. abscess, and sepsis. Implicated organisms com-
Along with curative therapy, it is extremely monly include Staphylococcus aureus from the
important to provide adequate supportive care for patient’s own skin flora, and gram negative
aplastic anemia patients. Supportive includes organisms from the gastrointestinal flora
prompt and aggressive management of infections (Walkovich and Boxer 2013).
as well as transfusion support for cytopenias.
anagement of a Neutropenic
M
Neutropenia Patient
Neutropenia in children is divided into four cate- The evaluation of a child with neutropenia should
gories based on severity: (1) mild (1000 to not only include screening questions for the
1500 μL−1), (2) moderate (500–1000 μL−1), (3) above manifestations, but also a detailed family
severe (200–500 μL−1), and (4) very severe (below history and physical examination to rule out con-
200 μL−1). The severity of the neutropenia corre- genital anomalies, which can indicate an inher-
lates with susceptibility to severe bacterial infec- ited cause. Acquired neutropenia is more
tion, and the duration of the neutropenia common than the inherited form. It can be
compounds this risk. induced by infection (viral or bacterial), drugs,

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Update in Pediatric Hospital
Medicine 12
Elizabeth J.N. Davis and Ricardo Quinonez
Acute Viral Bronchiolitis Society (CPS) published updated recommenda-

tions on the diagnosis, management, and preven-
Introduction tion of bronchiolitis in November of 2014 (Ralston
et al. 2014; Friedman et al. 2014). As a reflection
Bronchiolitis is the most common cause of hospi- of most of the literature that surrounds the man-
talization for infants less than 12 months of age agement of this challenging entity, the new guide-
with the disease causing approximately 100,000 lines contain a majority of action statements that
annual hospitalizations in the United States recommend against the use of tests and therapies.
(Ralston et al. 2014; Friedman et al. 2014; Table 12.1 summarizes the major updates between
Hasegawa et al. 2013). A significant amount of the AAP 2006 and 2014 iterations.
literature on this subject has been published since
the first 2006 iteration of the American Academy
of Pediatrics (AAP) Clinical Practice Guideline Background
(American Academy of Pediatrics Subcommittee
on Diagnosis and Management of Bronchiolitis Viral lower respiratory tract pathogens are the
2006). Both the AAP and the Canadian Paediatric cause of bronchiolitis in infants and children
less than 2 years old. The disorder is self-limit-
ing and is characterized by edema, acute inflam-
E.J.N. Davis, M.D., F.A.A.P (*) mation, and necrosis of the epithelial cells lining
Division of Pediatric Hospital Medicine,
the small airways combined with increased
Baylor College of Medicine, mucous production. The clinical patient mani-
Houston, TX, USA festations typically include cough and rhinitis at
The Children’s Hospital of San Antonio, the start of the illness that often progresses to a
San Antonio, TX, USA variable degree of respiratory distress with
e-mail: Elizabeth.Davis2@bcm.edu; accessory muscle use, tachypnea, wheezing,
Elizabeth.davis2@christushealth.org
rales, nasal flaring, and/or hypoxia. Those with
R. Quinonez, M.D. a mild manifestation of symptoms can often be
Division of Pediatric Hospital Medicine,
managed as an outpatient, but many still require
Baylor College of Medicine, hospitalization for supportive care of moderate
Houston, TX, USA to severe disease (Ralston et al. 2014; Friedman
Texas Children’s Hospital, Houston, TX, USA et al. 2014; Agency for Healthcare Research and
e-mail: Quinonez@bcm.edu Quality 2003). The decision to admit a patient


332 E.J.N. Davis and R. Quinonez
Table 12.1 Key changes in recommendations for round (Agency for Healthcare Research and
the management of acute viral bronchiolitis in 2014
Quality 2003).
(Ralston et al. 2014; American Academy of Pediatrics
Subcommittee on Diagnosis and Management of
Bronchiolitis 2006)
Bronchodilators • Do not administer Diagnosis
bronchodilators (albuterol,
salbutamol, epinephrine) The diagnosis of bronchiolitis should be made
• Monitored trial no longer clinically with history and physical exam. The
recommended
provider should use the clinical assessment to
Hypertonic saline • Not mentioned in 2006
guideline distinguish between viral bronchiolitis and other
• Do not give in outpatient or disorders, characterize the severity of illness, and
emergency department settings identify risk factors for severe disease. Both
• Option to give in hospitalized
guidelines recommend against routine use of
patients
chest x-rays, viral testing, or other lab testing as
Oxygen • No need to give if oxygen
saturation is >90% these studies do not correlate with disease sever-
• No need to use continuous pulse ity or clinical outcomes, provide no value to the
oximetry patient, and may lead to unnecessary antibiotics
Corticosteroids • Do not administer (upgraded or hospitalizations (Ralston et al. 2014; Friedman
from do not give routinely)
et al. 2014; Mansbach et al. 2012; Swingler et al.
Hydration • Administer nasogastric or
intravenous fluids if unable to
1998; Schuh et al. 2007).
take fluids orally
Palivizumab • Do not give to otherwise healthy
infants with gestational age Management
≥29 weeks, 0 days
Second-hand • Inquire about second-hand The mainstay of treatment in bronchiolitis is sup-
smoke exposure smoke exposure
• Counsel about risks of exposure portive care with nasal suctioning and supple-
mental oxygen if needed. Providers should not
give antibiotics to patients with viral bronchiol-
should be based on clinical judgment with itis unless there is a concomitant bacterial infec-
assessment of the respiratory status, ability to tion, and they should not give corticosteroids or
maintain hydration, risk of severe disease pro- use chest physiotherapy (Ralston et al. 2014;
gression, and the family’s ability to care for the Friedman et al. 2014).
patient at home (Friedman et al. 2014).
Respiratory syncytial virus (RSV) is the most Bronchodilators
common etiology of bronchiolitis (Agency for Several studies, including many meta-analyses
Healthcare Research and Quality 2003; Miller and systematic reviews on the use of bronchodi-
et al. 2013; Mullins et al. 2003). Other viruses lators in bronchiolitis, have shown a lack of effect
that cause the same clinical manifestations on need for hospitalization, disease resolution, or
include human rhinovirus, influenza, coronavi- length of stay (LOS), and the effect they may
rus, human metapneumovirus, and parainfluenza have on clinical symptom scores is transient
virus (Miller et al. 2013). December through (Ralston et al. 2014; Friedman et al. 2014; Kellner
March is typically the time with the highest inci- et al. 1996; Flores and Horwitz 1997; Zorc and
dence of RSV, but regional variations demon- Hall 2010; Wainwright 2010; Gadomski and
strate high RSV prevalence as early as August Scribani 2014). As such, a major change to the
and as late as May (Mullins et al. 2003; Centers treatment recommendations in the AAP guide-
for Disease Control and Prevention 2013). Also, line and also included in the CPS guideline is the
some of the other viruses are present in other recommendation against the use of bronchodila-
months meaning bronchiolitis can be seen year tors (albuterol or salbutamol) for bronchiolitis,

12 Update in Pediatric Hospital Medicine 333
even as a trial (Ralston et al. 2014; Friedman Zhang et al. 2008). Both guidelines suggest that
et al. 2014). HTS may be used on hospitalized patients due to
Both guidelines also recommend against the some available literature showing a reduction in
use of nebulized epinephrine in hospitalized length of stay (LOS) (Zhang et al. 2008, 2015;
patients with bronchiolitis due to multiple studies Badgett et al. 2015). The published literature,
and reviews showing lack of effect on LOS or however, had inconsistent findings on this poten-
other outcomes such as change in respiratory tial effect, and the reduction in LOS only involved
rate, respiratory effort, or time on oxygen patient populations with an average LOS of
(Hartling et al. 2003, Hartling et al. 2011a, b; >3 days (the average LOS in the US is 2.4 days)
Wainwright et al. 2003; Skjerven et al. 2013). (Ralston et al. 2014; Friedman et al. 2014; Brooks
One large multicenter study also found that using et al. 2016).
it on a fixed schedule prolonged LOS (Skjerven Since the publications of the guidelines, newer
et al. 2013). The use of epinephrine in the emer- evidence suggests that the original reported ben-
gency department or outpatient setting, however, efits of HTS may have been overstated. First, the
remains controversial. One large, multicenter, results of two US randomized controlled trials
randomized, double-blind, placebo-controlled failed to show any effect of HTS as it relates to
trial with 800 infants compared hospitalization length of stay. Second, in June of 2016, Brooks
rates over 7 days between four study groups: neb- et al. (2016) published a reanalysis of the studies
ulized epinephrine plus oral dexamethasone, included in two prior meta-analyses. Among the
nebulized epinephrine plus oral placebo, nebu- 18 RCTs reporting LOS as an outcome, they
lized placebo plus oral dexamethasone, and neb- found two main sources of excessive heterogene-
ulized placebo plus oral placebo (Plint et al. ity. First, there was an outlier study population
2009). They found that the group receiving epi- with significantly different discharge criteria and
nephrine combined with dexamethasone was less substantially longer than expected LOS. Second,
likely to be hospitalized by day 7 than the double they found baseline differences between the
placebo group. However, when they adjusted for treatment arms in the day of illness at enrollment
multiple comparisons, this difference was no lon- resulting in a systematic bias favoring the treat-
ger statistically significant. A Cochrane review ment arm in most of the small positive studies
(Hartling et al. 2011a) also found that rates of (those presenting later in illness were more likely
hospital admissions were reduced on the day of to be allocated to the HTS group). Once the
the first emergency department visit but not over- authors controlled for these factors to resolve the
all (by day 7). While the CPS guideline suggests heterogeneity, HTS no longer had any effect on
that providers may trial a dose of nebulized epi- LOS.
nephrine with careful monitoring of clinical
response, the AAP guideline cautions against its Suctioning
use since home use is not routine, and the tran- Nasal suctioning has long been a common thera-
sient effect seen during observation does not peutic intervention to clear the increased mucous
affect the overall course of the illness (Ralston produced in bronchiolitis and temporarily reduce
et al. 2014; Friedman et al. 2014). increased work of breathing. Despite the obvious
reasons for use as a supportive measure, very lit-
Hypertonic Saline tle data exists on the role of suctioning in the
New for the AAP 2014 management guideline management of patients with bronchiolitis. A ret-
and also included in the CPS guideline are rec- rospective cohort study published in 2013
ommendations on the use of hypertonic saline (Mussman et al. 2013) assessed the relationships
(HTS). HTS should not be administered to between frequency and type of suctioning with
patients in the outpatient or emergency depart- LOS. The authors hypothesized that repeated
ment settings as it has no effect on hospitalization nasopharyngeal suctioning (“deep” suction),
rates (Ralston et al. 2014; Friedman et al. 2014; compared to noninvasive nasal suctioning, would

lead to worse outcomes due to local trauma and groups. There was no difference in parent satis-
that frequent noninvasive suctioning would faction scores between the groups, but the NG
improve outcomes. Infants 2–12 months of age route had a higher success rate of insertion and
were included with 740 infants in the device type fewer required attempts of insertion than the IV
cohort (deep vs noninvasive suctioning) and 695 route (Oakley et al. 2013). More recently, a
infants in the suctioning lapse cohort. They descriptive, retrospective cohort study exam-
excluded patients who were intubated, with a trained the use of NG fluids in infants <2 months
cheostomy, admitted to the PICU, or who had a of age with bronchiolitis and found no differ-
LOS less than 12 h and included only index ence in the rate of adverse events between the
admissions. The percentage of deep suctioning NG and IV groups, no aspiration events, and no
exposures in the first 24 h of admission were cal- difference in LOS (Oakley et al. 2016).
culated and categorized into four ranges, and the
data was analyzed using a multivariable model Oxygen
adjusted for inverse weighting of propensity to Over the past two decades, the hospitalization
receive deep suctioning. For the suctioning lapse rate of children with bronchiolitis has signifi-
group, the number of sequential suctioning events cantly increased while the mortality rate has
separated by more than 4 h was counted for the remained constant. One of the implicated con-
first 24 h of admission. They found a statistically tributors to this rise in hospitalizations is the
significant association of increased length of stay increased use of pulse-oximetry during this time
for the group that had deep suctioning in the first (Schroeder et al. 2004). Oxygen saturation does
24 h and for those with lapses greater than 4 h not correlate with and is not a proxy for respira-
(mean difference 0.6 days and 1 day, respec- tory distress (Wang et al. 1992), and yet it has
tively). While further studies are needed, this been shown to be a main factor in the decision to
study suggests that aggressive nasopharyngeal admit and lengthening of LOS (Ralston et al.
(“deep”) suctioning may prolong LOS, and 2014; Schroeder et al. 2004; Cunningham and
patients benefit from frequent less aggressive McMurray 2012). Physiologically, when the oxy-
nasal suctioning. These findings complement a gen saturation is 90%, it takes much higher eleva-
prior study from 2011 on predictors of LOS in tions in the arterial pressure of oxygen to cause
bronchiolitis that also found a significant associa- further increases in the saturation versus when
tion between nasopharyngeal suctioning early in the saturation is <90%, and increasing satura-
the hospitalization and increased LOS tions above the 90% threshold has no clear clini-
(Weisgerber et al. 2011). cal benefit (Ralston et al. 2014; Anaesthesia UK
2005). Also, studies on healthy infants show that
eeding and Hydration
F transient hypoxemia occurs commonly without
Infants with poor feeding or difficulty feeding apparent harm (Hunt et al. 1999), and the inter-
safely due to level of respiratory distress may mittent hypoxemia that asthmatic children expe-
receive either nasogastric (NG) or intravenous rience does not cause intellectual impairment or
fluids (Ralston et al. 2014; Friedman et al. behavioral problems (Rivetveld and Colland
2014). The inclusion of NG fluids is new to the 1999; Bender et al. 1987). Based on this data,
AAP guideline recommendations, and hydra- both guidelines give the recommendation that
tion via this route appears to be safe for both providers may choose not to use oxygen in
older and young infants (Oakley et al. 2013, patients with oxyhemoglobin saturations equal to
2016). A multicenter, open, randomized trial or higher than 90% (Ralston et al. 2014; Friedman
(Oakley et al. 2013) comparing NG and IV fluid et al. 2014) or use continuous pulse-oximetry in
therapy in infants 2–12 months of age with infants and children with bronchiolitis (Ralston
bronchiolitis found no significant difference in et al. 2014). More data has since been published
length of stay, escalation of care, need for venti- that further supports this recommendation
lator support, or adverse events between the (Cunningham et al. 2015; McCulloh et al. 2015).

Cunningham et al. (2015) performed a multi- and expected course of the illness (Ralston et al.
center, randomized, controlled, double-blind 2014).
equivalence study to see if the ≥90% target for
infants with bronchiolitis was equivalent to the
≥94% target for illness resolution. To accomplish Urinary Tract Infections
this, they randomly assigned one group of infants With and Without Bacteremia
(307) to be connected to a modified oximeter that
would display a measured value of 90% as 94%. Summary of Updated Guideline
Another group of infants (308) were placed on a
standard oximeter that displayed the accurate Urinary tract infections (UTIs) are the most com-
measured values. Each group only received oxy- mon serious bacterial infection (SBI) in young
gen if the displayed value was <94%, as was the children (Roberts et al. 2011; Roman et al. 2015),
standard practice. They found that the ≥90% and the diagnosis and treatment of infants and
oxygen saturation target to be equally safe and young children with febrile UTIs has seen major
effective as the ≥94% target with no difference changes over the past few years. The AAP pub-
between the groups in adverse events or escala- lished an updated clinical practice guideline in
tion of care. The modified group also had a sig- 2011 for the diagnosis and management of an ini-
nificantly shorter LOS and time on oxygen but tial febrile UTI in the 2–24 month ages (Roberts
fewer readmissions and no increase in post- et al. 2011). One of the most important changes
discharge parental anxiety. In a multicenter, ran- included requiring both the evidence of infection
domized, superiority trial, McCulloh et al. (2015) in the urinalysis (pyuria and/or bacteriuria) and
studied the effect of intermittent versus continu- the presence of at least 50,000 colony-forming
ous pulse-oximetry use on LOS in nonhypoxemic units (CFUs) per ml in the urine culture of a spec-
bronchiolitis patients. While they found similar imen obtained by catheterization or suprapubic
LOS in both groups, the intermittent group did aspiration to positively diagnose a UTI. The
not have more escalations of care or require more guideline now recommends against the routine
diagnostic or therapeutic interventions suggest- use of a voiding cystourethrogram (VCUG) after
ing that providers can routinely consider using the initial febrile UTI. They advise instead to
intermittent pulse-oximetry monitoring on screen with a renal and bladder ultrasound
patients with bronchiolitis who are clinically (RBUS). A VCUG is then only advised if the
improving. RBUS shows hydronephrosis, scarring, or other
signs of high-grade vesicoureteral reflux or
obstructive uropathy, or for recurrent febrile
Prevention UTIs (Roberts et al. 2011).
Exposure to tobacco smoke increases both the

severity of the illness and the risk for hospitaliza- Diagnosing a UTI in Young Infants
tion. Providers should screen every patient with
bronchiolitis for tobacco smoke exposure, coun- The updated guideline included the requirement
sel the caregivers about the risks associated with of evidence of pyuria in the UA to diagnose a
it, and provide recommendations and resources UTI to distinguish a true UTI from asymptomatic
for smoking cessation to these families. Providers bacteriuria since the presence of pyuria indicates
should also recommend and encourage exclusive the presence of the inflammatory response of a
breastfeeding for at least 6 months to reduce the true infection (Roberts et al. 2011; Roberts 2015).
incidence and severity of bronchiolitis. Shared However, concerns over the sensitivity of the UA
decision-making between provider and caregiver in young infants continued since the guideline
can happen if the provider educates about the did not include infants <2 months of age and
evidence-based diagnosis, treatment, prevention, since the sensitivity of a UA in children has been

reported as 75–85% (Schroeder et al. 2015). The (RIVUR) trial (Hoberman et al. 2014) showed
question, however, is whether a negative UA with that prophylactic antibiotics (trimethoprim-
a positive urine culture represents a false-negative sulfamethoxazole) reduced the risk of recurrent
UA or a false-positive urine culture (asymptom- UTI in children with VUR by 50% and was
atic bacteriuria) in febrile infants. To assess the particularly effective in those whose initial
diagnostic accuracy of the UA in generally UTI was febrile and in those with baseline
healthy febrile infants <3 months of age, bowel or bladder dysfunction. When compar-
Schroeder et al. (2015) used a population of ing the effect based on severity of VUR,
infants with a bacteremic UTI (defined as the though, prophylaxis was more effective in
same organism in the urine and blood with those with grades I–II reflux vs the higher risk
≥50,000 CFUs per ml in the urine culture) from a grades III–IV. Also, they did not find a differ-
multicenter database to represent those with true ence in the occurrence of renal scarring
infection (245 infants). To calculate UA specific- between the study and placebo groups, and the
ity, they used a sample of febrile infants study group had a 3.3 times higher rate of
<3 months of age who had a negative urine cul- resistant organisms causing the recurrent infec-
ture in their workup for a serious bacterial infections (Hoberman et al. 2014).
tion (115 infants). Leukocyte esterase had a The question about the effect of prophylactic
sensitivity of 97.6% (95% CI 92.5–99.2%) and a antibiotics on the occurrence of renal scarring
specificity of 93.9% (95% CI 87.9–97.5%). could not truly be answered by this study given
Pyuria (>3 white blood cells/high-power field) that it was underpowered to detect this outcome.
had a sensitivity of 96% (95% CI 92.5–98.1%) While the RIVUR trial shows the effectiveness of
and a specificity of 91.3% (95% CI 84.6–95.6%). prophylactic antibiotics in preventing recurrent
The results did not differ significantly between UTIs in children with VUR, others have ques-
infants ≤30 days old and infants >30 days old. tioned the efficiency of this management
This study highlights the UA as a highly sensitive approach (Afshar 2014; Cara-Fuentes et al.
test in diagnosing a UTI. While the authors 2015). Based on the number needed to treat, one
acknowledge that the results could be due to would have to treat eight children for 2 years with
spectrum bias, they discuss the literature that prophylactic antibiotics to prevent one UTI
supports a lack of difference between non- (Afshar 2014). Others have highlighted the fact
bacteremic and bacteremic UTIs (discussed that it takes 2 years to see a significant difference
below) (Roman et al. 2015; Schroeder et al. in the rate of UTIs, that the difference was only
2016). The discrepancy between these results seen in patients younger than 2 years old with
showing the high sensitivity of UA and the prior grades I–II VUR vs grades III–IV, and that the
lower sensitivities reported is more likely due to resolution of VUR seen in many of the patients
the urine culture being a faulty gold standard that may have contributed to the effects (Cara-Fuentes
was used in prior studies with many of the posi- et al. 2015).
tive urine cultures representing asymptomatic The decision of whether to use prophylactic
bacteriuria (Schroeder et al. 2015; Roberts 2015). antibiotics continues to be multifactorial.
Providers should consider factors such as morbid-
ity related to UTIs, costs, side effects, the potential
rophylactic Antibiotics in Children
P for resistant organisms, the number needed to
with Vesicoureteral Reflux treat, the likelihood of compliance, and parent
preference with shared decision-making. It is also
Whether to give prophylactic antibiotics to worth highlighting that the natural history of VUR
infants and young children with vesicoureteral is self-resolution in almost all but the worse cases
reflux (VUR) remains a source of debate. (Roberts et al. 2011). Looking instead at sub-
The results of the Randomized Intervention groups of patients who may be the most likely to
for Children with Vesicoureteral Reflux benefit, such as those with bowel and bladder dys-

function, may be the wiser choice in the ongoing to longer hospitalizations with parenteral therapy
debate of UTI prophylaxis (Afshar 2014). (Honkinen et al. 2000; Magin et al. 2007;
Averbuch 2014; Brady et al. 2010).
Expanding on this, Schroeder et al. (2016)
Bacteremic UTIs conducted a multicenter, retrospective cohort
study to assess the predictors of parenteral antibi-
A significant amount of evidence supports the otic duration and the association between this
conclusion that oral and parenteral antibiotics are treatment duration and relapses within 30 days in
equally efficacious in infants and young children infants <3 months of age with a bacteremic
with febrile UTIs (Roberts et al. 2011; Hoberman UTI. They included 251 infants with a bactere-
et al. 1999; Strohmeier et al. 2014). These mic UTI from 20 hospitals in 11 healthcare insti-
patients do not routinely require hospitalization tutions across the United States, excluding those
for parenteral antibiotics unless the patient is with major comorbidities or indwelling urinary
ill-appearing or cannot tolerate oral intake well or central venous catheters at the time of cultures
enough to maintain hydration (Roberts et al. and those initially managed in the ICU. They
2011). How to manage patients with a bacteremic again found significant variability in the duration
UTI (same organism in urine and blood) and of parenteral antibiotics with the most prevalence
when to obtain a blood culture in patients with a at 3, 7, 10, and 14 days but without impact on
UTI pose challenges that the current guidelines outcome. None had a relapsed bacteremic UTI,
do not address. However, current evidence dem- and none deteriorated during treatment. Only six
onstrates that despite variability in management, had a relapsed non-bacteremic UTI with the same
there is little difference in clinical outcome organism (2.4%, 95% CI 0.8–5.1%), but these
(Roman et al. 2015; Schroeder et al. 2016). were associated with an abnormal VCUG, and
Multiple studies have demonstrated that bactere- there was no difference in duration of parenteral
mic UTIs occur infrequently with the prevalence antibiotics in those with and without relapsed
decreasing with increasing age, and patients with non-bacteremic UTI. Institutional practices
and without bacteremia lack easily identifiable accounted for some of the variability in duration,
clinical differences (Hoberman et al. 1999; and they found five independent predictors of
Honkinen et al. 2000; Schnadower et al. 2010; duration that only partially accounted for vari-
Newman et al. 2002). In 2015, Roman et al. ability. Older age, female gender, and year of
(2015) published a retrospective, cross-sectional, blood culture were associated with a slightly
double cohort study from a large institution that shorter course while a positive repeat blood cul-
confirmed these findings. In addition, the study ture during acute treatment and a non-E. coli
demonstrated the decline in number of blood cul- organism lengthened treatment, although only
tures obtained in infants with UTIs between 1998 13.5% of infants had the latter factors. Rather
and 2012 (study period), the different treatment than clinical response to therapy guiding the
courses, and yet equal 30-day outcomes in infants duration of parenteral antibiotics, the tendency
<1 year of age with UTIs with and without bacte- toward certain numbers of days (3, 7, 10, 14 days)
remia. Despite the considerable variation in man- suggests that providers instead pick a fixed num-
agement of bacteremic infants, (parenteral ber of treatment days (Schroeder et al. 2016).
antibiotics ranged from 0 to >14 days), the clini- These large, retrospective studies provide the
cal outcomes were excellent with no infant hav- largest sets of data that demonstrate bacteremic
ing a recurrent UTI within 30 days, requiring UTIs may be no different than non-bacteremic
ICU transfer or other escalation of care, having a UTIs. They question the need for blood cultures in
positive CSF culture in those tested, or having a infants with a UTI and show lack of apparent ben-
positive repeat blood culture (Roman et al. 2015). efit of prolonged hospitalizations and p arenteral
Despite these findings, this study and other litera- antibiotics for infants with a bacteremic UTI who
ture has found that detection of bacteremia leads have recovered clinically, especially in the face of

more obvious risks of hospitalization (Roman the discussion about the changing types and
et al. 2015; Schroeder et al. 2016). causes of SBI in young infants (Biondi et al.
2013; Mischler et al. 2015). These studies dem-
onstrate that current empiric antibiotic strategies
Bacteremia in Young Infants for treating young infants at risk for SBI may be
outdated as the epidemiology of bacterial patho-
Changing Epidemiology gens changes over time.
While fever without a localizing source in young

infants continues to be a common problem and Time to Blood Culture Positivity
presents a clinical dilemma, the changing epide-
miology of serious bacterial infections (SBI) in Another changing trend in the inpatient evalua-
this age group has largely been understudied with tion of otherwise healthy febrile infants ≤90 days
few changes in the choice of empiric antibiotic of age is the length of the observation period. The
therapy (Biondi et al. 2013; Mischler et al. 2015). standard to observe these infants for 48–72 h was
Not only has vaccine development largely set during a time when blood cultures were man-
reduced the incidence of bacteremia and menin- ually assessed at infrequent intervals (Biondi
gitis, but also the change in epidemiology over et al. 2014). Now that most laboratories use con-
the past two decades is largely the result of tinuous, automated monitoring systems, the time
changes in screening and treatment for group B to detection of bacterial growth is significantly
Streptococcus (GBS) prior to delivery and more shorter. In a large, multicenter, retrospective
rigorous food safety guidelines (Mischler et al. study, 91%, 96%, and 99% of the pathogenic
2015). Many studies characterizing the epidemi- blood cultures in this patient population turned
ology of bacteremia during this era were limited positive by 24, 36, and 48 h, respectively (Biondi
by small sample sizes and geographic isolation et al. 2014). These findings combined with the
(Biondi et al. 2013; Mischler et al. 2015). In overall low rate of bacteremia in this age group
2013, Biondi et al. (2013) published the first suggest that a 24 h observation period is adequate
large, geographically diverse study to identify the to detect most clinically significant bacteremia.
causes of bacteremia in otherwise healthy febrile The impact of this is noteworthy given the possi-
infants ≤90 days old outside of the intensive care bility of significant decreases in length of stay for
unit (ICU). They performed a retrospective this common reason for hospitalization in infants.
review of positive blood cultures of this patient Safely reducing the observation time of many
population admitted to general inpatient units infants in this patient population can reduce the
across six hospital systems across the United risks, costs and complications associated with
States. They found that in the 181 patients with hospitalization (Biondi et al. 2014).
pathogenic blood cultures, E. coli was the most
prevalent organism, GBS was the second most
prevalent, and they found no Listeria monocyto- rief Resolved Unexplained Event
B
genes (Biondi et al. 2013). Similarly, in the fol- (BRUE)
low-up study published in 2015 (Mischler et al.
2015) with a larger, more nationally representa- Introduction
tive sample (392 samples from 17 sites across the
country), they again demonstrated that E. coli An apparent life-threatening event (ALTE) is
was the most prevalent, followed by GBS with no defined as “an episode that is frightening to the
cases of Listeria monocytogenes. Both studies observer and that is characterized by some
also discussed the rates of concurrent UTI and combination of apnea (central or occasionally

meningitis for each pathogen and contribute to obstructive), color change (usually cyanotic or

pallid but occasionally erythematous or pletho- conditions that high risk infants may have
ric), marked change in muscle tone (usually (Tieder et al. 2016).
marked limpness), choking, or gagging. In some
cases the observer fears that the infant has died.”
(National Institutes of Health 1987) This defini- Definition
tion comes from a consensus development con-
ference held in 1986 by the National Institutes of A BRUE is defined as an event occurring in an
Health with the purpose of addressing the rela- infant less than 1 year of age that the observer
tionship between sudden infant death syndrome describes as sudden, brief, resolved, and includ-
(SIDS) and apnea and the safety and effective- ing ≥1 of the following: cyanosis or pallor;
ness of home monitoring (National Institutes of absent, decreased, or irregular breathing; marked
Health 1987). Young patients are often hospital- change in tone, meaning hyper- or hypotonia;
ized for observation after having an ALTE largely and an altered level of responsiveness (see
because of the uncertainty providers and parents Table 12.2 for full list of inclusion and exclusion
feel in knowing if the patient is at risk for a repeat criteria). The term BRUE should be used as the
event or if there is a serious underlying condition diagnosis only when there is no explanation for
that precipitated such an event. Much of this the event after obtaining an appropriate history
uncertainty comes from the lack of specificity in and physical exam. For instance, if fever, nasal
the definition of an ALTE and the lack of consen- congestion, and increased work of breathing are
sus on how to manage a well-appearing patient present, then the event may be explained by a
who had an unexplained ALTE (Tieder et al. temporary airway obstruction from a viral infec-
2013, 2016). tion. Alternatively, an event with choking after
In May 2016, the American Academy of feeding and spitting up may indicate gastro-
Pediatrics published the first clinical practice esophageal reflux (GER) or another gastrointesti-
guideline for the evaluation of infants who have nal cause. The BRUE definition provides some
had an apparent life threatening event (Tieder specificity that the original ALTE definition
et al. 2016). The guideline achieves three pri- lacked, allowing it to be more applicable to clini-
mary objectives: to give the recommendation to cal care and research. With specific criteria, the
replace the term “apparent life threatening event provider can focus on the infants who have an
(ALTE)” with the more specifically-defined unexplained reason for the event and clearly
“brief resolved unexplained event (BRUE)”, to assess risk as well as remove those who have fea-
stratify infants into low or high risk (based on tures consistent with normal infant physiology or
the likelihood of a serious underlying condi- a self-limited condition. Also, the diagnosis is
tion), and to provide evidence-based manage- based on the objective characterization of fea-
ment recommendations of lower-risk infants. tures that the clinician makes rather than the care-
By providing recommendations for evaluation giver’s perception that the event was
and management of lower- risk infants, the life-threatening, as the prior definition suggested.
guideline intends to reduce unnecessary and A more precise diagnosis, made after a thorough
costly interventions, promote patient- and fam- history and physical, may prevent unnecessary
ily-centered care, and improve patient out- testing and hospitalizations by removing the
comes. It also provides support for its uncertainty and perceived risk of a recurrent
implementation and identifies areas of needed event that compels such testing and observation
research. The guideline avoids providing rec- in the first place. The guideline provides an
ommendations for higher-risk infants because extensive list of historical and physical exam fea-
there is insufficient evidence or there are clini- tures providers should consider in the evaluation
cal practice guidelines available for the specific of a potential BRUE (Tieder et al. 2016).

Table 12.2 BRUE definition and factors for inclusion and exclusion (Tieder et al. 2016)
Includes Excludes
Brief Duration <1 min; typically 20–30s Duration ≥1 min
Resolved Patient returned to baseline state of At the time of evaluation:
health after the event • Fever or recent fever
Normal vital signs • Apnea, bradypnea, tachypnea, Bradycardia or
Normal appearance tachycardia
• Hypertension, hypotension, or hemodynamic
instability
• Mental status changes, somnolence, lethargy
• Hyper- or hypotonia
• Vomiting
• Petechiae, bruising, or other signs of trauma
• Abnormal growth parameters
• Stridor, stertor, wheezing
• Repeat event(s)
Unexplained Not explained by an identifiable • E vent consistent with nasal congestion, GER,
medical condition swallow dysfunction, etc.
• H istory or PE concerning for child abuse,
congenital airway abnormality, etc.
Event characterization
Cyanosis or pallor Central cyanosis: blue or purple • Perioral cyanosis or acrocyanosis
coloration of face, gums, trunk • Rubor
Central pallor: pale coloration of
face or trunk
Absent, decreased, or Central apnea, obstructive apnea, or • Periodic Breathing of the newborn
irregular breathing mixed obstructive apnea • Breath-holding spell
Marked change in tone Hypertonia • Hypertonia associated with crying, gagging, or
(hyper- or hypotonia) Hypotonia choking due to problems feeding or GER
• Tone changes associated with breath-holding
spell
• Nystagmus or tonic eye deviation
• Tonic-clonic seizure activity
• Infantile spasms
Altered responsiveness Loss of consciousness, mental • Loss of consciousness with breath-holding spell
status change, lethargy,
somnolence, postictal phase
Adapted from: Tieder JS, et al. Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and
Evaluation of Lower-Risk Infants. Pediatrics. 2016;137 (2003):e20160590
Risk Assessment and Management The following criteria encompass lower

risk:
Based on an extensive review of the ALTE litera-
ture, the new BRUE guideline identifies the • Age >60 days
subset of patients who are unlikely to have a • Gestational age ≥32 weeks and postconcep-
recurrent event or an undiagnosed serious condi- tional age ≥45 weeks
tion. These patients are at lower risk of adverse • First BRUE ever and not occurring in clusters
outcomes and can likely be managed safely with- • Duration of event <1 min
out extensive diagnostic evaluation or hospital- • No CPR required by a trained medical
ization (Tieder et al. 2016). provider

Table 12.3 Choosing wisely pediatric hospital medicine • Initiate home cardio-respiratory monitoring
recommendations
• Prescribe acid suppression therapy or anti-
Don’t order chest radiographs in patients with asthma epileptic medications
or bronchiolitis
Don’t use bronchodilators in children with
Providers need not
bronchiolitis
Don’t use systemic corticosteroids in children with
lower respiratory tract infections • Obtain viral respiratory testing, urinalysis,
Don’t treat gastroesophageal reflux in infants with blood glucose, serum bicarbonate, serum lac-
acid suppression therapy tic acid, or neuroimaging
Don’t use continuous pulse oximetry routinely in • Admit the patient to the hospital solely for
children with acute respiratory illness unless they are cardiorespiratory monitoring
on supplemental oxygen
This new guideline, while limited in its scope,

• No concerning historical features (see offers an initial pathway for standardizing man-
Table 12.2 in guideline) agement of this common inpatient entity. The
• No concerning physical exam findings (see guideline does, however, have significant limita-
Table 12.3 in guideline) tions. The most important of these is that the
authors decided to limit recommendations to
After identifying that the patient had a BRUE children over 2 months of age. A significant num-
and falls into the lower risk category, the provider ber of children who present to the hospital with a
can then follow the key action statements regard- BRUE are less than 2 months. Thus, this guide-
ing recommended management that are catego- line may not apply to a significant number of the
rized based on the strength of the recommendation patients where standardization is most needed.
(Tieder et al. 2016). Future research should address management and
Providers should: diagnosis in younger infants (under 2 months of
age), who currently fall into the high risk group.
• Educate caregivers about BRUEs and engage
in shared-decision-making to guide evalua-
tion, disposition, and follow-up Osteomyelitis
• Offer resources for CPR training to caregiver
Introduction
Providers may:
Osteomyelitis is a bacterial infection that
• Obtain pertussis testing and a 12-lead ECG accounts for 1% of all pediatric hospitalizations.
• Briefly monitor patients with continuous It generally requires hospitalization for the initial
pulse-ox and serial observations diagnosis and management, and it often involves
a prolonged course of antibiotics to prevent
Providers should not: chronic infection and other complications
(Zaoutis et al. 2009). After resolution of acute
• Obtain a WBC count, blood culture, CSF symptoms of fever, pain, and disability, most
analysis or culture, serum sodium, potassium, children complete 4–6 weeks of antibiotic ther-
chloride, blood urea nitrogen, creatinine, cal- apy at home. Until recently, the recommended
cium, ammonia, blood gases, urine organic route of administration has been through central
acids, plasma amino acids or acylcarnitine, venous catheters, usually a peripherally inserted
chest radiograph, echocardiogram, EEG, stud- central catheter (PICC) (Keren et al. 2015).
ies for GER, or lab evaluation for anemia However, published case series have demon-

strated excellent outcomes in patients who were data on 1969 children 2 months to 17 years with
treated with a short course of parenteral antibiot- acute osteomyelitis meeting inclusion criteria
ics and transitioned early to oral antibiotics to from 29 freestanding children’s hospitals. Of
complete therapy (Peltola et al. 1997; Le Saux these, 1021 had a central venous catheter (CVC)
et al. 2002; Jagodzinski et al. 2009; Kolyvas et al. for prolonged IV antibiotics while 948 did not
1980; Arnold et al. 2012). Benefits of early tran- and were transitioned to oral antibiotics prior to
sition to oral antibiotic therapy include lower discharge. There were no significant differences
costs and complications. While PICCs are effec- between the groups in terms of demographics,
tive at delivering antibiotics, they are often asso- site of infection, LOS, surgical intervention,
ciated with a high rate of infectious, thrombotic, infecting organism, disease severity, or in-
and mechanical complications (Ruebner et al. hospital antibiotic therapy. They found no differ-
2006; Bourgeois et al. 2011). ence in treatment failure between the groups (5%
[54 of 1021] in the IV group, 4% [38 of 948] in
the oral group). The authors also demonstrated
ral Versus Intravenous Antibiotic
O significant variation across hospitals in the pro-
Therapy portion of children who had a CVC for prolonged
antibiotics ranging from 10% to 95%. Data from
While there are no large prospective random- their secondary outcomes showed that children in
ized controlled trials (RCT) comparing oral and the prolonged IV therapy group were more likely
intravenous (IV) routes of antibiotic therapy, to have treatment-related complications (e.g.
there are two large retrospective cohort studies catheter related complications, antibiotic related
comparing early transition to oral versus IV complications), had a significantly higher read-
antibiotics in children with osteomyelitis mission rate for antimicrobial complications, and
(Zaoutis et al. 2009; Keren et al. 2015). The sec- had a significantly higher overall 6-month rehos-
ond of these studies was designed in a way to pitalization rate for any reason. The authors con-
mimic an RCT (Keren et al. 2015). Both studies cluded that the two methods of treatment are
used data from the Pediatric Health Information equally effective, that early transition to oral
System (PHIS database), which contains admin- therapy is associated with fewer complications,
istrative and billing data from over 45 freestand- and that the results of the study should encourage
ing children’s hospitals associated with the hospitals to develop clinical practice guidelines
Children’s Hospital Association. Data from this and protocols for early transition to oral antibiot-
system includes information on demographics, ics and thus reduce practice variation (Zaoutis
diagnosis, medications, procedures, and repeat et al. 2009).
hospitalizations. While promising, the above study had signifi-
Zaoutis et al. (Zaoutis et al. 2009) published cant limitations that may have partly contributed
the first of these large studies in 2009 looking at to the lack of widespread reduction in PICC use
the degree of variation across hospitals in the use in favor of the oral treatment route among most
of early transition to oral antibiotics and whether hospitals. These limitations included its retro-
there is an association between this therapy and spective nature and lack of validation of the
treatment failure. The primary outcome of treat- osteomyelitis diagnosis and treatment choice,
ment failure was defined as rehospitalization adjustment for severity of illness, and informa-
within 6 months due to acute or chronic osteomy- tion about reasons for readmissions and revisits.
elitis, a potential complication of acute osteomy- In 2015, Keren et al. (2015) published a subse-
elitis, or a musculoskeletal surgical procedure. quent study seeking to again compare the effec-
Secondary outcomes were rehospitalization tiveness and complication rates of the two
within 6 months due to a catheter-related compli- treatment modalities (early transition to oral anti-
cation, an antibiotic-related adverse drug reac- biotics vs prolonged IV antibiotics) while
tion, or any other reason. The authors obtained addressing some of Zaoutis et al.’s limitations.

Treatment failure was again the primary out- 100%. The authors concluded that discharging
come, which was defined as a revisit to the ED or otherwise healthy patients with osteomyelitis
rehospitalization for a change in the antibiotic or to complete antibiotic therapy via an invasive
length of treatment, a switch from the oral to PICC offers no advantage over the less inva-
PICC route, a pathologic bone fracture, or a sur- sive oral antibiotic option, and the latter con-
gical procedure related to the infection (i.e. fers fewer risks and complications (Keren et al.
abscess drainage, debridement, bone biopsy, 2015).
etc.). Secondary outcomes included a return ED
visit or rehospitalization for antibiotic- or PICC-
related complications or a composite of these When to Transition to Oral Antibiotics
with treatment failure. This study also utilized
administrative data from the PHIS database, but With the above studies as well as previously pub-
they supplemented it with additional clinical lished case series demonstrating the safety and
information from detailed, manual chart review, efficacy of transitioning from parenteral to oral
thus validating treatment allocation, outcomes, antibiotic therapy in the treatment of acute osteo-
and covariates. This study also used within- and myelitis, others have studied the best way to
across-hospital full matching based on propen- determine the timing of this transition. In one
sity scores to account for confounders at the hos- such study (Arnold et al. 2012), authors con-
pital and patient levels. While still not as robust at ducted an 8-year single-center retrospective
avoiding confounders as a randomized trial, pro- study where it was standard practice to transition
pensity based matching mimics an RCT by most from parenteral antibiotics to oral antibiotics
closely comparing similar patients in both arms when the patient had clinical improvement and a
of the study. In addition, this study improves on C-reactive protein (CRP) level <2–3 mg/dL. Of
the prior study by including children hospitalized the 194 patients reviewed, only one had a treat-
between 2009–2012 when methicillin-resistant S ment failure, and this was due to a retained
aureus (MRSA) was more prevalent (Keren et al. infected bone fragment in the joint space. This
2015). study only included patients with culture-positive
Their results were nearly identical to Zaoutis infection, but it did include MRSA infections
et al. There were 1005 children in the oral anti- (Arnold et al. 2012).
biotic group and 1055 children in the PICC Another single-center study (Chou and
antibiotic group across 36 hospitals. Treatment Arjandas 2016) evaluated patients in the author’s
failure rates were similar in the oral group (5% institution who were transitioned from parenteral
[50 of 1005]) and PICC group (6% [63 of antibiotics to oral antibiotics once the CRP level
1055]), including those in the matched analy- had declined by ≥50%, as per their protocol.
ses. In the stratified analyses, they did find that They included both culture-positive and culture-
the risk for treatment failure was increased in negative infections. They found that using a
children older than 5 years in the PICC group. decline in the CRP level by ≥50% over a 4 day
However, having MRSA as the causative period combined with clinical improvement was
organism did not impact the outcome of treat- a safe way to determine the timing of transition in
ment failure based on treatment route. For the therapy (Chou and Arjandas 2016).
secondary outcomes, 15% (158 of 1055) in the Using clinical improvement combined with a
PICC group had a PICC-related complication. declining CRP level (whether by ≥50% or to near
As such, the PICC group had a significantly normal levels of <2–3 mg/dL) is a useful way in
higher risk of needing a return ED visit or hos- determining when it is safe to transition from par-
pitalization for an adverse event in any matched enteral to oral antibiotic therapy and may help to
analysis. The across-hospital variation in the shorten the length of stay and standardize
use of the PICC route to give antibiotics on dis- practice.
charge was again broad and ranged from 0% to

High Value Care Table 12.4 Possible ovediagnosed conditions in

pediatrics
Introduction Neuroblastoma
Bacteremia
Pediatric hospitalists have been at the forefront of Medium-chain acyl-CoA dehydrogenase deficiency
high value care in pediatrics. This is reflected by Hyperbilirubinemia
publications in the field in the last few years. Vesicoureteral reflux
While this issue has received much attention in Hypercholesterolemia
adult medicine, few publications in pediatrics Food allergy
have addressed this issue. Particularly, the issue Gastroesophageal reflux
of overuse in pediatrics has received very few Hypoxemia in bronchiolitis
Urinary tract infection
pages in journals. Overuse has been defined as
Aspiration
“the provision of health care when the risk of
Attention deficit hyperactivity disorder
harm exceeds its potential benefit, when the ben-
Cholelithiasis
efits are negligible, or when fully informed
Skull fracture
patients would forego care.” It includes overtreat-
Obstructive sleep apnea
ment and overdiagnosis (Morgan et al. 2016). A
recent publication in Pediatrics, led by pediatric
hospitalists, reviewed a year’s worth of publica- Overdiagnosis
tions dealing with the issue of overuse in pediat-
rics (Coon et al. 2017). In 2014, some of the same authors involved in the
Choosing Wisely campaign published a compre-
hensive review of overdiagnosis in pediatrics
Choosing Wisely (Coon et al. 2014). While overdiagnosis has been
frequently observed in adult care, this first of its
The American Board of Internal Medicine kind review explored conditions in pediatrics that
Foundation (ABIM-F) has developed the may suffer from overdiagnosis.
Choosing Wisely® campaign (www.choosing- Table 12.4 shows the list of conditions
wisely.org). Through this campaign ABIM-F reviewed by the authors. The conditions range
has encouraged medical societies to develop a from ADHD to bacteremia. Since the publication
list of five items within their scope of practice, of this review, further evidence has given support
“Things Providers and Patients Should to possible overdiagnosis. One clear example is
Question.” In 2013 The Society of Hospital overdiagnosis of hypoxemia in bronchiolitis.
Medicine published the first pediatric list. The Since the 1980’s the widespread use of portable
methodology and evidence supporting this list pulse oximeters has seen a concomitant increase
was also later published in The Journal of of up to 300% in admissions for bronchiolitis
Hospital Medicine (Quinonez et al. 2013). The (Hasegawa et al. 2013). Several studies have
list is heavily focused on respiratory illnesses, demonstrated that pulse oximetry readings have a
particularly bronchiolitis. This is not unex- strong influence over a clinician’s decision to
pected given the frequency of this diagnosis in admit a patient to the hospital (Mower et al.
the inpatient setting. The investigators encour- 1995). Most convincingly, a recent Canadian ran-
aged hospital medicine practitioners to utilize domized controlled trial showed that a difference
this list as a guide to prioritize quality improve- of just 3% points, all within the normal range in
ment projects. Indeed, the recommendation to oxygen saturations, influenced the decision to
limit pulse oximetry has led to at least one such admit patients to the hospital in a significant way,
project (Schondelmeyer et al. 2015), and this despite having no other clinical differences
recommendation was later incorporated into the (Schuh et al. 2014). This same group has also
2014 AAP bronchiolitis guidelines (Ralston demonstrated that significant desaturations, even
et al. 2014) (Table 12.3). to the 70s, occur in patients managed in the

o utpatient setting frequently and have little asso- Chou A, Arjandas M. The use of C-reactive protein as
a guide for transitioning to oral antibiotics in pedi-
ciation to proximal outcomes such as revisits to
atric osteoarticular infections. J Pediatr Orthop.
care (Principi et al. 2016). 2016;36(2):173–7.
Coon ER, Quinonez RA, Moyer VA, Schroeder
AR. Overdiagnosis: how our compulsion for
diagnosis may be harming children. Pediatrics.
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Update in Pediatric Infectious
Disease 13
Archana Chatterjee and Maya Gogoi
Introduction to the development of cervical, vulvar, vaginal,

penile, anal and oro-pharyngeal cancers as well
In the ever-changing field of pediatric infectious as pre-cancerous lesions, and ‘low-risk’ geno-
diseases, it is difficult to focus on just a few of types (6 and 11) which are associated with 90%
them. This chapter will provide an overview and of ano-genital warts and recurrent respiratory
brief summary of a number of emerging issues in papillomatosis (RRP) (Forman et al. 2012; Bhatia
pediatric infectious diseases including: the impact et al. 2013; Larson and Derkay 2010). Of all
of human papillomavirus (HPV) vaccines, despite HPV-related cancers, approximately 94% occur
their relatively poor uptake in the past decade; the in women and 88% affect the cervix (Jemal et al.
ongoing outbreaks of measles in the United States; 2011). While screening programs for cervical
the rise in Clostridium difficile infections in chil- intraepithelial neoplasia (CIN), a precursor to
dren; the introduction of meningococcal B vac- cervical cancer, have substantially reduced the
cines; the Zika virus outbreak and its implications; incidence and mortality from this disease in
the status and management of methicillin-resistant industrialized countries, such programs are often
Staphylococcus aureus (MRSA) infections; the unavailable in resource-poor settings. Thus, vac-
role of antibiotic stewardship in pediatric facilities; cination against HPV is a major advancement, as
and the management of congenital cytomegalovi- it offers primary prevention against the infectious
rus (CMV) infections. agent that is the main cause of the disease, irre-
spective of the availability or utilization of sec-
ondary prevention through cervical cancer
HPV screening and HPV testing programs (Bosch
et al. 2008, 2011).
HPVs are small dsDNA viruses, classified into HPV vaccination has been recommended for
‘high-risk’ genotypes (16, 18, 31, 33, 35, 39, 45, females in the United States (US) since mid-
51, 52, 56, 58, 59, 66, and 68), which are related 2006 and for males since 2011 (Markowitz et al.
2014). Routine vaccination is recommended for
females and males aged 11 or 12 years and for
females through age 26 years and males through
age 21 years if not previously vaccinated.
A. Chatterjee, M.D., Ph.D. (*) • M. Gogoi Three prophylactic HPV vaccines are licensed
Department of Pediatrics, University of South Dakota in the US, and have been shown in clinical tri-
Sanford School of Medicine, Sioux Falls, SD, USA als to have high efficacy for prevention of HPV
e-mail: Archana.Chatterjee@SanfordHealth.org;
mrg235@cornell.edu vaccine-type infection and associated diseases


350 A. Chatterjee and M. Gogoi
(Paavonen et al. 2007; FUTURE II Study Group compared with the pre-vaccine era, with vac-
2007; Joura et al. 2015). The bivalent vaccine cine effectiveness for prevention of infection
(2vHPV) targets HPV-16 and -18; the quad- estimated at 82% (Markowitz et al. 2013). A
rivalent vaccine (4vHPV) targets HPV-6, -11, more recent study shows that between the pre-
-16, and -18; and the 9-valent vaccine (9vHPV) vaccine and vaccine eras, 4vHPV type preva-
targets HPV-6, -11, -16, and -18 as well as 5 lence declined from 11.5% to 4.3% among
additional HPV types (31, 33, 45, 52, and 58) females aged 14–19 years and from 18.5% to
(Chatterjee 2014). 12.1% among females aged 20–24 years with
Although the rates of HPV vaccination have no decrease noted in older age groups
been increasing in the US over the past decade, (Markowitz et al. 2016). Within the vaccine era,
coverage remains low compared to other vac- among sexually active females aged
cines recommended for adolescents (Fig. 13.1) 14–24 years, 4vHPV type prevalence was lower
(Reagan-Steiner et al. 2015). In 2014, a national in vaccinated (≥1 dose) compared with unvac-
survey found that 60% of 13- to 17-year-old cinated females: 2.1% vs. 16.9%, with no sta-
females had received at least 1 dose and 39.7% tistically significant changes in other HPV type
had received 3 doses of HPV vaccine (Reagan- categories that indicate cross-protection
Steiner et al. 2015). Despite this modest rate of (Markowitz et al. 2016). These compelling data
uptake, data from the National Health and illustrate the population impact of HPV vacci-
Nutrition Examination Surveys (NHANES) nation. Despite the modest uptake of HPV vac-
demonstrated a 56% decrease in 4vHPV type cines, after only 6 years of vaccine introduction,
prevalence among females aged 14–19 years in there was a 64% decrease in 4vHPV type preva-
the first 4 years of the vaccine era (2007–2010) lence among females aged 14 to 19 years and a
100 Revised APD definition††

Tdap*
90 ≥1 MenACWY†
≥2 MenACWY§
80 ≥1 HPV (females)¶
≥3 HPV (females)¶
≥1 HPV (males)**
70
≥3 HPV (males)**
60
% vaccinated
50
40
30
20
10
0
2006 2007 2008 2009 2010 2011 2012 2013 2014
Survey year
Fig. 13.1 Estimated vaccination coverage with selected diphtheria toxoid, and acellular pertussis, MenACWY
vaccines and doses among adolescents aged 13–17 years, meningococcal conjugate, HPV human papillomavirus,
by survey year—National Immunization Survey–Teen, ACIP Advisory Committee on Immunization Practices,
United States, 2006–2014. Tdap tetanus toxoid, reduced APD adequate provider data

13 Update in Pediatric Infectious Disease 351
34% decrease among those aged 20–24 years The introduction of HPV vaccines has encoun-
(Markowitz et al. 2016). tered some significant hurdles, including an anti-
Some countries, including Australia and vaccine lobby that has tried to use misinterpreted
the United Kingdom (UK), adopted universal, adverse events in vaccine recipients unrelated to
publicly funded immunization of young women vaccination, as well as adverse events in placebo
before the onset of sexual activity and, as of recipients to suggest that the vaccines are not safe
2013, the Australian program has been extended (Chatterjee 2014). In the US, post-licensure vac-
to young men (Chatterjee 2014). The Australian cine safety monitoring and evaluation indicated
program has had a 73% uptake rate of vaccina- that from June 2006 through March 2013,
tion among 12- to 13-year-old girls, with the approximately 56 million doses of HPV4 were
virtual disappearance of genital warts, not only distributed, and from October 2009 through May
among immunized younger women, but also 2013, a total of 611,000 doses of HPV2 were dis-
among unimmunized younger men, presumably tributed (Sudenga et al. 2011; Centers for Disease
as a result of the protective effects of herd Control and Prevention (CDC) 2013). Because
immunity (Ali et al. 2013). Australia was also HPV4 accounts for 99% of the doses distributed
the first to report a significant decline in the rate in the United States, analysis of vaccine safety
of high-grade precancerous lesions (Ali et al. data was limited to HPV4. During June 2006 to
2013). In addition, significant reductions in the March 2013, the Vaccine Adverse Event
prevalence of HPV 16 and 18 DNA have been Reporting System (VAERS) received a total of
observed in cervical smear samples from 18- to 21,194 adverse event reports occurring in females
24-year-old women (Tabrizi et al. 2012). In after receipt of HPV4; 92.1% were classified as
England, the prevalence of HPV 16/18 infection non-serious (Centers for Disease Control and
in a post- immunization survey in 2013 was Prevention (CDC) 2013). Reporting peaked in
6.5% among 16–18 year olds, compared to 2008 and decreased each year thereafter; the pro-
19.1% in the baseline survey prior to the intro- portion of reports to VAERS that were classified
duction of HPV immunization in 2008 in the as serious reports peaked in 2009 at 12.8% and
UK (Mesher et al. 2013). decreased thereafter to 7.4% in 2013 (Fig. 13.2)
Other studies have also confirmed the effec- (Centers for Disease Control and Prevention
tiveness of HPV vaccines. In countries with HPV (CDC) 2013). Ongoing safety monitoring for
vaccination coverage of at least 50% in females, HPV vaccines has shown that most reports are
HPV type 16 and 18 infections decreased signifi- non-serious (Markowitz et al. 2014). The most
cantly between the pre-vaccination and post- commonly reported adverse events are injection
vaccination periods by 68%, with a significant site pain, swelling and erythema. Among sys-
decrease (61%) in ano-genital warts in girls temic adverse events the most frequently cited
13–19 years of age, and significant reductions in are headache, nausea, vomiting, and fever
HPV types 31, 33, and 45 in girls 13–19 years of (Markowitz et al. 2014). Syncope continues to be
age, suggesting cross-protection (Drolet et al. reported following vaccination among adoles-
2015). Significant reductions in ano-genital warts cents, but adherence to a 15-min observation
were also reported in boys younger than 20 years period after vaccination minimizes this.
of age and in women 20–39 years, suggesting It is evident that HPV vaccines are highly
herd effects. In countries with HPV vaccination effective, and that education about HPV-related
coverage in females lower than 50%, while there diseases and the vaccines to prevent them, is key
were significant reductions in HPV types 16 and to their successful deployment. Education regard-
18 infection and in ano-genital warts occurred in ing HPV-related diseases and vaccines needs to
girls younger than 20 years of age, there was no be directed at health care professionals, govern-
indication of cross-protection or herd effects ments, recipients, parents and schools to ensure
(Drolet et al. 2015). effective delivery programs.

7,000
6,000 Nonserious reports (n = 19,523)
Serious reports (n = 1,671)

5,000
No. of reports
4,000
3,000
2,000
1,000
0
2006 2007 2008 2009 2010 2011 2012 2013
Year
Fig. 13.2 Number of serious and nonserious reports of rus vaccine in females, by year, in the United States dur-
adverse events after administration of quadrivalent human ing June 2006 to March 2013. Reporting peaked in 2008
papillomavirus (HPV4) vaccine in females, by year— and decreased each year thereafter; the proportion of
Vaccine Adverse Event Reporting System, United States, reports to the Vaccine Adverse Event Reporting System
June 2006 to March 2013. The figure shows the number of that were classified as serious reports peaked in 2009 at
reports (serious and nonserious reports) of adverse events 12.8% and decreased thereafter to 7.4% in 2013
after administration of quadrivalent human papillomavi-
Measles vaccine refusal is the rate of parents claiming

non-medical exemptions to school immunization
While many childhood vaccine-preventable dis- requirements. Such exemptions have steadily
eases have been effectively controlled, recent increased in recent years, and shown to be related
outbreaks of some of these diseases has prompted to the outbreak of measles in California and other
concern among clinicians, public health officials, states (Majumder et al. 2015; Clemmons et al.
politicians, the media and the public (Whitney 2015; Chiem 2015; Zipprich et al. 2015; Omer
et al. 2014; Yang et al. 2015; Halsey and Salmon et al. 2012).
2015). One of the best-known is the outbreak of It is instructive to review the history of measles
measles in late 2014 that originated at Disneyland control and elimination in the US. Measles-
in Anaheim, California (Majumder et al. 2015; containing vaccines were first introduced in the
Clemmons et al. 2015; Chiem 2015). It resulted US in 1963, with two intensive elimination efforts
in 111 cases reported from seven US states, over the next two decades. The incidence of mea-
Canada and Mexico (Chiem 2015). Nearly half sles fell from >300 cases/100,000 population
occurred in unvaccinated individuals, most of in the pre-vaccine era to a median of 1.3
who were eligible for vaccination, but intention- cases/100,000 from 1982 to 1988 (Hamborsky
ally remained unvaccinated (Zipprich et al. et al. 2015). A resurgence in measles cases
2015). The reasons that some members of the occurred from 1989 to 1992, attributed to subop-
public refuse vaccination for themselves and timal vaccine coverage among preschool-aged
their children are multifactorial and may be dif- children and vaccine failures after a single dose of
ficult to pinpoint, but the most direct measure of measles-containing vaccine. A third elimination

effort was launched in the 1990s, and included the c hildren from harm may in fact, have the opposite
recommendation for a second dose of measles- effect and put not only them but others at risk for
containing vaccine, which culminated in the suc- contracting measles and suffering its conse-
cessful elimination of measles in the US by 2000 quences. As long as measles remains endemic in
(Katz and Hinman 2004). However, measles out- other parts of the world, maintaining high vacci-
breaks linked to individuals who acquired it out- nation rates in the US is imperative.
side the US have persisted, with 23 occurring in
2014, associated with 667 cases of measles (the
largest number recorded since elimination) C. difficile
(Centers for Disease Control and Prevention
2015). The US also recorded its first measles- C. difficile is emerging as an important cause of
associated death in 12 years (McCarthy 2015). healthcare- and community-associated diarrhea
A recent article reviewed the published litera- in children. Originally described as a commensal
ture to examine the association between vaccine organism in infants (<1 year of age), C. difficile
delay, refusal, or exemption and the epidemiol- is considered primarily a diarrheal agent of the
ogy of measles (Phadke et al. 2016). Eighteen elderly (Hall and O’Toole 1935). However, epi-
measles studies were evaluated. A total of 1416 demiologic studies have demonstrated that up to
cases ranging in age from 2 weeks to 84 years 71% of children are asymptomatically colonized
were reported, with 178 cases occurring in chil- with C. difficile and through a paradigm shift
dren under 12 months of age, and 56.8% having over the past decade, it is increasingly being rec-
no history of measles vaccination. Of 970 mea- ognized as an important pediatric enteric patho-
sles cases for whom detailed vaccination data gen (Sammons and Toltzis 2013; Al-Jumaili
were available, 574 were unvaccinated despite et al. 1984). Surveillance has revealed that the
being vaccine eligible, and 405 (70.6%) had incidence of C. difficile infection (CDI) is
received non-medical exemptions. Unvaccinated increasing in children, including those without
individuals made up a greater proportion of mea- traditional risk factors (Benson et al. 2007;
sles cases in the index or first generation of a Sandora et al. 2011; Kim et al. 2008; Nylund
cumulative epidemic curve. Children with vac- et al. 2011; Zilberberg et al. 2010; Khalaf et al.
cine exemptions had a significantly higher risk of 2012). Although testing of infants is not recom-
acquiring measles than fully vaccinated children, mended, one study reported that up to 26% of
with one study reporting that children with a vac- children hospitalized with CDIs were infants
cine exemption were 35 times more likely to con- younger than 1 year, and 5% were neonates (Kim
tract measles compared to vaccinated children et al. 2008). C. difficile carriage rates average
(Salmon et al. 1999). The authors concluded that 37% for infants 0–1 month of age, 30% between
a substantial proportion of measles cases in the 1 and 6 months of age, 14% at 6–12 months of
US in the era after elimination occurred in inten- age and 0–3% by 3 years of age (Jangi and
tionally unvaccinated individuals, and that higher Lamont 2010). Breastfed infants have lower car-
rates of vaccine exemption in a community are riage rates than do formula fed infants (14% vs.
associated with greater measles incidence among 30%, respectively) (Benno et al. 1984). Carriage
both the exempt and nonexempt population rates in hospitalized children approximate 20%
(Phadke et al. 2016). (Cohen et al. 2010).
This brief discussion of recent measles out- Recognized risk factors for older children
breaks and their causes in the US illustrates the acquiring CDI include antimicrobial therapy, use
importance of continued vigilance as well as pub- of proton pump inhibitors, repeated enemas, use
lic health efforts and education that are necessary of diapers, prolonged nasogastric tube insertion,
to prevent the resurgence of this potentially deadly gastrostomy and jejunostomy tubes, underlying
disease. Non-medical exemptions obtained by bowel disease, gastrointestinal tract surgery,
parents who believe they are protecting their renal insufficiency, cystic fibrosis and impaired

humoral immunity (Sandora et al. 2011; Schutze method used for C. difficile toxins is the commer-
et al. 2013; Samady et al. 2014; Pohl et al. 2011). cially available enzyme immunoassay (EIA),
In one study, 67% of pediatric cases had chronic which detects toxins A and/or B. Mean test sensi-
medical conditions including neuromuscular, tivities range from 72% to 82%, with mean speci-
cardiovascular, respiratory, renal, gastrointesti- ficities of 97–98%, compared with the CCNA
nal, hematologic, immunologic, metabolic, (Crobach et al. 2009). Molecular assays using
malignancy, or congenital disorders (Kim et al. nucleic acid amplification tests (NAATs) are
2008). CDI is transmitted fecal-orally, through approved by the US Food and Drug Administration
person-to-person contact or contaminated envi- (FDA) and are now preferred by many laborato-
ronmental surfaces. The organism has been ries including those in children’s hospitals
recovered from the hands of hospital personnel, (Schutze et al. 2013). NAATs combine good sen-
baby baths, oximeters, electronic thermometers, sitivity and specificity, and have turnaround times
and hospital floors. comparable to EIAs. Routine testing for C. diffi-
CDI causes a spectrum of symptoms, includ- cile in children younger than 1 year of age is not
ing asymptomatic colonization; mild, watery recommended because carriage is common in
diarrhea; and severe pseudomembranous colitis this age group. Testing for C. difficile can be con-
(Khalaf et al. 2012; Pant et al. 2013; Enoch et al. sidered in children 1–3 years of age with diar-
2011; Sammons et al. 2013; Morris et al. 2013). rhea, but testing for other causes of diarrhea,
Infants are usually asymptomatically colonized, particularly viral, is recommended first (Sandora
whereas most symptomatic children experience et al. 2011; Schutze et al. 2013). C. difficile, its
mild-moderate watery diarrhea, associated with toxins, and genome are shed for long periods
fever, anorexia, or abdominal pain (Khalaf et al. after resolution of diarrheal symptoms so EIAs
2012). Approximately 20–30% of children will and NAATs should not be used as tests of cure
experience ≥1 recurrence following their initial after treatment of CDIs (Schutze et al. 2013).
episode and chronic diarrhea may lead to growth The management of CDI involves three basic
retardation (Morinville and McDonald 2005; principles:
Sutphen et al. 1983). The NAP1 strain of C. dif-
ficile which has been described as causing severe 1. Supportive care.
disease, including an increased incidence of 2. Discontinuing the precipitating antibiotic(s).
symptomatic infection, recurrent disease, sepsis, 3. Initiation of effective anti-C. difficile therapy.
toxic megacolon, bowel perforation, and mortal-
ity, has been reported in the pediatric population Symptomatic support is critical for children,
at lower rates (10–19%) than reported for adults who may require aggressive intravenous hydra-
(>50%) (Toltzis et al. 2009). NAP1-associated tion. Adjunctive anti-motility agents are discour-
CDIs occur in children without exposure to aged due to concerns of increased intestinal
health care facilities and/or to antimicrobial contact time with toxins. Discontinuation of the
agents (Bryant and McDonald 2009). offending antibiotic(s) may be sufficient for the
Evaluation for CDI should be reserved for resolution of mild symptoms and facilitates
children with diarrheal symptoms, defined as reconstitution of the normal enteric flora. While
passage of ≥3 loose stools within a 24-h period. no prospective clinical trials for CDI treatment in
Only unformed stools should be tested. children have been conducted, for primary mild-
Diagnostic methods for CDI in children are moderate CDI in children, oral metronidazole is
evolving (Sammons and Toltzis 2015). Once con- considered the drug of choice (Khalaf et al. 2012;
sidered the reference standard, cell culture cyto- Schutze et al. 2013; Li et al. 2015). Oral vanco-
toxicity neutralization assay (CCNA) has been mycin or vancomycin administered by enema
abandoned by many laboratories because of its with or without intravenous metronidazole is
slow turnaround time and labor requirements indicated as initial therapy for patients with
(Peterson et al. 2007). The more common testing severe disease and for patients who do not

respond to oral metronidazole (Cohen et al. programs (ASPs) in all acute care hospitals by
2010). Pediatric studies evaluating fidaxomicin 2020 and for the Centers for Medicare and
(approved for use in adults) are ongoing (Khalaf Medicaid Services to issue a Condition of
et al. 2012). Up to 30% of patients treated for Participation that participating hospitals develop
CDIs experience a recurrence after discontinuing programs based on recommendations from the
therapy (Schutze et al. 2013). Recurrences repre- Centers for Disease Control and Prevention’s
sent either relapse with the original isolate or (CDC) Core Elements of Hospital Antibiotic
reinfection with a new isolate. For recurrent CDI, Stewardship Programs (Centers for Disease
a second course of the initially successful antibi- Control and Prevention (CDC) 2014).
otic is recommended with the first recurrence. If Antibiotic stewardship has been defined in a
this treatment fails, then tapered or pulsed vanco- consensus statement from the Infectious
mycin regimens can be used (Schutze et al. Diseases Society of America (IDSA), the Society
2013). Fecal microbiota transplantation or probi- for Healthcare Epidemiology of America
otics have been successfully used in case reports (SHEA), and the Pediatric Infectious Diseases
of children with CDI (Khalaf et al. 2012; Walia Society (PIDS) as “coordinated interventions
et al. 2014; Goldenberg et al. 2013). designed to improve and measure the appropri-
Judicious antibiotic usage, standard plus con- ate use of [antibiotic] agents by promoting the
tact isolation, decontamination of surfaces with selection of the optimal [antibiotic] drug regi-
sporicidal cleaning agents, and handwashing are men including dosing, duration of therapy, and
critical components of nosocomial prevention of route of administration” (Fishman 2012). The
C. difficile transmission (Khalaf et al. 2012). benefits of antibiotic stewardship include
Alcohol-based hand sanitizers may not be as improved patient outcomes, reduced adverse
effective as handwashing with soap and water events including CDI, improvement in rates of
because of spore resistance to alcohol. antibiotic susceptibilities to targeted antibiotics,
In summary, C. difficile is emerging as an and optimization of resource utilization across
important enteric pathogen in children. Historically the continuum of care. Evidence-based guide-
considered a commensal in infants, CDI should be lines for implementation and measurement of
considered in the differential diagnosis of older antibiotic stewardship interventions in inpatient
children with diarrhea, particularly those who populations were prepared by a multidisciplinary
have risk factors for it. Appropriate testing and expert panel including clinicians and investiga-
treatment modalities should be instituted to man- tors representing internal medicine, emergency
age children with CDI. Further studies investigat- medicine, microbiology, critical care, surgery,
ing the significance of C. difficile detection among epidemiology, pharmacy, and adult and pediatric
different age groups, the pathogenesis of CDI, and infectious diseases specialties (Barlam et al.
optimal therapeutic and preventative strategies in 2016). Selected recommendations from the
children are needed. guidelines (based on the availability of pediatric
data) are presented below. These recommenda-
tions address the best approaches for antibiotic
Antibiotic Stewardship stewardship programs to influence the optimal
use of antibiotics in children.
A discussion of antibiotic stewardship is proba-
bly fitting following the section on CDI. The 1. The guidelines recommend preauthorization
need for antibiotic stewardship across the spec- and/or prospective audit and feedback (PAF),
trum of healthcare has been recognized in the which have been associated with a signifi-
National Action Plan for Combating Antibiotic- cant reduction in the use of restricted agents
Resistant Bacteria issued by the White House in and of associated costs (Metjian et al. 2008).
March 2015 (The White House 2015). This plan PAF has been effective in children’s hospitals
calls for establishment of antibiotic stewardship by significantly reducing antibiotic use and

dosing errors, limiting the development of 7. The authors suggest development of strati-
antibiotic resistance, and reducing CDI rates fied antibiograms over solely relying on non-
without a negative impact on patient out- stratified antibiograms to assist ASPs in
comes (Newland et al. 2012; Di Pentima developing guidelines for empiric therapy.
et al. 2011). When one institution constructed a pediatric-
2. While recommending against relying solely specific antibiogram for Escherichia coli and
on didactic educational materials for steward- compared it with antibiograms generated
ship, the guidelines do endorse the use of pas- from combined data from both adult and
sive educational activities, such as lectures or pediatric isolates, there were significant anti-
informational pamphlets, to complement biotic susceptibility differences between E.
other stewardship activities. Academic medi- coli isolates obtained from pediatric patients
cal centers and teaching hospitals are also vs. the hospital-wide antibiogram data
advised to integrate education on fundamen- (Boggan et al. 2012). Provision of pediatric-
tal antibiotic stewardship principles into their specific data optimized prescribing choice
preclinical and clinical curricula. Educational when compared with no antibiogram and
strategies should include medical, pharmacy, also with the hospital-wide antibiogram.
physician assistant, nurse practitioner, and Another institution also found age-specific
nursing students and trainees. differences with overestimation of resistance
3. Since there is evidence that facility-specific in E. coli and S. aureus for children (Swami
guidelines promote the use of narrower- and Banerjee 2013).
spectrum antibiotic regimens (Newman et al. 8. Although studies of the value of ASP inter-
2012), the authors suggest that ASPs develop ventions based on rapid testing for respira-
facility-specific clinical practice guidelines tory viruses are lacking, some data are
coupled with a dissemination and implemen- available on decreased inappropriate antibi-
tation strategy. otic use with rapid viral testing. These stud-
4. The guidelines suggest incorporation of ies have been performed primarily in
computerized clinical decision support at the pediatric populations such as children pre-
time of prescribing into ASPs, as implemen- senting to physicians’ offices(Jennings et al.
tation of computerized decision support sys- 2009) or emergency departments (Bonner
tems for prescribers has been associated with et al. 2003; Doan et al. 2009; Wishaupt et al.
improved antibiotic dosing, fewer prescrib- 2011), children requiring hospitalization
ing errors, and reduced antibiotic costs (Byington et al. 2002) or immunocompro-
(Mullett et al. 2001). mised children (Kadmon et al. 2013). Based
5. Due to limited evidence, the authors give no on these, the authors support the use of rapid
recommendation about the utility of alterna- viral testing for respiratory pathogens to
tive dosing strategies for vancomycin. reduce the use of inappropriate antibiotics.
However, continuous-infusion vancomycin 9. The authors suggest that ASPs develop
has been associated with few adverse effects facility-specific guidelines for fever and neu-
and no nephrotoxicity in children (McKamy tropenia management in hematology-
et al. 2012). oncology patients. As an example of the
6. The authors recommend that ASPs imple- benefits from these, Pakakasama et al. dem-
ment guidelines and strategies to reduce anti- onstrated that implementation clinical guide-
biotic therapy to the shortest effective lines in pediatric cancer patients resulted in
duration. One study demonstrated that pre- statistically significant reductions in septic
scription of shorter courses of antibiotic ther- shock (intervention vs. control: 3.5% vs.
apy is associated with outcomes similar to 10.9%; P = 0.011), ICU admissions (2.9%
those with longer courses and few adverse vs. 9.4%; P = 0.016), and death (0% vs.
events (Saini et al. 2011). 6.5%; P = 0.001) (Pakakasama et al. 2011).

10. One question in the guideline is devoted to infections in children, and a national study
ASPs in the neonatal intensive care unit showed an increase in the number of hospitalized
(NICU). The authors acknowledge that lim- children with MRSA infection (Gerber et al.
ited evidence is available to determine the 2009; Kaplan et al. 2005). Similarly, numerous
most effective ASP strategies in the NICU, outbreaks in NICUs have been attributed to
but state that general principles should apply strains of both health care and community ori-
(Patel and Saiman 2012). Antibiotic policy gins, and increasing trends in late onset infec-
and guidelines have been shown to be effec- tions in US NICUs caused by MRSA have been
tive in the NICU (Murki et al. 2010). After reported (Lessa et al. 2009). A retrospective anal-
implementing a vancomycin guideline, Chiu ysis of 25 children’s hospitals reported that the
et al. (2011) saw a 35% reduction in the ini- incidence of MRSA infections increased 10-fold
tiation of vancomycin and a 65% overall between 1999 and 2008 (2 cases vs. 21 cases per
decrease in exposure to vancomycin com- 1000, P < 0.001) with a doubling in the propor-
pared with the preimplementation period. tion of staphylococcal infections due to MRSA in
Zingg et al. (2011) evaluated antibiotic use the same time period (15% vs. 36%) (Herigon
after initiating a policy to shorten antibiotic et al. 2010). A recent study evaluated reports of
therapy for sepsis and coagulase-negative invasive MRSA infections in pediatric patients
staphylococcal infection, and to stop pre- identified from population-based surveillance
emptive treatment if blood cultures were during 2005–2010 and found that 35% of cases
negative. They found an overall 2.8% yearly were hospital-onset, 23% were health care–asso-
reduction in antibiotic use (P < 0.001) with- ciated community-onset, and 42% were
out increasing mortality. CA-MRSA (Iwamoto et al. 2013). The incidence
of invasive CA-MRSA infection per 100,000
This short discussion of the guidelines for children increased from 1.1 in 2005 to 1.7 in
implementing ASPs in pediatric settings is a first 2010. The estimated invasive MRSA incidence in
step in assisting them to improve the utilization 2010 was higher among infants aged <90 days
of antibiotics in their facilities. Further research compared with older infants and children (43.9
is definitely needed to provide a strong scientific vs. 2.0 per 100,000) and among black children
basis for the guidelines. compared with other races (6.7 vs. 1.6 per
100,000) (Iwamoto et al. 2013).
Due to the rise in MRSA infections in recent
MRSA years, the percentage of hospitalized children
with S. aureus infection that received anti-
MRSA is a significant cause of both health care- MRSA antibiotics increased between 1999 and
associated and community-associated infections 2008 (52% vs. 79%), while the percentage of
in children, causing a wide spectrum of disease hospitalized children receiving beta lactam drugs
ranging from skin and soft tissue infections to decreased (66% vs. 30%, P < 0.001) (Herigon
life-threatening systemic infections (Pendleton et al. 2010). During this time period, the percent-
and Kocher 2015; Vardakas et al. 2013). Invasive age of hospitalized children with S. aureus infec-
MRSA in children is associated with high mor- tion given clindamycin and linezolid increased
bidity, mortality and healthcare costs (Cosgrove (clindamycin, 21% vs. 63%; linezolid, 0% vs.
et al. 2003; Song et al. 2010). The epidemiology 5%) while vancomycin use remained stable
of infections among children is distinct from that (36% vs. 37%) (Herigon et al. 2010). Current
in adults e.g. the incidence of invasive infections treatment recommendations for infants with
is relatively high in infants and young children MRSA infection based on the clinical practice
(Klevens et al. 2007). Studies in some centers guidelines by the IDSA vary depending on the
have shown increases in both invasive and site of infection (Liu et al. 2011). For children
noninvasive community associated (CA) MRSA with minor skin infections (such as impetigo)

and secondarily infected skin lesions (such as day, counters, door knobs, bath tubs, and
eczema, ulcers, or lacerations), mupirocin 2% toilet seats) that may contact bare skin or
topical ointment can be used (Liu et al. 2011). uncovered infections.
For hospitalized children, if the patient is stable (b) Using commercially available cleaners or
without ongoing bacteremia or intravascular detergents appropriate for the surface
infection, empirical therapy with clindamycin being cleaned according to label instruc-
10–13 mg/kg/dose IV every 6–8 h (to administer tions for routine cleaning of surfaces.
40 mg/kg/day) is an option if the clindamycin 5. Decolonization may be considered in selected
resistance rate is low (≤10%) with transition to cases if:
oral therapy if the strain is susceptible (Liu et al. (a) A patient develops a recurrent SSTI
2011). Linezolid 600 mg PO/IV twice daily for despite optimizing wound care and
children >12 years of age and 10 mg/kg/dose hygiene measures.
PO/IV every 8 h for children,12 years of age is (b) Ongoing transmission is occurring among
an alternative (Liu et al. 2011). First-line treat- household members or other close con-
ment is recommended to be with intravenous tacts despite optimizing wound care and
(IV) vancomycin for severe of MRSA infections hygiene measures.
(Liu et al. 2011). Alternative antibiotics include 6. Decolonization strategies should be offered
clindamycin, linezolid, daptomycin, quinupris- in conjunction with ongoing reinforcement
tin/dalfopristin, rifampin, telavancin, or trime- of hygiene measures and may include the
thoprim/sulfamethoxazole (Durand et al. 2014; following:
Gostelow et al. 2014). Over the last 15 years, six (a) Nasal decolonization with mupirocin
drugs have been approved for the treatment of S. twice daily for 5–10 days.
aureus infections, but PK and safety data in (b) Nasal decolonization with mupirocin

infants are only available for linezolid and dap- twice daily for 5–10 days and topical
tomycin, while quinupristin/dalfopristin has body decolonization regimens with a skin
been studied only in non-infant pediatric popula- antiseptic solution (e.g., chlorhexidine)
tions (Durand et al. 2014). for 5–14 days or dilute bleach baths. (For
Recurrent MRSA skin and soft tissue infec- dilute bleach baths, 1 teaspoon per gallon
tions (SSTIs) can be a particular problem in chil- of water [or ¼ cup per ¼ tub or 13 gallons
dren. The following measures are recommended of water] given for 15 min twice weekly
to manage these (Liu et al. 2011): for 3 months can be considered.)
7. Oral antimicrobial therapy is recommended
1. Keep draining wounds covered with clean,
for the treatment of active infection only and
dry bandages. is not routinely recommended for decoloniza-
2. Maintain good personal hygiene with regular tion. An oral agent in combination with
bathing and cleaning of hands with soap and rifampin, if the strain is susceptible, may be
water or an alcohol-based hand gel, particu- considered for decolonization if infections
larly after touching infected skin or an item recur despite above measures.
that has directly contacted a draining wound. 8. The role of cultures in the management of
3. Avoid reusing or sharing personal items (e.g., patients with recurrent SSTIs is limited:
disposable razors, linens, and towels) that (a) Screening cultures prior to decolonization
have contacted infected skin. are not routinely recommended if at least
4. Environmental hygiene measures should be one of the prior infections was docu-
considered in patients with recurrent SSTI in mented as due to MRSA.
the household or community setting by: (b) Surveillance cultures following a decolo-
(a) Focusing cleaning efforts on high-touch nization regimen are not routinely recom-
surfaces (i.e., surfaces that come into fre- mended in the absence of an active
quent contact with people’s bare skin each infection.

In summary, both invasive and non-invasive cCMV are not recommended due to their poor
infections due to MRSA in children remain chal- specificity (Plosa et al. 2015).
lenging to manage. Care for pediatric patients Treatment for cCMV infection with antiviral
with MRSA infections should be optimized by agents has been controversial. A study conducted
utilizing published evidence-based guidelines for by the National Institute of Allergy and Infectious
these infections. Diseases (NIAID) Collaborative Antiviral Study
Group (CASG) reported that among neonates
with symptomatic cCMV disease involving the
Congenital CMV central nervous system (CNS), ganciclovir
administered intravenously over a period of
Congenital CMV (cCMV) infection is the lead- 6 weeks was associated with improved audio-
ing nongenetic cause of sensorineural hearing logic outcomes at 6 months of life, but there was
loss (SNHL) in newborns worldwide (Fowler a suggestion that this benefit could wane over the
and Boppana 2006; Boppana et al. 2013). The first 2 years of life (Kimberlin et al. 2003).
impact of cCMV infection on pediatric health Treated infants had fewer developmental delays,
is significant, affecting 0.5–2% of all live-born according to Denver Developmental evaluations,
infants worldwide (Schleiss and Heineman than untreated infants (Oliver et al. 2009). In a
2005; Manicklal et al. 2013). Although cCMV follow-up study, the CASG determined the dose
infection is rare overall, it accounts for 21% of of oral valganciclovir (the prodrug of ganciclo-
children with hearing loss at birth and 24% of vir) that results in systemic exposure to ganciclo-
those with hearing loss at 4 years of age vir that is similar to that with intravenous
(Grosse et al. 2008). An estimated 10% of ganciclovir (Kimberlin et al. 2008). Treatment
infected infants exhibit neurological sequelae with intravenous ganciclovir or oral valganciclo-
at birth, while an additional 10–15% of infected vir for 6 weeks is now an accepted treatment
infants develop SNHL in the first 2 years of option for patients with symptomatic cCMV dis-
life, up to two thirds have neurologic deficits, ease involving the CNS (Plosa et al. 2015).
and 4% die during the newborn period A recent randomized, placebo-controlled trial
(Boppana et al. 2013; Schleiss and Heineman of valganciclovir in neonates with symptomatic
2005). In the United States, approximately cCMV disease, compared 6 months of therapy
30,000 congenital infections occur annually, of with 6 weeks of therapy (Kimberlin et al. 2015).
which more than than 5000 infections lead to A total of 96 neonates underwent randomization,
permanent disabilities, including SNHL, of which 86 had follow-up data at 6 months that
growth restriction, seizures, and motor and could be evaluated. Best-ear hearing at 6 months
cognitive disability (Boppana et al. 2013; was similar in the 6-month group and the 6-week
Schleiss and Heineman 2005). group (Kimberlin et al. 2015). Total ear hearing
Proof of cCMV infection requires virologic (hearing in one or both ears that could be evalu-
detection of CMV in urine, oral fluids, respira- ated) was more likely to be improved or to remain
tory tract secretions, blood, or CSF obtained normal at 12 months in the 6-month group than in
within 2–4 weeks of birth (Plosa et al. 2015). The the 6-week group (73% vs. 57%, P = 0.01)
analytical sensitivity of CMV DNA detection by (Kimberlin et al. 2015). The benefit in total-ear
PCR assay of dried blood spots is low, so these hearing was maintained at 24 months (77% vs.
specimens should not be used for screening for 64%, P = 0.04), and the 6-month group had better
cCMV infection (Boppana et al. 2010). neurodevelopmental scores on the Bayley Scales
Differentiating between intrauterine and postna- of Infant and Toddler Development (third e dition)
tal infection is difficult beyond 2–4 weeks of age (Bayley 2006), on the language-composite com-
unless clinical manifestations such as chorioreti- ponent (P = 0.004) and on the receptive-
nitis or intracranial calcifications occur (Plosa communication scale (P = 0.003) (Kimberlin
et al. 2015). Serologic methods for diagnosis of et al. 2015). Grade 3 or 4 neutropenia occurred in

19% of the participants during the first 6 weeks, over time. The majority of invasive meningococ-
and in 21% of the participants during the next cal cases across Europe from 2008 to 2009 were
4.5 months of the study in the 6-month group and caused by serogroup B (71%), and the incidence
in 27% of those in the 6-week group (P = 0.64) rate for adolescents aged 15–19 years in 2009
(Kimberlin et al. 2015). The authors concluded was approximately 1.7 cases per 100,000 popula-
that the data from this controlled study suggest tion (European Centre for Disease Prevention
that among infants with symptomatic cCMV dis- and Control 2011). Australia and New Zealand
ease, 6 months of oral valganciclovir therapy has report similar incidence rates (Harrison et al.
a moderately favorable effect on long- term audi- 2009; Communicable Diseases Network
ologic and neurodevelopmental outcomes (after Australia: Commonwealth Department of Health
adjustment for baseline CNS involvement) with- and Ageing 2007). Low to moderate endemic
out an excess risk of neutropenia or the need to rates (of predominant serogroup B) in the
maintain intravenous access for prolonged peri- Americas range from 0.3 to 4 cases per 100,000
ods of time (Kimberlin et al. 2015). However, population (Harrison et al. 2009; World Health
ganciclovir does have toxic effects on the gonads Organization (WHO) 2011; Jafri et al. 2013). The
and is carcinogenic in animal models (Roche incidence of MenB disease is stable and low in
Pharmaceuticals 2001), and although these toxic US adolescents and young adults aged
effects have not been seen in humans, this infor- 11–23 years, with approximately 50–60 cases
mation should be conveyed to families of neo- and 5–10 deaths reported annually, the majority
nates for whom valganciclovir therapy is being (>80%) of which occur in older adolescents and
considered. It should be noted that the results of young adults aged 16–23 years (MacNeil et al.
the study do not apply to infants with asymptom- 2015). Whereas several outbreaks of MenB dis-
atic cCMV infection, as there are no controlled ease have occurred in recent years on college
studies showing a benefit in this population and campuses in the US, 98% of cases are sporadic
the possibility of harm exists (Kimberlin et al. (Folaranmi et al. 2015).
2015). Since CMV-associated SNHL fluctuates Adolescents and young adults are uniquely
over time in more than one third of patients as susceptible to poor outcomes from invasive
part of the natural history of this disease, pro- meningococcal disease and are therefore tar-
spective, controlled trial designs are critical to geted for vaccination in order to protect them as
assess treatment benefit in patients with asymp- well as impact carriage rates, thereby leading to
tomatic cCMV infections. ‘herd protection’. While the incidence of menin-
gococcal disease is highest in infants <1 year of
age, there tends to be a second peak in adoles-
Meningococcal B Vaccines cents, aged 11–19 years (Jafri et al. 2013).
Nasopharyngeal carriage is more prevalent
Meningococcal disease caused by the encapsu- among adolescents (Christensen et al. 2010;
lated organism Neisseria meningitidis remains a Soeters et al. 2015). The high carriage rate and
feared and devastating illness due to its rapid peak of disease incidence in adolescents and
onset and associated morbidity and mortality young adults is thought to be due largely to fac-
(Rouphael and Stephens 2012). Differences in tors associated with social behaviors such as
the polysaccharide capsule surrounding the close living quarters (e.g. university dormitories,
organism allow classification into 12 serogroups, military barracks), crowded venues (e.g. bars,
of which A, B, C, W and Y are predominantly clubs), intimate contact (e.g. kissing, sharing
responsible for invasive disease (Rouphael and drinks), smoking, and sleep deprivation (Delbos
Stephens 2012). Meningococcal disease due to et al. 2013; Broderick et al. 2012).
serogroup B (MenB) is endemic in many coun- Conjugate vaccines have been successfully
tries in Europe, the Western Pacific, and the used to protect against disease caused by menin-
Americas where incidence rates are dynamic gococci with ACWY capsular polysaccharides

(Halperin et al. 2012). This approach has been following rates: pain at the injection site (83–
unfeasible for MenB as its capsular polysaccha- 85%), headache (33–35%), myalgia (30–48%),
ride is antigenically similar to the human fetal fatigue (35–40%), induration (28%), nausea
neural cell adhesion molecule resulting in poor (18%), chills (15%), and arthralgia (13%) (Wyeth
immunogenicity and the potential to induce auto- Pharmaceuticals Inc 2014; Novartis Vaccines and
antibodies (Bai et al. 2011). Consequently, atten- Diagnostics Inc 2015). The CDC’s Advisory
tion has focused on alternative non-capsular Committee on Immunization Practices (ACIP)
vaccine candidates, which are immunogenic, has recommended that a MenB vaccine series
highly conserved and expressed among all may be administered to adolescents and young
meningococci, in order to provide broad protec- adults aged 16–23 years to provide short-term
tion against diverse MenB strains (Panatto et al. protection against most strains of MenB disease
2011; Tan et al. 2010). Utilizing the natural abil- with the preferred age for vaccination being
ity of meningococci to shed outer membrane 16–18 years (recommendation Category B)
vesicles (OMV) during growth, initially, mon- (MacNeil et al. 2015). It states that MenB vac-
ovalent OMV vaccines were developed from cines may be administered concomitantly with
local outbreak strains in response to epidemics in other vaccines indicated for this age, but at a dif-
Norway, Cuba, Chile and New Zealand (Bai et al. ferent anatomic site, if feasible (MacNeil et al.
2011). However, protection induced by these 2015). In 2015, the ACIP recommended routine
vaccines is generally strain specific and unable to use (recommendation Category A) of MenB vac-
provide protection in areas with heterogeneous cines in certain groups of persons at increased
epidemiology. risk for MenB disease, including during out-
The first broad-spectrum multicomponent breaks of MenB disease (Folaranmi et al. 2015).
vaccine against serogroup B meningococcus College campuses that have recently experienced
(MenB), 4CMenB (Bexsero®), was approved by an outbreak of MenB disease should continue to
the European Medicines Agency (EMA) in 2013, follow the recommendations for use of MenB
for prevention of MenB disease in all age groups, vaccines in outbreak settings that recommend
and by the US Food and Drug Administration vaccination for persons aged ≥10 years
(FDA) in January 2015 for use in adolescents (Folaranmi et al. 2015).
aged 10–25 years (MacNeil et al. 2015; Seib Thus, while it is encouraging to have new
et al. 2015). A second protein-based MenB vac- MenB vaccines for adolescents and young adults,
cine has also been approved in the US for adoles- they are at present being routinely recommended
cents aged 10–25 years (Trumenba®) (MacNeil only for people with increased risk for MenB dis-
et al. 2015; Seib et al. 2015). Both vaccines con- ease and in outbreak settings. It will be interest-
tain the lipoprotein factor H-binding protein ing to follow the impact of these vaccines and
(fHbp), while 4CMenB also contains Neisseria evaluate changes in the epidemiology of MenB
adhesin A (NadA), Neisserial Heparin Binding disease over time.
Antigen(NHBA) fused with GNA1030, and
OMV from the New Zealand out-break strain
NZ98/254 (NZ OMV) (Seib et al. 2015; Donnelly Zika Virus
et al. 2010; Nolan et al. 2015; Perrett et al. 2015;
Findlow 2013). Trumenba® was licensed in the Zika virus (ZIKV) was discovered in monkeys of
US in October 2014 as a 3-dose series given at 0, the Zika Forest in Uganda in 1947 and was first
2, and 6 months and has recently received documented in humans in 1952 (World Health
approval for 2 doses at 0 and 6 months (Wyeth Organization 2016a). Fourteen confirmed cases
Pharmaceuticals Inc 2014). Bexsero® is licensed were documented in African and Asian countries
in the US for 2 doses at 0 and ≥1 month (Novartis throughout the latter half of the twentieth century
Vaccines and Diagnostics Inc 2015). Both vac- (Broutet et al. 2016). In 2007, an outbreak in
cines produce local and systemic reactions at the Micronesia signaled the spread of ZIKV, with 49

confirmed cases and over 50 unconfirmed. From GBS and the syndrome seems to resolve within a
2013 to 2014 confirmed cases were documented few weeks of onset.
throughout Oceania and in April 2015 a ZIKV The most alarming complication of ZIKV
outbreak began in Brazil (Roth et al. 2014; Saiz infection is the development of severe birth
et al. 2016). Since then it has spread to countries defects, including: microcephaly, decreased
in South America, Central America, Mexico, and brain parenchymal volume resulting in ventricu-
the Caribbean. For the last half century ZIKV had lomegaly, lissencephaly, and calcifications in the
lurked in the shadows of other mighty mosquito- basal ganglia and subcortical-cortical transition
borne infections such as dengue, yellow fever, area (Cavalheiro et al. 2016). The most severe
West Nile virus and malaria. However it has birth defects occur upon infection during the first
become clear that ZIKV does in fact pose a great trimester.
threat to public health due to the concurrent rise Differential diagnoses for ZIKV infection
in birth defects and Guillian-Barre Syndrome include dengue and chikungunya. Blood or urine
(GBS) associated with it. tests may confirm ZIKV infection; however,
ZIKV is an enveloped, icosahedral flavivirus blood tests may produce false positives due to
related to dengue, yellow fever, and West Nile cross-reactivity with antibodies for other flavivi-
viruses (Saiz et al. 2016). It has a non-segmented, ruses (especially dengue and yellow fever)
positive-sense, ssRNA genome allowing for rapid (Petersen et al. 2016). In pregnant women amnio-
replication within host cells and subsequent centesis may determine if the infection has spread
transfer to vectors. Arthropod vectors of ZIKV to the fetus.
include at least 15 species of mosquitos from the There is no specific antiviral therapy for or
Aedes genus, mainly A. aegypti (Americas) and vaccine to prevent ZIKV infection at this time.
A. albopictus (Asia) (Centers for Disease Control General precautions against mosquito exposure
and Prevention 2016a). Other modes of transmis- should be taken and pregnant women should be
sion include mother to child, sexual contact (virus advised about the risks of traveling to ZIKV
may reside in sperm unknown period of time), endemic areas. Rest, fluids, and acetaminophen
blood transfusions, and laboratory exposure. The to control fever/pain are the only recommended
exact pathogenesis of ZIKV is still unknown, but interventions. NSAIDs should be avoided until
is inferred from that of similar flaviviruses. dengue can be ruled out to avoid bleeding
Most cases of ZIKV are relatively minor with (Centers for Disease Control and Prevention
incubation periods of 3–12 days (Brito 2015). 2016b). Healthcare providers should monitor
About 18% of cases are symptomatic and present pregnant women diagnosed with ZIKV infection
with influenza-like features (Saiz et al. 2016). through serial ultrasounds and discuss termina-
Common symptoms include fever, pink maculo- tion of pregnancy on an individual basis. ZIKV
papular rash, joint pain, and conjunctivitis; less guidelines from the CDC and WHO are available
common symptoms include vomiting, headaches, for practitioners to follow (Centers for Disease
edema, and jaundice (Centers for Disease Control Control and Prevention 2016d; World Health
and Prevention 2016b). Occasionally, gastroin- Organization 2016b).
testinal complications may occur, manifesting as
abdominal pain, diarrhea, constipation, or ulcers
(Saiz et al. 2016). Symptoms generally resolve Summary/Conclusion
within a week, however joint pain and weakness
may last up to month post-infection. It appears This chapter has focused on several contempo-
that there is an epidemiologic link between ZIKV rary topics in pediatric infectious diseases includ-
infection and the development of GBS; this asso- ing the impact of HPV vaccines; the ongoing
ciation is yet to be confirmed (Centers for Disease outbreaks of measles in the US; the rise in C. dif-
Control and Prevention 2016c). No deaths have ficile infections and their management in children;
been reported in ZIKV infected patients with the role of antibiotic stewardship in pediatric

facilities; the status and management of MRSA Boppana SB, Ross SA, Novak Z, et al. Dried blood spot
real-time polymerase chain reaction assays to screen
infections; the management of congenital CMV
newborns for congenital cytomegalovirus infection.
infections; the introduction of meningococcal B JAMA. 2010;303:1375–82.
vaccines; and the Zika virus outbreak and its Boppana SB, Ross SA, Fowler KB. Congenital cytomega-
implications. This sample of subjects exemplifies lovirus infection: clinical outcome. Clin Infect Dis.
2013;57(Suppl 4):S178–81.
the dynamic and diverse nature of the subspe-
Bosch FX. Human papillomavirus: science and technolo-
cialty, as emerging and re-emerging infections gies for the elimination of cervical cancer. Expert
keep this field engaged in ongoing research and Opin Pharmacother. 2011;12(14):2189–204.
scholarship. Bosch FX, Castellsague X, de Sanjose S. HPV and cer-
vical cancer: screening or vaccination? Br J Cancer.
2008;98(1):15–21.
Brito C. Zika virus: a new chapter in the history of medi-
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Update in Clinical Genetics
and Metabolics 14
Christine M. Armour and Matthew A. Lines
Clinical genetics has undergone unprecedented Updates in Clinical Genetics

change in recent years. The increasing sophistica-
tion of molecular genetic testing, together with the The advent of improved genetic testing methods
accelerating tempo of disease gene discovery, has has dramatically changed the landscape of testing
led to greatly enhanced rates of successful clinical options available in the genetics clinic, providing
diagnosis. New and powerful techniques such as improved rates of diagnosis and providing new
whole-exome sequencing have made it possible to insights into many rare conditions. Given the
efficiently catalogue most of the protein-coding increasing diagnostic power of genetic testing,
genetic variation in an individual. At the same these techniques seem poised to gradually transi-
time, a great deal has been learned about the clini- tion into primary care; providers will need to
cal spectra of many genetic syndromes; in particu- become more familiar with the capabilities and
lar, mild or non-classical presentations of many limitations of these tests.
disorders are becoming increasingly recognized. New test methods that have been developed
The field of Metabolics has also advanced due to over recent years include:
the increasingly widespread adoption of mass-
spectrometry-based expanded newborn screening 1. High resolution chromosomal microarray (also
programs, allowing earlier detection of many called array comparative genomic hybridiza-
treatable metabolic disorders. The role of trans- tion, aCGH): This test uses a chip technology to
plantation, both of solid organs and of hematopoi- assess all of a patient’s chromosomes for miss-
etic stem cells, has continued to expand, as have ing (deleted) or extra (duplicated) material.
the roles of enzyme replacement, small-molecule 2. Massively parallel DNA sequencing, also

therapy, and novel targeted therapies for many called Next Generation Sequencing (NGS):
classic genetic disorders. These techniques allow tremendous amounts
of DNA sequence to be read simultaneously,
permitting the simultaneous testing of many
C.M. Armour, M.D., M.Sc., F.R.C.P.C (*)
genes with high accuracy and efficiency.
Regional Genetics Unit, Children’s Hospital
of Eastern Ontario, 401 Smyth Road, Ottawa, NGS-based tests include ‘gene panel’ tests
ON K1H 8L1, Canada (genes grouped together by common pheno-
e-mail: carmour@cheo.on.ca type, e.g. genes associated with ciliopathies
M.A. Lines, M.D, F.R.C.P.C., F.C.C.M.G or intellectual disability) and whole-exome
Metabolics, Department of Pediatrics, Children’s sequencing (WES), which attempts to read
Hospital of Eastern Ontario, 401 Smyth Road,
the coding regions of all or most protein-
Ottawa, ON K1H 8L1, Canada
e-mail: mlines@cheo.on.ca coding genes. WES has recently become


370 C.M. Armour and M.A. Lines
available in some jurisdictions. Whole- symptoms) and/or penetrance (likelihood of caus-

genome sequencing (WGS) is available pri- ing any symptoms). To aid in interpretation of the
marily on a research basis. results, the reporting clinical laboratory provides
an interpretation of any findings, classifying each
As with any test, it is essential that the funda- CNV as one of: pathogenic, a variant of unknown
mentals of these tests are understood prior to significance (VOUS), or likely benign. Common,
applying them in patient care. Consideration or relatively common, benign CNVs are not
should be given to appropriate clinical indica- usually reported. Reporting standards vary by

tions, limitations of the test, and the uncommon, jurisdiction.
but real chance of incidental findings. Incidental
findings (also referred to as secondary findings)
are highly predictive of a medically actionable Pathogenic copy number variants (dele-
condition, but are unrelated to the primary indi- tions or duplications) are thought to account
cation for testing. One example of an incidental for approximately 8–20% of the cases of
finding could be the detection of a mutation for global developmental delay and/or multi-
an adult-onset cancer predisposition (e.g. BRCA1 ple congenital anomalies (Michelson et al.
mutation) when ordering a test for developmental 2011; Miller et al. 2010).
delay. Further details on specific technologies are
discussed below.
The main advantage of CMA over conven-
tional karyotyping is the ability to detect much
Chromosomal Microarray smaller deletions or duplications. For example,
depending on the specific type of array used,
Chromosomal microarray (CMA) has become CMA may detect CNVs above 40–100 kilobases
an integral tool in the first line of investigations (kb) in size, whereas traditional karyotype typi-
for a number of common clinical presentations, cally detects only changes above 4–6 megabases
such as developmental delay/intellectual dis- (Mb). As with traditional karyotypes, complete
ability, autism spectrum disorders and congeni- trisomy or loss of an entire chromosome (e.g. tri-
tal anomalies in many jurisdictions (Miller somy 18 or Turner syndrome), are also detected
et al. 2010; Michelson et al. 2011; Moeschler by CMA.
et al. 2014). As described above, the term There are some important limitations of CMA:
‘chromosomal microarray’ refers to a group of
technologies that allows detailed analysis of 1. CMA cannot detect balanced rearrangements
chromosomes to assess for duplicated or deleted (those which produce no net loss or gain of
segments of chromosome. Such duplications or chromosomal material). Practically speaking,
deletions are referred to as ‘copy number vari- this is not typically of major concern in the
ants’ (CNVs). evaluation of patients with intellectual disabil-
Chromosome variants may be either benign ity, autism or MCA.
(without medical significance) or pathogenic (dis- 2. Arrays are not a sensitive method for assess-
ease-causing), and this distinction is not always ing mosaicism, particularly mosaicism below
straightforward. The gene content and location of approximately 20–30% (Miller et al. 2010).
the CNV are important factors in assessing its 3. Like karyotypes, CMA does not inspect indi-
pathogenicity. Many smaller CNVs may be found vidual genes in detail, and will not detect
in healthy individuals. On the other hand, CNVs single point mutations, trinucleotide repeat
may be the clear cause of the presenting com- expansions, or very small deletions/duplica-
plaints (e.g. the microdeletion responsible for tions below the resolution of the CMA. Other
22q11.2 microdeletion syndrome). Other CNVs technologies are required for this level of
are variable in their expressivity (severity of detail.

14 Update in Clinical Genetics and Metabolics 371
The two most commonly-used array types

are oligonucleotide arrays and the single nucle- Pre-test and post-test counselling should
otide polymorphism (SNP) arrays, the latter include (but is not limited to):
being the more commonly used in many labora-
tories at present. While both types of array can • A brief explanation of what the test can
provide information about CNVs, SNP arrays and cannot detect (e.g. segments of
also have the advantage of highlighting genomic chromosomes but not gene level data)
intervals which are homozygous (i.e. where • The likelihood of identifying a patho-
both maternal and paternal chromosomes con- genic finding, which varies by indication
tain identical material). SNP analysis is useful • The likelihood of identifying an inci-
in the detection of uniparental disomy (which dental finding
may lead to imprinting disorders), parental con- • The implication of an incidental finding
sanguinity, and triploidy (in which an individual in your jurisdiction (e.g. insurance bias)
has three sets of all chromosomes); such infor- • Whether or not one is able to ‘opt out’ of
mation cannot be obtained from oligonucleotide incidental findings
array. Many laboratories will report the loss of • Follow up testing that may be indicated,
heterozygosity (LOH) in terms of the amount as in the case of variants of uncertain
and location that is identified. The ordering pro- significance
vider should be aware of the type of array being • Overall benefits and drawbacks of testing
used so that they understand the limits and
information gained.
While the reason for offering CMA to a patient Sequencing-Based Technologies
remains identification of the cause of the pheno-
type, it is imperative to be aware of the other General Principles
types of findings that may arise, so that the Next Generation Sequencing (NGS) is a high-
patient/parents/guardians are appropriately coun- throughput sequencing technology that allows
selled so that they are adequately informed prior many millions of molecules of DNA to be ampli-
to deciding on proceeding, or not. This may fied and analyzed in a shorter time frame than
become relevant for example for insurance earlier methods (e.g. Sanger sequencing). The
purposes. volume of data from NGS is orders of magnitude
Incidental findings are occasionally identi- greater than from earlier forms of genetic test-
fied on CMA. Rates vary by study, but inciden- ing. With this comes the need for better bioinfor-
tal findings may occur in approximately matic methods to interpret the many thousands of
0.3–1.0% of cases (Pichert et al. 2011; Boone genetic variants potentially observed in a given
et al. 2013). Examples of incidental findings on patient. There are a number of general principles
CMA could include detection of a deletion that ought to be considered when ordering a NGS
encompassing a cancer-predisposition gene, or based test, many of which are similar to those
identification of a heterozygous deletion in the described for CMA. As for other tests in medi-
DMD gene in a female, implying that her male cine, if unfamiliar with the test methods and/or
offspring would be at risk of Duchenne muscu- its interpretation, it is often better not to order the
lar dystrophy. When ordering an array, pre-test test, and to instead refer the patient.
counselling should include the possibility of Appropriate use
incidental finding(s), and the potential outcomes
of information found (e.g. insurance discrimina- 1. An important current principle is that of lim-
tion). Although obvious, it bears mention that iting sequencing to testing of Mendelian
the individual tested should be the affected indi- conditions (single gene). At present, the clini-
vidual, rather than an asymptomatic relative cal utility of performing genetic testing for
(e.g. parent). apparently multifactorial conditions (e.g.

hypertension, myocardial infarction) has not sequenced fewer than 20 times, and may contain
been established (Boycott et al. 2015). mutations which have gone undetected.
2. For single-gene disorders, it is appropriate to
analyze the pertinent gene individually, as Appropriate pre- and post-test counselling
opposed to using a broader test (e.g. panel). The counselling for NGS is similar to that for
However, as the cost of sequencing decreases, CMA, with the addition of details pertinent to the
and bioinformatics methods improve, this level of DNA sequence.
may become less of an issue. Pre-test and post-test counselling for NGS-
3. As the number of genes examined increases, based testing should include (but is not limited to):
the likelihood of incidental findings and/or
variants of unclear significance also increases. • Overall benefits and drawbacks of testing
• A brief explanation of what the test can and
Sorting natural variation from pathogenicity cannot detect
In interpreting NGS data, it is important to appreci- • The likelihood of identifying a pathogenic
ate that there is significant natural variation amongst finding (odds of a diagnostic test result),
humans at the level of DNA sequence, and only a which varies by indication
very small proportion of this variation is clinically • The possibility of one or more incidental
relevant (Cooper and Shendure 2011). In making finding(s)
its interpretation, the laboratory must select only • Whether or not one is able to ‘opt out’ of inci-
those few variants which are likely to be disease- dental findings
causing, from this enormous natural background
variation. Non-specialists and patients commonly Follow-up testing that may be indicated, as in
over-ascribe clinical significance to reported vari- the case of variants of uncertain significance.
ants which may or may not be meaningful.
Limitations Pre-test and post-test counselling for NGS-

A critical limitation of NGS is that some types of based testing should include (but is not lim-
genetic alterations (large deletions or duplica- ited to):
tions, trinucleotide repeats, etc.) cannot be easily
detected. Examples of relevant conditions that • Overall benefits and drawbacks of
would not detected using current NGS methods testing
include chromosomal disorders in general, Fragile • A brief explanation of what the test can
X syndrome, and Myotonic Dystrophy, among and cannot detect
many others. Diseases with multiple genetic eti- • The likelihood of identifying a patho-
ologies, such as with Angelman syndrome (which genic finding (odds of a diagnostic test
can arise from deletions, uniparental disomy, or result), which varies by indication
single gene changes), may or may not be detected. • The possibility of one or more inciden-
The reliability of an NGS result depends on tal finding(s)
several technical factors. The regions targeted for • Whether or not one is able to ‘opt out’ of
sequencing (e.g. the genes of interest) may or may incidental findings
not be covered in their entirety, and/or the depth of • Follow-up testing that may be indicated,
coverage (the average number of sequence ‘reads’ as in the case of variants of uncertain
corresponding to a given region) may or may not significance.
be adequate to ensure that mutations are success-
fully identified (Sims et al. 2014). For example, if
99% of the target is covered to an average depth of Types of Applications
20-fold, this indicates that 99% of the DNA bases
in the gene have been sequenced at least 20 times. There are a number of ways in which NGS can be
The remaining 1% of base pairs have been used to examine genes. The two principal clinical

uses are ‘gene panels’, which are in use in many Often only variants in genes with a known clinical
laboratories for a wide variety of indications, phenotype are reported. It is currently estimated
and whole-exome sequencing (WES), which is that humans have approximately 19,000–25,000
offered by an increasing number of laboratories genes (International Human Genome Sequencing
worldwide. Consortium 2004; Ezkurdia et al. 2014). Of these,
current estimates suggest that about 5000 are
Gene Panels known to be associated with a condition (OMIM
Multiple genes associated with similar pheno- 2016). It is unclear what, if any, clinical importance
types are often co-analyzed as part of an NGS should be ascribed to variants in genes of unknown
panel. One such example is the Noonan syn- function (outside of a research context). WES is a
drome spectrum, which is caused by mutations of very powerful tool for novel disease gene discovery
several genes in a common biological pathway, in the context of research (discussed below). WES
the RAS/mitogen-activated protein kinase (Ras/ has become available for clinical use in some juris-
MAPK) signalling pathway (reviewed in Aoki dictions, but access may be limited in some cases
et al. 2016). There are numerous gene panels for by its relatively high present cost.
many different phenotypes available through While very powerful, WES does not diagnose
many academic and commercial laboratories. all patients, or even all patients with a Mendelian
Panels vary in their contents, and ‘more is not disorder. Diagnostic yield for the technique
always better’; when ordering, one should be depends heavily on numerous factors, such as the
aware of the genes included on the panel, and clinical presentation, the point in the diagnostic
consider if they are all well-associated with the workup at which WES is employed, and the
condition. Some laboratories include genes that experience and technical capabilities of the labo-
may be only loosely associated with the condi- ratory. Importantly, WES is more likely to yield a
tion in question. In addition, some panels may specific molecular diagnosis when the analysis is
‘lump together’ a variety of phenotypically carried out as a ‘trio’ of the proband and their
diverse conditions which would not usually be biological parents, as parental data enhance the
co-considered clinically. For example, if a inves- classification of variants in the proband (Retterer
tigating a child a with apparently non-syndromic et al. 2016).
hearing loss, some panels may include syndromic WES is used primarily for the diagnosis of
forms of hearing loss with other medical implica- Mendelian conditions and there is little evidence
tions beyond hearing alone (e.g. a variant of to support its use for multifactorial conditions.
unknown significance in a gene for Alport syn- Factors suggestive of a single-gene disorder
drome may lead to additional screening and/or include family history consistent with Mendelian
insurance bias). inheritance (autosomal dominant, autosomal
recessive, X-linked recessive, etc.), consanguin-
ity (recessive disorders), familial recurrence, or
unusually severe and/or young-onset phenotypes.
“Gene panels are currently best suited to
Some medical conditions (e.g. retinitis pigmen-
presentations that are relatively specific in
tosa) are both heterogeneous and almost
regard to their clinical features and do not
exclusively genetic; the yield of WES is likely to
have very high genetic heterogeneity”
be highest in this group (Boycott et al. 2015).
(CCMG statement, Boycott et al. 2015).”
hole-Exome Sequencing (WES)

W The overall diagnostic yield of WES is
WES refers to the sequencing of the coding regions often approximately 30%, varying greatly
(exons) of most or all protein-coding genes by clinical features and indication (Boycott
(Boycott et al. 2015). Non-coding sequences, such et al. 2015; Retterer et al. 2016).
as introns and regulatory regions are not examined.

Incidental Findings in WES and recommended that the sequence data be

filtered so as to minimize incidental findings
Incidental or secondary findings are medically (Boycott et al. 2015). They endorsed the abil-
relevant results which are unrelated to the clinical ity of consenting adults to decline to be
indication. At present, there are limited data informed, while supporting the disclosure (to
about the overall rate of incidental findings in parents) of all incidental results in highly-
WES; estimates in broad groups of patients are in penetrant genes that are medically actionable
the range of approximately 4.6–6.2% (Lee et al. during childhood.
2014; Yang et al. 2014; Retterer et al. 2016).
Professional bodies have issued statements It behooves physicians ordering NGS-based
regarding disclosure of incidental findings; these tests to be well versed in the policies of their
have been not without controversy, and vary by jurisdiction, and of the laboratory from which
jurisdiction. they are ordering the testing, regarding incidental
findings, and to convey those to the patient and
• The European Society of Human Genetics family accurately during the consent process.
(ESHG) has recommended the analysis of Guidelines are likely to continue to evolve as the
NGS data (the ‘bioinformatic pipeline’) medical community gains experience with the
include filtering of known genetic variants use of these techniques.
with limited or no clinical utility to exclude In summary, WES is a powerful technology
genetic variants in genes unrelated to the pri- which is changing the practice of clinical genet-
mary indication to minimise inadvertent ics. In using WES, the technical and ethical con-
diagnosis (van El et al. 2013). At the same siderations implicit in its use must be borne in
time, they recommended that if a variant with mind. Practitioners making use of WES should
serious health implications is identified be well-acquainted with the technology, its limi-
(either for the patient tested or a close rela- tations, and the patient’s unique clinical context,
tive), it should be reported back to the patient. prior to deciding whether it is the most appropri-
They also recommended that guidelines ate test to offer the patient.
around consent for such testing needed to be
developed. Whole-Genome Sequencing
• The American College of Medical Genetics WGS refers to the sequencing of an almost all of
(ACMG) detailed a minimum list of 56 genes an individual’s genome (Boycott et al. 2015).
they deemed medically actionable for which While WGS yields a great deal more sequence
laboratories should report pathogenic variants information than even WES, practical applica-
regardless of the clinical indication for testing tions for WGS are currently few, as the large
(Green et al. 2013). They originally recom- majority of detected variants reside in non-
mended that these 56 genes should be ana- coding regions (i.e. outside of recognized genes),
lyzed on all samples undergoing genome-wide and are without obvious medical significance.
sequencing, with mandatory reporting to the The volume of data generated by WGS is enor-
ordering clinician. They later amended their mous, and manipulation and storage of the data
recommendations to allow patients to opt-out are additional concerns. There are only a few
of receiving such results, or any incidental clinical laboratories worldwide offering clinical
findings (ACMG 2015). WGS, and its use is not yet well-integrated into
• The Canadian College of Medical Genetics the clinic.
(CCMG) stated that they do not ‘endorse
intentional clinical analysis of disease genes Research Testing
unrelated to the primary indication, even if While WES, and to a much lesser degree
the results might be medically actionable’, WGS, has emerged into clinical use in some

jurisdictions, many research studies are ongoing An exhaustive review of medical therapy for
to study the use of these techniques, to apply genetic disorders is beyond the scope of this
them in different clinical scenarios, and to share chapter, and the reader is encouraged to refer to
data between multiple institutions in order to the literature on a case-by-case basis, as needed.
accelerate the discovery of novel disease genes. Many high-quality resources exist to guide
To this end, a research study may be a viable practitioners with respect to the care of patients
option for some patients, particularly those who with genetic syndromes. For example, the
may not have access to clinical testing. The American Academy of Pediatrics has produced a
Canadian College of Medical Geneticists has series of free online guidelines for health care
also endorsed “the option of having coded or supervision of a number of more common syn-
anonymised genome-wide and phenotypic data dromes such as Fragile X or Williams syn-
deposited and stored in an international data- drome (AAP Committee on Genetics 2001; Hersh
base to assist in interpretation of genome-wide et al. 2011). Likewise, the National Center for
studies of themselves and other patients” and to Biotechnology Information (US) hosts a clinically-
“understand the relationship of genome-wide oriented review series, ‘GeneReviews’, which is a
variants found in them and clinical abnormali- ‘one stop’ shop for diagnosis, management and
ties” (Boycott et al. 2015). counseling guidelines for many disorders [https://
www.ncbi.nlm.nih.gov/books/NBK1116/].
Management of Genetic Diseases Gene Therapy

In most jurisdictions gene therapy remains in the
Although genetic diseases are innate to the indi- research realms and/or entering clinical trials.
vidual and have historically been challenging to A detailed discussion of gene therapy is beyond
treat, many genetic conditions do have specific the scope of this chapter but specific examples of
management. At minimum, specific surveillance advancements in gene therapy include:
measures (imaging, specialist clinical surveil-
lance, etc.) and/or developmental supports (phys- • recent approval of ‘Strimvelis’, a type of gene
ical therapy, occupational therapy, speech/ therapy approved for Adenosine deaminase
language therapy) exist for many genetic syn- (ADA) deficiency which leads to severe com-
dromes. Many metabolic disorders have specific bined immune deficiency, by the European
dietary or pharmacological treatments, and these Medicines Agency (Hoggatt 2016).
are discussed in the metabolics section below. • numerous promising trials are ongoing that
Moreover, a few classical genetic syndromes trial gene therapy for hemophilia A and B,
have in recent years received specific (pathway- with more success currently being observed
directed) small-molecule treatments. Selected with Hemophilia B (reviewed in Ward and
examples include: Walsh 2016).
• Treatment of the aortopathies (e.g. Marfan

syndrome, Loeys-Dietz syndrome) with Updates in Metabolics
β-blockers or angiotensin-converting enzyme
inhibitors. Angiotensin II receptor antagonists The human genome encodes thousands of
may mitigate dilatation of the aorta (Lacro enzymes and transporters, each of which has
et al. 2014). evolved over evolutionary time to fulfil a specific
• Treatment of rapidly growing renal angio- metabolic role. With that complexity in mind,
myolipomas in Tuberous Sclerosis with this section aims to provide a general overview of
mTOR inhibitors is now considered clinical inborn errors of metabolism (IEMs), with empha-
first-line therapy (Kingswood et al. 2016). sis on recent developments in the field. For

greater detail on specific disorders, the reader is s ymptoms and signs; recognition is largely clini-
referred to any of several encyclopedic refer- cal, and laboratory tests serve to confirm the
ences (Valle et al. 2016; Saudubray et al. 2016; clinical impression. Small-molecule disorders
Nyhan et al. 2012; Pagon et al. 1993). Vademecum and organellar diseases can be further subclassi-
Metabolicum is a useful pocket reference which fied into ‘families’ of disorders (Tables 14.2 and
is also available both online and as a free mobile 14.3, respectively) on the basis of the affected
‘app’ (Zschocke and Hoffmann 2011). pathway (e.g. ‘urea cycle disorders’, ‘fatty acid
oxidation disorders’), and/or the specific labora-
tory test employed for diagnosis (e.g. ‘organic
General Clinical Paradigms acidurias’).
IEMs can be roughly divided into two main ‘Small-Molecule’ Disorders

groups (Table 14.1): Small-molecule IEMs are characterized by defi-
ciency of an enzyme, enzyme cofactor, or trans-
(a) Small-molecule disorders of intermediary porter, with a resulting ‘block’ in one or more
metabolism. metabolic pathway(s). This, in turn, results in
(b) Organellar diseases. either (1) toxic accumulation of ‘upstream’
substrate(s), and/or (2) deficiency of the path-
In general and with many exceptions, small- way’s ‘downstream’ product(s) (Fig. 14.1).
molecule disorders follow a (sub)acute or epi- Although some small-molecule disorders present
sodic course, exhibit relatively nonspecific with recognizable symptoms and signs, presenta-
clinical symptoms and signs, and require use of tions are more typically nonspecific. Some small-
the biochemical laboratory for diagnosis. In con- molecule IEMs present suggestive findings on
trast, organellar diseases are chronic condi- routine laboratory studies (blood gases, electro-
tions which often exhibit characteristic clinical lytes, CBC, glucose, lactate, ammonia, etc.);
Table 14.1 General clinical paradigms in metabolism

‘Small-molecule’ disorders ‘Organellar’ diseases
Course Acute or episodic > chronic Chronic +/− initial normal
period
Clinical presentation Nonspecific Often suggestive or specific
‘Routine’ lab investigationsa Often suggestive (when patient symptomatic) Normal or non-specifically
(Table 14.4) abnormal
‘Metabolic’ lab investigations – ‘Small molecule metabolic screen’b – Specific metabolite tests for
– Specific enzyme or metabolite tests each condition
– Genetic testing – Specific enzyme test
– Genetic testing
Newborn screening Some disorders targeted Few disorders targeted
Typical treatments Varies by condition, may include: Varies by condition, may
– Supportive measures include:
– Modified diet – Supportive measures
– Vitamin/cofactor supplements – HSCT
– Drugs – ERT
– HSCT – Drugs
– Solid organ (e.g. liver) transplantation
ERT enzyme replacement therapy, HSCT hematopoietic stem cell transplantation
a
Typically: Complete blood count, blood gas, electrolytes, glucose, lactate, ammonia (free-flowing venous sample,
transport on ice, analyze promptly)
b
Typically: Plasma amino acids, total homocysteine, urine organic acids, plasma acylcarnitine profile, free and total
carnitine, other tests as indicated clinically

Table 14.2 Major categories of small-molecule IEMs

Group Examples Typical presentations Key investigations
Amino acidopathies PKU Various Amino acids
Tyrosinemia type I Homocysteine (CBS)
MSUD
Homocystinuria (CBS)
NKH
Organic acidurias ‘Classic’ OAs (MMA, Acute metabolic crisis, high-anion- Urine organic acids
PA, IVA, etc.) gap metabolic acidosis, Acylcarnitine profile
neutropenia Ammonia
‘Cerebral’ OAs (GA-I, Acute and/or chronic Brain MRS
Canavan, etc.) encephalopathy Urine organic acids
Acylcarnitine profile
Urea cycle OTC Hyperammonemic crises, protein Ammonia
Citrullinemia (I + II) intolerance Plasma amino acids
ASA lyase Urine orotic acid
Arginase deficiency
HHH
CPS
NAGS
Fatty acid oxidation MCAD Variously, any of: Acylcarnitine profile
disorders and VLCAD Fasting hypoketotic hypoglycemia, Free, total carnitine
carnitine shuttle LCHAD/MTP cardiomyopathy, rhabdomyolysis, Urine organic acids
CPT 1a, CPT 2 neuropathy, retinopathy, or Beta-hydroxybutyrate
CACT multiple organ systems failure Free fatty acids
MADD/GA2
Disorders of vitamin Cobalamin disorders Various Various
and cofactor (several)
metabolism BTD
PDE
Biopterin defects
Cerebral folate
deficiency
Carbohydrate Classical galactosemia Acute liver failure, gram-negative Galactose-1-phosphate
disorders sepsis GALT activity
HFI Postprandial hypoglycemia, Glucose, lactate, uric acid,
hepatic injury ALT, AST (when
symptomatic)
Molecular testing
Glycogen storage GSD I (Von Gierke), Predominantly hepatic, e.g. Glucose, lactate,
diseases (excl. III, VI, IX hepatomegaly, fasting intolerance, triglycerides, uric acid,
Pompe) hypoglycemia with ketosis Abdominal U/S
GSD V (McArdle), VII Predominantly muscle, e.g. CK
postexertional rhabdomyolysis Non-ischemic forearm test
or cycle ergometry
GSD 0 (glycogen Postprandial hyperglycemia and Molecular testing
synthase) fasting hypoglycemia
Porphyrias AIP Episodic delirium Urine PBG and ALA
PCT and/or (when obtunded)
EPP Cutaneous photosensitivity Plasma, urine, and/or stool
porphyrins, or free
erythrocyte protoporphyrin
Metal metabolism Menkes disease Developmental delay, steel-wool Copper
hair, cutis laxa, bladder Ceruloplasmin
diverticulae Bladder U/S
(continued)

Purine and Lesch-Nyhan Hematological, neurological, and/ Urine purines, pyrimidines
pyrimidine ADA-SCID or joint symptoms Uric acid
metabolism
Pentose phosphate G6PD Hemolytic anemia G6PD screen
pathway
Neurotransmitter Various Encephalopathy CNS neurotransmitters
disorders
List is not comprehensive: Only selected disease categories are shown, and only selected ‘classical’ examples are
shown for each category. For all disorders, genetic testing may be considered in parallel with other investiga-
tions. For brevity, the word ‘deficiency’ has been omitted. ADA-SCID: Adenosine deaminase deficiency/severe com-
bined immunodeficiency; AIP: Acute intermittent porphyria; ALA: delta-aminolevulinic acid; ASA: Argininosuccinic
acid; BTD: Biotinidase; CACT: Carnitine-acylcarnitine translocase; CBS: Cystathionine beta-synthase; CPS:
Carbamoyl phosphate synthetase; CPT: Carnitine palmitoyltransferase; EPP: Erythropoietic protoporphyria; G6PD:
Glucose-6-phosphate dehydrogenase; GA-I: Glutaric aciduria type I; GA-II: Glutaric aciduria type II; GALE: Galactose
epimerase; GALT: Galactose-1-phosphate uridyltransferase; GSD: Glycogen storage disease; HFI: Hereditary fructose
intolerance; HHH: Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome; IVA: Isovaleric acidemia;
LCHAD: Long chain hydroxyacyl-coA dehydrogenase deficiency; MADD: Multiple acyl-coA dehydrogenase; MCAD:
Medium-chain acyl-coA dehydrogenase; MRS: Magnetic resonance spectroscopy; MSUD: Maple syrup urine disease;
MMA: Methylmalonic aciduria; MTP: Mitochondrial trifunctional protein deficiency; NAGS: N-acetylglutamate syn-
thase; NKH: Nonketotic hyperglycinemia; OA: Organic aciduria; OTC: Ornithine transcarbamoylase; PA: Propionic
acidemia; PBG: Porphobilinogen; PCT: Porphyria cutanea tarda; PDE: Pyridoxine-dependent epilepsy; PKU:
Phenylketonuria; VLCAD: Very long-chain acyl-coA dehydrogenase
Table 14.3 Major categories of organellar diseases

Mitochondrial Leigh syndrome High clinical and genetic heterogeneity Lactate
Alpers syndrome (Reviewed in Vafai and Mootha 2012) Plasma amino acids
MELAS Progressive involvement of one or (Ala, Pro, Gly)
MERRF more highly-oxidative tissues (CNS, Acylcarnitine profile
NARP retina, peripheral nerves, myocardium, Urine organic acids
SANDO skeletal muscle, pancreatic beta cell, GDF-15 (Davis et al.
Kearns-Sayre syndrome liver, etc.) 2016)
Pearson syndrome Consider muscle biopsya
Lysosomal Gaucher type Ib Splenomegaly, bruising, short stature Beta-glucosidase
with Erlenmeyer flask deformity of activity in WBCs
tibiae, ‘bone crises’, ‘spleen crises’
CNS sphingolipidoses (e.g. Neurological plateau/regression Specific enzyme test in
GM1, GM2, NPA/B, MLD, +/− cherry red macular spots, WBCs (most) or
Krabbe, Gaucher types II/ macrocephaly, hepatosplenomegaly, or fibroblasts (NPA/B)c
III, etc.) implacable crying episodes (Krabbe)
Mucopolysaccharidoses Dysostosis multiplex, organomegaly, Urine MPS spot
(e.g. Hurler/MPS I, Hunter/ macrocephaly, contractures, coarse Urine MPS fractionation
MPS II) features, developmental delay/regression, Urine oligosaccharides
Oligosaccharidoses +/− any of: corneal clouding, cardiac
Mucolipidoses (valvular) disease, angiokeratomata
Pompe (GSD II) (infantile Skeletal myopathy with massive ECG, echo
form) myocardial hypertrophy Acid maltase activity
Neuronal ceroid Retinopathy, seizures, neurological Skin biopsy for EM
lipofuscinoses decline PPT1, TPP1
enzymologies
Cystinosis Photophobia, proximal renal WBC cystine
tubulopathy, rickets Slit-lamp exam (corneal
crystals)
Urinalysis, urine amino
acids, urine phosphate

Peroxisomal Peroxisomal biogenesis Hypotonia, dysmorphism (large VLCFAs
(Zellweger spectrum) fontanelle, midface hypoplasia, broad RBC plasmalogens
D-bifunctional protein nasal bridge), CNS, hepatic, and renal Bile acids in urine by
(‘pseudo-Zellweger’) disease FAB-MS
X-ALD Behavioural/cognitive decline, white VLCFAs
matter changes, and/or adrenal Head MRI
insufficiency, and/or myelopathy
RCDP Rhizomelic limb shortening, calcific RBC plasmalogens
stippling of epiphyses
Congenital N-linked CDGs Highly heterogeneous (reviewed in Transferrin IEF (not
disorders of – Type I (endoplasmic Sparks and Krasnewich 2005) sensitive)
glycosylation reticulum) (CGD Ia): Abnormal cutaneous fat N-linked glycans by MS
– Type II (Golgi) pads
O-linked CDGs (e.g. Neuronal migration defects, congenital CK
Walker-Warburg, myopathy Brain MRI
Muscle-Eye-Brain) O-linked glycans by MS
Lipid SLO Various 7-dehydrocholesterol
disorders CTX (SLO)
Cholestanol (CTX)
List is not comprehensive: Only selected disease categories are shown, and only selected ‘classical’ examples are
shown for each category. For all disorders, genetic testing may be considered in parallel with other investiga-
tions. For brevity, the word ‘deficiency’ has been omitted. CDG: Congenital disorder of glycosylation; CK: Creatine
kinase; CTX: Cerebrotendinous xanthomatosis; EM: Electron microscopy; FAB: Fast atom bombardment; GDF-15:
Growth/Differentiation factor 15; GM1: GM1 gangliosidosis; GM2: GM2 gangliosidosis (Tay-Sachs disease/Sandhoff);
IEF: Isoelectric focusing; MELAS: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes;
MERRF: Myoclonic epilepsy with ragged red fibres
MLD: Metachromatic leukodystrophy; MPS: Mucopolysaccharidosis; MS: Mass spectrometry; NARP: Neuropathy,
ataxia, and retinitis pigmentosa; NPA/B: Niemann-Pick disease type A/B; PPT1: Protein palmitoylthioesterase-1; RBC:
Red blood cells; RCDP: Rhizomelic chondrodysplasia punctata; SANDO: Sensory ataxic neuropathy, dysarthria, and
ophthalmoparesis; SLO: Smith-Lemmli-Opitz syndrome; TPP1: Tripeptidyl peptidase-1; WBC: White blood cell;
X-ALD: X-linked adrenoleukodystrophy
a
Often second-line if genetic panel testing is normal, or first-line if clinical suspicion for large mitochondrial DNA
deletion(s) or depletion
b
Distinguished here from the other pediatric-onset sphingolipidoses by lack of CNS involvement (type I only)
c
False-positives due to pseudodeficiency are common in the evaluation of MLD; confirm with a second method (e.g. DNA test)
diet when present, these patterns (Table 14.4) should

prompt evaluation for an IEM. In contrast, other
small-molecule IEMs (such as phenylketonuria,
EC maple syrup urine disease, glutaric aciduria type
S P I, etc.) may present no clues on routine lab inves-
P* tigations even during an acute metabolic crisis;
d
specific biochemical investigations are required.
Fig. 14.1 A model metabolic pathway. (After Clarke In the patient with undifferentiated symptoms
2006, Fig. 11). In the above example, substrate S, which is (e.g. acute encephalopathy), many practitioners
essential in the diet, is metabolized to product P via employ a ‘small molecule screen’ (at least: CBC,
enzyme E and enzyme cofactor C. Deficiency of E or C
blood gases, electrolytes, glucose, lactate, ammo-
will cause S to accumulate with concurrent deficiency of
P. In an alternative pathway (dashed arrow), drug d can nia, plasma amino acids, total homocysteine,
react with S to form an alternative product, P*. Potential urine organic acids, plasma acylcarnitine profile,
treatment strategies could include: Restricting S in the and other tests depending on the clinical situa-
diet, supplementing P, supplying drug d, replacing E by
tion). This workup, ideally performed while the
enzyme replacement, or enhancing E’s activity with sup-
raphysiologic amounts of C. All of these strategies are patient is acutely symptomatic, will identify
used clinically in the treatment of small-molecule IEMs many (not all) treatable small-molecule IEMs.

Once a particular IEM is suspected, the diagnosis (with dietary modification, drugs, supplements or
can be confirmed by proving a deficient activity cofactors, by solid organ (e.g. liver) transplanta-
of the pertinent enzyme or transporter activity, tion, or, less commonly, by hematopoietic stem
and/or (increasingly) by identifying mutation(s) cell transplantation (HSCT) or enzyme replace-
in the corresponding gene(s). ment therapy (ERT) (Table 14.5). A subset of
It is important to recognize that some small- these disorders are targets of newborn screening
molecule disorders are specifically treatable in industrialized countries (see below).
Table 14.4 High-value ‘routine’ laboratory findings in metabolism

Key finding Metabolic Ddx Metabolic investigations
Hyperammonemia UCDs Plasma amino acids
(exclude factitious)a OAs Urine organic acids and orotic acid
HHH Urine amino acids
LPI Acylcarnitine profile
FAODs Free and total carnitine
HI/HA
Hypoglycemia (hypoketotic)b FAODs Plasma acylcarnitine profile
(exclude factitious)c Carnitine shuttle (CPT1a) Free and total carnitine
Ketogenesis defects (e.g. HMG-CoA) Free fatty acids
Hyperinsulinismd Beta-hydroxybutyrate
Insulin, growth hormone, cortisol
Urine organic acids
Hypoglycemia (ketotic) GSDs (esp. I, III, VI, IX, 0) Abdominal ultrasound (hepatomegaly)
Gluconeogesis defects (e.g. F-1,6-BP) CBC, lactate, uric acid, ALT/AST,
Ketolytic defects triglycerides (GSDI)
Hypopituitarismd Genetic testing if high suspicion
‘Benign ketotic hypoglycemia’d
Hypoglycemia (immediately HFI Dietary history: sweets avoidance
postprandial) Uric acid, transaminases (during
symptoms)
Genetic testing if high suspicion
High anion gap metabolic OAs Urine organic acids
acidosis (unexplained)e Cobalamin disorders Acylcarnitine profile
Ketolytic defects Total homocysteine
Ammonia
CBC
Lactic acidosis Mitochondrial Lactate, uric acid, ALT/AST,
PDH (postprandial) triglycerides (GSDI)
PC (fasting) Plasma amino acids
Krebs cycle Urine organic acids
GSD type I (fasting, with Acylcarnitine profile
hepatomegaly) Consider PDH, PC activities in skin
fibroblasts (skin biopsy)
Consider muscle biopsy
Consider first-line genetic testing
(mitochondiopathy panel or clinical
whole exome)
Anemia (macrocytic) Cobalamin disorders Total homocysteine
Folate cycle Plasma amino acids
Urine organic acids
Acylcarnitine profile
Folate
B12

Key finding Metabolic Ddx Metabolic investigations
Coagulopathy Galactosemia Galactosemia screen/GALT activity
Tyrosinemia I Succinylacetone
Plasma amino acids
List is not comprehensive. Some treatable IEMs may present with normal routine lab results. For all disorders, genetic
investigations (e.g. single-gene or panel-based sequencing) may be considered in parallel with biochemical testing
Abbreviations: CPT1a: Carnitine palmitoyltransferase 1a deficiency; Ddx: Differential diagnosis; F-1,6-BP: Fructose-1,6-
bisphosphatase deficiency; FAODs: Fatty acid oxidation disorders; GALT: Galactose-1-phosphate uridyltransferase; GSDs:
Glycogen storage diseases (includes GSD0, glycogen synthase deficiency); HHH: Hyperammonemia-hyperornithinemia-
homocitrullinuria syndrome; HFI: Hereditary fructose intolerance; HI/HA: Hyperinulinism-hyperammonemia syndrome;
HMG-CoA: 3-hydroxy-3-methylglutaryl-coA lyase deficiency; LPI: Lysinuric protein intolerance; OAs: Organic Acidurias;
PDH: Pyruvate dehydrogenase deficiency; PC: Pyruvate Carboxylase deficiency; UCDs: Urea cycle defects
a
Collect free-flowing venous (or arterial) sample, on ice, and analyze promptly
b
ie. Ketosis is less than expected given the degree of hypoglycemia. See also: Fig. 14.1 (nomogram: free fatty acids
versus beta-hydroxybutyrate) in [PMID#8869190]
c
Confirm with laboratory glucose measurement
d
Etiologically heterogeneous
e
i.e. ([Na+]–[Cl−]–[HCO3−]) > 16 mmol/L, not fully accounted for by lactate and/or ketones
Table 14.5 Therapeutic approaches in metabolism

Approach Examples
Correct the underlying mutation (‘gene therapy’) – ADA-SCID
Correct the underlying mutation in selected tissue(s) by – HSCT transplantation for Hurler syndrome,
transplantation X-ALD, etc.
– Liver transplantation for urea cycle defects
– Combined Liver/kidney transplant for MMA
Pharmacological replacement of the deficient enzyme – ERT for Gaucher type I
activity (‘enzyme replacement therapy’)
(Cofactor defects) Replacement of missing enzyme cofactor – IM Hydroxocobalamin for disorders of
intracellular cobalamin metabolism
(Partial enzyme defects)
• Pharmacological induction of the relevant gene’s – Hydroxyurea in sickle-cell disease
expression
• Pharmacological enhancement of enzyme activity with – Tetrahydrobiopterin (BH4) for BH4-responsive
supraphysiological doses of the enzyme’s cofactor phenylketonuria
• Pharmacological stabilization of an unstable mutant – N/A
enzyme with a chemical chaperone
(Deficiency syndromes) Supplementation of a deficient – Uncooked cornstarch therapy for GSD Ia
product or alternative
(Intoxication syndromes) – Phenylalanine restriction in phenylketonuria
• Dietary restriction of a dietarily-essential substrate or (PKU)
precursor
• Pharmacological inhibition of a preceding pathway step – Nitisinone therapy (prevents succinylacetone
to block formation of the toxic substrate in question accumulation) in tyrosinemia type I
• Removal of toxic product by hemodialysis (acutely) – HD for hyperammonemia in UCDs
• Removal of toxic product with detoxifying drugs – Sodium benzoate and sodium phenylacetate
(acutely or chronically) therapy for hyperammonemia in UCDs
• Block transport of toxic product into end organ(s) of – Large neutral amino acid supplementation in
interest PKU (block brain transport of phenylalanine)
Abbreviations (unlisted disease abbreviations are as per Table 14.2): ERT: Enzyme replacement therapy; HD:
Hemodialysis; HSCT: Hematopoietic stem cell transplantation; NTBC: Nitisinone

Organellar Diseases of storage material. Once the clinical suspicion of

In contrast to small-molecule disorders, organellar a particular organellar disease has been raised, the
diseases are primarily recognized clinically on the diagnosis is confirmed by specific biochemical
basis of characteristic clinical symptoms and and/or enzymological testing, and/or by molecular
signs. Organellar disorders are quite variable in testing of the relevant gene(s). Because many
their presentations but common signs may include: organellar diseases are dreaded, life- and family-
Dysmorphic features, organomegaly, skeletal and/ altering diagnoses, it is often prudent to ‘prove’
or connective tissue abnormalities, developmental one’s clinical suspicion using several independent
regression, macrocephaly, progressive white mat- test methods before conferring a diagnosis.
ter disease, cherry-red macular spots, etc. (Tables A handful of organellar diseases are treatable by
14.3 and 14.6). Organellar diseases can be sub- HSCT, ERT, or with drugs (Table 14.5), although
classified by affected organelle, into: mitochon- the effect of treatment is generally partial at best,
drial diseases, peroxisomal disorders, lysosomal and many conditions are entirely without disease-
storage diseases, and congenital disorders of gly- modifying treatment. Until recently, organellar
cosylation types I and II (involving endoplasmic diseases have not been targeted for neonatal
reticulum and Golgi, respectively) (Table 14.3); screening; a few such disorders are now being tar-
lysosomal disorders are further subdivided by type geted, as discussed below.
Table 14.6 Selected classical ‘syndromic’ presentations in metabolism

Symptom complex Major metabolic DDx Biochemical investigations
Hypotonia, CNS malformations, Peroxisomal (Zellweger spectrum, VLCFA
enlarged anterior fontanelle DBP) Bile acid precursors
Red cell plasmalogens
Rhizomelia Peroxisomal (Rhizomelic Red cell plasmalogens
Calcific epiphyseal stippling chondrodysplasia punctata)
Dysostosis multiplex, macrocephaly, Mucopolysaccharidoses Urine MPS spota
organomegaly, hernias/hydroceles, Oligosaccharidoses Urine MPS fractionation
+/− corneal clouding, Mucolipidosis III Urine oligosaccharides
angiokeratomata GM1 gangliosidosis Specific enzyme assay
MSD
Cherry-red macular spots and Sphingolipidoses (GM1, GM2 Specific enzyme activities in
developmental deceleration/ [Tay-Sachs/Sandhoff], Niemann-Pick WBCs or cultured fibroblasts
regression +/− macrocephaly, A/B, MLD, MSD, sialidosis, others)
organomegaly
Nonimmune, non-hematological fetal Various lysosomal Urine MPS spotb
hydrops Urine MPS fractionation
Urine oligosaccharides
Urine sialic acid
Blood smear/bone marrow
Consider NGS panel or WES
Abnormal fat pads on thighs/buttocks, CDG-N, esp. CDG Ia Isoelectric focusing of serum
inverted nipples transferrin
Dysmorphism, congenital anomalies CDG-N Transferrin IEF
(various) with CNS involvement N-linked glycans by FAB-MS in
urine
Polymicrogyria, occipital CDG-O (Walker-Warburg, CK
encephalocele Muscle-eye-brain) O-linked glycans by FAB-MS in
urine

Symptom complex Major metabolic DDx Biochemical investigations
Midface hypoplasia, short PFs, Energy metabolism (esp. PDH, Lactate
periventricular cysts, +/− mitochondrial disorders) Plasma amino acids (Ala, Pro,
cardiomyopathy and multisystem Gly)
involvement Acylcarnitine profile
Urine organic acids
Brain MRS
Lactate:pyruvate ratio, PDH, PC
enzymologies (skin fibroblasts)
Consider muscle biopsy, incl.
Respiratory chain enzymology
Dysmorphism, cardiomyopathy, Energy metabolism (esp. GA-II, Acylcarnitine profile
multiple renal cysts, +/− CNS Carnitine shuttle, FAODs) Free and total carnitine
malformations Urine organic acids
Hypotonia, steel-wool hair, bladder Menkes Serum copper
diverticulae Ceruloplasmin
Microcephaly, growth retardation, Smith-Lemli-Opitz Serum 7-dehydrocholesterol
hypospadias, Y-shaped 2–3
syndactyly of toes, polydactyly, heart
and structural anomalies
Only selected conditions are shown. In each case, genetic testing (single-gene or panel) can also be considered
alongside biochemical investigations
CDG: congenital disorders of glycosylation (−N: N-linked; −O: O-linked); CK: Creatine kinase; CNS: Central nervous
system; DBP: D-bifunctional protein deficiency; FAODs: Fatty acid oxidation disorders; FAB-MS: Fast atom
bombardment-mass spectrometry; GA-II: Glutaric aciduria type II; IEF: Isoelectric focusing; MPS: Mucopolysaccharides;
MRS: Magnetic resonance spectroscopy; MSD: Multiple sulphatase deficiency; MLD: Metachromatic leukodystrophy;
NGS: Next-generation sequencing; PDH: Pyruvate dehydrogenase deficiency; PC: Pyruvate carboxylase deficiency;
PFs: Palpebral fissures; VLCFAs: Very long chain fatty acids; WBCs: White blood cells
a
Absent in some conditions
b
Neither specific nor sensitive
he Expanding Role of Newborn

T In most highly-industrialized countries, tandem
Screening mass spectrometry (MS:MS), which can rapidly
measure the abundance of multiple compounds in
The aim of newborn screening (NBS) is second- a dried blood spot card or other stable sample, has
ary prevention, i.e. to identify children at become the primary platform for NBS (Charrow
increased risk of having a treatable IEM, prior to et al. 2000). MS:MS-based NBS programs now
the onset of clinical symptoms. Cost and other screen for dozens of treatable IEMs in addition to
practical considerations limit NBS programs to a ‘classic’ targets such as phenylketonuria and con-
specific list of (relatively few) targeted condi- genital hypothyroidism. The structure of the NBS
tions; criteria for selecting appropriate targets system and the list of disorders screened varies by
have been constructed (Andermann et al. 2008; jurisdiction; many programs use some variation of
Wilson and Jungner 1968). In general, valid tar- the U.S. Department of Health and Human
gets are conditions which are medically serious, Services’ Recommended Uniform Screening
display a presymptomatic phase during which Panel (RUSP), which currently includes 31 disor-
treatment is beneficial, and for which robust (e.g. ders (U.S. D.H.H.S. 2015). Classically, screened
highly predictive), practical, and cost-effective conditions have tended to be small-molecule IEMs
test(s) are available. (e.g. phenylketonuria) and/or endocrinological

disorders (e.g. congenital hypothyroidism) readily I ncreasing Reliance on DNA-Based

amenable to medical and/or dietary therapy. Testing
Recently, however, the RUSP has recently added
X-linked adrenoleukodystrophy and Hurler syn- Classically, clinical diagnosis of an IEM involves
drome (both treatable via early HSCT), and Pompe the following steps: A clinical phenotype
disease (treatable by ERT). NBS has also been compatible with an IEM is recognized; one or
tried for Krabbe disease (Globoid cell leukodys- more metabolites are measured at abnormal
trophy), another lysosomal storage disease, concentration(s); a corresponding enzyme activ-
although outcomes have been disappointing ity is shown to be deficient; and mutation(s) are
(Wasserstein et al. 2016). In general, targeted lyso- confirmed in a corresponding gene. Ideally the
somal therapies (e.g. ERT and HSCT) are complex clinical presentation, metabolite measurements,
and resource-intensive, and in some disorders/ enzymology, and genetic results are all congruent,
cases the magnitude of clinical benefit may be so that the diagnosis has been secured by several
unclear. Although lab methods for multiplexed independent means. Recent advances in molecu-
lysosomal disease screening by MS continue to lar genetic testing appear poised to upend the
develop (Elliott et al. 2016), there are a number of classical approach. As described earlier in this
medical, technical, ethical, economic, and health chapter, NGS is a disruptive technology which
systems considerations to be carefully weighed. permits the simultaneous testing of tens to thou-
As end-users of NBS programs, pediatri- sands of genes efficiently and at low cost. In the-
cians and primary care providers should be ory, NGS offers several advantages over ‘standard’
aware of (1) the limitations of screening, and biochemical testing, namely: (1) convenient sam-
(2) what to do in the event of a positive screen. pling (nearly all testing can be performed using
With respect to the former: Firstly, many treat- peripheral blood), (2) state-independence (results
able IEMs (e.g. most urea cycle disorders) are are unaffected by illness, dietary status, medica-
not targeted for screening for technical or prac- tions, etc.), (3) standardization and relative ease
tical reasons (e.g. lack of an appropriate test). of use, (4) direct applicability of results to genetic
Other disorders (e.g. classical galactosemia, counselling, if desired, and, importantly, (5) low
urea cycle defects, organic acidurias, severe clinical bias, i.e. improved recognition of very
fatty acid oxidation defects) may present symp- rare or atypically-presenting disorders. In con-
tomatically during the first days of life, before trast, many biochemical tests are methodologi-
the screen’s results have been reported. As with cally complex, limited to few centers worldwide,
any laboratory test, false- positive and false- and/or have collection requirements which are
negative results may occur, as may sample mis- either state-specific (e.g. during illness) or inva-
collection, mishandling, or misidentification sive (e.g. tissue biopsy, lumbar puncture). DNA-
(e.g. of twin samples). With respect to the lat- based tests are therefore becoming increasingly
ter: In the event of a positive screen, physicians accepted as ‘first-line’ investigations for many
should recognize that the situation is poten- metabolic disorders. Situations where first-line
tially an emergency even if the child is initially genetic testing for IEMs may be appropriate could
well-appearing. Clinicians should know where include:
to locate appropriate management resources
and/or diagnostic algorithms; these are often • Avoidance of invasive testing: For example,
provided by the NBS program itself, or alterna- up to ~25–50% of patients with a primary
tively can be found online courtesy of the mitochondrial disorder can be diagnosed via
American College of Medical Geneticists NGS, obviating the need for diagnostic mus-
(ACMG) (ACMG 2001). It will likely be neces- cle biopsy (Calvo et al. 2012; Lieber et al.
sary to contact the appropriate pediatric con- 2013).
sulting service (e.g. metabolics, endocrinology, • Nonspecific clinical presentations with a very
immunology) for expert advice. broad associated genetic/metabolic differential

diagnosis (e.g. nonimmune fetal hydrops) liver/kidney) transplantation, such that patients
(Shamseldin et al. 2015) may become asymptomatic (at least from a
• Where pretest probability of an IEM is high, hepatic point of view) on a normal diet (Yu et al.
a definitive genetic diagnosis is required 2015; Niemi et al. 2015; Matern et al. 1999). For
urgently, and/or where prenatal (e.g. amnio- enzymes expressed mainly (but not exclusively)
centesis) or preimplantation genetic diagnosis in the liver, domino transplantation (in which the
may later be considered. patient’s explanted liver is donated to another
individual) is an interesting option to address the
issue of organ scarcity, but care must be taken to
Disease-Modifying Therapy for IEMs ensure safety of recipients of IEM patient organs
(Popescu and Dima 2012).
IEMs should, in theory, be treatable using a wide ERT products are an expanding pharmaceuti-
variety of therapeutic strategies (Table 14.5), of cal market and many products have been brought
which gene therapy (in vivo reconstitution of the to market in recent years. Products are available
missing gene, e.g. using engineered virus vectors) for Gaucher and Fabry diseases, several of the
should be the most definitive. Currently, the prom- mucopolysaccharidoses (MPS I, II, IVa, VI, and
ise of clinical gene therapy remains largely unreal- VII), hypophosphatasia, acid lipase deficiency,
ized, and important technical, safety, and ethical/ and for ADA-deficiency SCID, among others.
legal obstacles remain to be addressed before it For some disorders, e.g. Gaucher disease type I,
enters widespread use in clinical genetics (Ginn ERT is highly effective in mitigating the principal
et al. 2013; ‘Gene-therapy trials’ (Editorial, disease manifestations; for others, the effect may
Nature), 2016). Specific forms of gene therapy, for be partial or even subtle. A major limitation of
instance in the context of autologous stem cell ERT for many lysosomal disorders is that exist-
transplantation, are used currently (e.g. in the ing products do not penetrate the blood-brain
treatment of severe combined immunodeficiency barrier. Another limitation is cost: In general, the
due to adenosine deaminase deficiency (ADA- agents are very costly, and this is a concern to
SCID) (Gaspar 2012)). Many IEMs characterized patients and to the health-care system even in
by intoxication should be particularly amenable to highly industrialized countries.
gene therapy, as most enzymes function very effi- A number of small-molecule strategies
ciently and only a few percent of the usual activity (beyond simple dietary supplementation) are
(in liver, for instance) may be needed to prevent employed in the treatment of IEMs. Cofactor
toxic substrate accumulation. It will be exciting to therapy (providing an enzyme with pharmaco-
see how this area evolves over the coming years. logical doses of a necessary cofactor to enhance
Another (arguably more pedestrian) means of its activity) is used in several conditions. Patients
‘replacing’ a missing enzyme or transporter is by with biopterin-responsive PKU can be given a
allogeneic organ or stem cell transplantation. In more liberal diet while taking tetrahydrobiopterin
patients post-HSCT, cells derived from donor (BH4) supplementation, BH4 being a prosthetic
hematopoietic stem cells engraft not only in the group for the deficient enzyme (phenylalanine
recipient’s bone marrow but also in the brain (as hydroxylase) (Somaraju and Merrin 2015).
microglia); some of the lysosomal enzymes Substrate reduction therapy (SRT), in which the
expressed by these cells are secreted and endocy- biosynthesis of an offending compound is
tosed by neighbouring host cells. This ‘lysosomal blocked pharmacologically, is a treatment option
cross-correction’ (Fratantoni et al. 1968) is the in Gaucher disease and Niemann-Pick disease
basis of HSCT for Hurler syndrome (Boelens type C (Platt and Jeyakumar 2008). Chaperone
et al. 2013). Liver-based small-molecule IEMs, therapy, that is, small molecules designed to bind
e.g. the urea cycle defects, some organic to enzymes and improve their stability in vivo, is
acidurias, and hepatically-based glycogen stor- another theoretical option which has not yet
age diseases, are greatly improved by liver (or entered routine clinical use.

Future Directions algorithm is demonstrated in Fig. 14.2, and gen-

eral clinical approaches for some of the more
‘Targeted’ Versus ‘Untargeted’ common referrals are described below.
Metabolomics
As the genome is the sum of all genetic informa-
tion in an individual, the metabolome is the sum he Patient Suspected of a Specific
T
of the (many thousands of) compounds trans- Genetic Syndrome
formed by the body’s metabolism. Metabolomics
is the simultaneous measurement of many metab- Patients with a clinically-recognized symptom
olites in order to gain insight into a biological complex represent the minority of referrals, and
system. Commonly-used biochemical lab tests the testing approach in these patients will neces-
are a form of targeted metabolomics, focused on sarily depend on the diagnosis in question. For
specific subsets of clinically-useful compounds example, in a patient with suspected Down syn-
(amino acids, organic acids, acylcarnitines, etc.). drome, a karyotype is the appropriate test, as this
In contrast, untargeted metabolomics aims to will confirm the diagnosis and provide useful
measure as many metabolites as possible (using information about chromosome structure (pres-
specialised MS instruments); in many cases, the ence or absence of mosaicism, or a Robertsonian
compounds identified may be novel and/or their translocation). On the other hand, in a patient
precise structure unknown. In general, targeted with a conotruncal heart defect, hypocalcemia,
metabolomics methods are hypothesis-testing, and absent thymus, a microarray is appropriate,
whereas untargeted metabolomics may be to demonstrate the expected chromosome 22q11
thought of as hypothesis-generating. Untargeted microdeletion. For disorders caused by point
metabolomics is new even in comparison with mutations within gene(s), sequencing and/or
WES, and is just entering clinical use (Miller deletion testing of the appropriate genes will
et al. 2015); it promises to greatly expand the likely be indicated.
chemical ‘space’ surveyed by clinical metabol-
ics, to identify new IEMs, and to yield new
insights into the pathophysiology of already- he Patient with an Undifferentiated
T
recognized IEMs. Syndrome
Patients with multiple congenital anomalies and/

Diagnostic Approach or dysmorphic features are relatively likely to
to the ‘Genetic’ or ‘Metabolic’ have an unrecognized syndrome, developmental
Patient sequence, infectious/teratogenic cause, or asso-
ciation. Initial investigations in these patients
Geneticists are, largely, specialists in the diagno- will typically include a chromosome microarray,
sis of rare and obscure disorders. The diagnostic imaging studies to identify associated malforma-
workup of genetics and metabolic patients tends tions, and dysmorphology examination by a
to be highly individualized, and thus difficult to geneticist or pediatrician. Many IEMs may pres-
express algorithmically. As always, the mainstay ent as a dysmorphic syndrome (Table 14.6), and
of assessment begins with the medical history, metabolic conditions should also be considered
family history (including three-generation his- in the evaluation of this group. In patients with a
tory for consanguinity, congenital anomalies, normal microarray, the next test of choice will
major medical or developmental concerns, often be an NGS panel or whole exome (ideally a
miscarriages and neonatal/childhood deaths), and trio of the patient and both parents), resources
physical examination. A simplified diagnostic permitting.

• Medical and family history

• Physical examination
• Routine clinical investigations*
• Literature search
Specific syndrome or
IEM suspected?
Yes no
Specific genetic and/or ‘Red flags’ for small–molecule IEMs?

metabolic testing as indicated. Examples: (consider urgent referral)
• aneuploidy (e.g. Down syndrome): Karyotype • acute neonatal onset
• microdeletion/duplication (e.g. 22q11del): Microarray • acute encephalopathy and/or liver failure
• single gene (e.g. NF1): Gene sequencing+/-deletion testing • decompensation during minor illness
• genetically heterogeneous conditions (e.g. Epilepsy): Consider gene panel • protein intolerance / avoidance
• specific IEM: Specific biochemical, enzymological, and/or gene testing • high–risk routine lab findings (Table 4)
• family history suggestive of recessive inheritance
Yes no
• small–molecule screen** Non–specific presentation

• if acute, consider urgent Metabolics referral (e.g. DD / ID/ ASD / dysmorphism or congenital anomalies )
• Microarray
• Fragile X (if DD/ID/ASD)
• Consider organellar diseases
diagnosis no diagnosis
• consider referral as required • consider other genetic testing (e.g. focused

gene panel vs other)
• consider referral for further investigations
Fig. 14.2 A generalized approach to the child with pos- findings); thyroid hormone indices, etc. (Double aster-
sible genetic/metabolic syndrome. For detailed discussion isks) At minimum: CBC, blood gases, electrolytes, glu-
see text in section ‘Clinical Approach’. DD developmen- cose, lactate, ammonia, plasma amino acids, urine organic
tal delay, ID intellectual disability, ASD autism spectrum acids, plasma acylcarnitine profile, free and total carni-
disorder. (Asterisk) As indicated clinically as part of routine, other tests as indicated for the clinical presentation
tine assessment, e.g.: MRI head (if focal neurological
he Patient with Undifferentiated
T he Patient with Metabolic
T
Developmental Delay and/or Autism- ‘Red Flags’
Spectrum Disorder
Acute medical illness in a neonate should prompt
This group comprises a large portion of clinic consideration of IEMs alongside other conditions
referrals, and the diagnostic yield in nondysmor- such as sepsis. Other ‘Red flags’ which should
phic patients with a normal examination is rela- prompt the pediatrician or general practitioner to
tively low, perhaps on the order of 10–25%. The consider small-molecule disorders include intol-
standard workup of these patients includes a erance of illness, fasting, or certain foods (e.g.
microarray and Fragile X testing (both boys and proteins, sweets), parental consanguinity, or
girls); some specialists advocate uniform meta- abnormal lab studies (Table 14.4). The diagnostic
bolic screening (van Karnebeek and Stockler- yield of small-molecule screening investigations
Ipsiroglu 2014). NGS panels for nonsyndromic is likely to be higher in these patients than in
intellectual disability are becoming increasingly patients with (for instance) undifferentiated
used, and useful, in this group of patients. developmental delay.

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for Krabbe disease in New York State. Genet Med.

Update in Pediatric Nephrology
15
Darcy Weidemann and Martin Bitzan
Introduction abnormal renal development and congenital

anomalies of the kidney and urological tract
Pediatric nephrology is a relatively young field (CAKUT), in particular progenitors of renal
which emerged as a distinct discipline in the development, branching morphogenesis and its
1950s–1970s. Several critical discoveries, includ- various factors and co-factors. There is an explo-
ing the use of glucocorticoids in the treatment of sion of the so-called “‘omics” approaches which
childhood idiopathic nephrotic syndrome, the include genomics, transcriptomics, proteomics,
development of the technique of percutaneous and metabolomics, all of which have led to expo-
renal biopsy which permitted classification of nential increases in available experimental data
glomerular disease and recognition of immuno- and development of large clinical databases
logical factors as key to its pathogenesis, and (Hanna et al. 2016). New approaches to renal and
innovation of advanced renal replacement thera- urinary tract imaging have allowed for improved
pies of dialysis and kidney transplantation are all diagnosis of acute and chronic kidney injury. The
scientific advances that established pediatric development and validation of novel biomarkers
nephrology as a pediatric subspecialty (Chesney for acute and chronic kidney disease is an active
2002). Pediatric nephrology as a discipline con- area of research with the promise of earlier diag-
tinues to evolve rapidly. The last few decades nosis, improved assessment of duration or sever-
have seen remarkable advancements in the epide- ity of kidney diseases, and prediction of disease
miology, etiology, pathogenesis, and treatment of progression and adverse clinical outcomes
children with kidney diseases. There is now a (Fassett et al. 2011). Evidence-based clinical
greater understanding of factors contributing to practice guidelines by a variety of professional
organizations including the National Kidney
Foundation Kidney Disease Outcomes Quality
D. Weidemann (*) Initiative (KDOQI) and Kidney Disease
Section of Pediatric Nephrology,
Improving Global Outcomes (KDIGO) aim to
University of Missouri – Kansas City School enhance the diagnosis and management of chil-
of Medicine, Children’s Mercy Hospital and Clinics, dren with kidney disease through evidence-based
Kansas City, MO, USA recommendations. The obesity epidemic has
e-mail: dkweidemann@cmh.edu
largely changed the landscape of diagnosis and
M. Bitzan management of pediatric hypertension. This
Division of Nephrology, Department of Pediatrics,
chapter will discuss several important recent
McGill University Health Center, Montreal
Children’s Hospital, Montreal, QC, Canada clinical advances in the field of pediatric

e-mail: martin.bitzan@mcgill.ca nephrology.


392 D. Weidemann and M. Bitzan
valuation and Management
E colonization, although a minority of infections
of Urinary Tract Infections (4–9%) are thought to result from bacteremia,
in Children predominantly in the neonatal period
(Hoberman et al. 1999; Smellie et al. 1994).
Background The most frequently identified uropathogens in
several recent pediatric studies are Escherichia
Urinary tract infections (UTI) are now one of the coli (54–67%), Klebsiella (6–17%), Proteus
most common causes of serious bacterial infec- (5–12%), Enterococcus (3–9%), and
tion in children, accounting for about 5% of chil- Pseudomonas spp. (2–6%) (Zhanel et al. 2005;
dren ages 2–24 months of age with fever without Prelog et al. 2008). Uropathogenic bacteria
a clinically apparent focus (Subcommittee on have several virulence factors which facilitate
Urinary Tract Infection SCoQI, Management and ascending infection into the bladder and kid-
Roberts 2011). Throughout childhood the cumu- ney. One of the best studied factors in E. coli
lative incidence is approximately 10% in girls are pili, hair-like appendages on the bacterial
and 3% in boys, with a recurrence risk of 8–30% cell surface that facilitate adherence to the uro-
(Conway et al. 2007). Febrile UTIs have the epithelium and are thought to generate a local
highest incidence during the first year of life in inflammatory response.
girls and uncircumcised boys. UTIs in infants Several risk factors for UTI have been iden-
and young children generally present as unilateral tified in children. UTIs appear to be more com-
or bilateral (febrile) pyelonephritis. Infections mon in Caucasians compared to other ethnic
limited to the bladder (cystitis) are typically seen groups and in boys <1 year and girls <4 years
in teenage girls, are afebrile, and easily treated (Shaikh et al. 2008). Although uncircumcised
with a short course of oral antibiotics. Concern boys have a four- to eightfold higher prevalence
about serious long-term consequences, renal of UTI (Shaikh et al. 2008), most uncircum-
scarring, hypertension, and progressive chronic cised infants do not develop UTIs, and a recent
kidney disease, have historically led to intensive systemic review found that 111 circumcisions
evaluation and treatment of children with UTIs. are needed to prevent one UTI (Singh-Grewal
Children with UTIs were routinely exposed to et al. 2005). Children with obstructive urologi-
invasive diagnostic imaging tests, received long- cal disease are at high risk of developing UTIs
term antibiotic prophylaxis, or underwent sur- due to urine stasis, which favors multiplication
gery for underlying anatomic abnormalities, and adherence of uropathogens. Anatomical
specifically for vesicoureteral reflux (VUR). obstruction (posterior urethral valves, uretero-
Controversies about direct links between renal pelvic junction obstruction, strictures), nephro-
scarring and UTI, and UTI and chronic kidney lithiasis and neurogenic bladder dysfunction all
disease (CKD), resulted in new guidelines for the predispose to UTI. Underlying bladder and
management of UTIs emphasizing a more selec- bowel dysfunction (BBD) has recently been
tive approach to diagnostic imaging and ques- recognized as an important but often over-
tioning of the value of long- term antibiotic looked risk factor for UTI. A combined analy-
prophylaxis (Subcommittee on Urinary Tract sis of 181 children with first or second UTI
Infection SCoQI, Management and Roberts enrolled in the longitudinal “Randomized
2011; Mori et al. 2007). Intervention for Children with Vesicoureteral
Reflux” (RIVUR) and “Careful Urinary Tract
Infection Evaluation” (CUTIE) studies demon-
Pathogenesis strated a remarkably high prevalence of 54%
children with underlying BBD and identified
Urinary tract infection is usually due to ascend- BBD as one of the most important factors for
ing enteric pathogens following periurethral UTI recurrence (Shaikh et al. 2016).

15 Update in Pediatric Nephrology 393
Clinical Presentation ficity for true UTI (Subcommittee on Urinary

Tract Infection SCoQI, Management and
Fever can be the only presenting symptom of UTI Roberts 2011; Bell and Mattoo 2009).
in young infants (Shaikh et al. 2007; Zorc et al.
2005), although irritability, emesis, poor feeding,
or lethargy may also be elicited. Older, verbal Treatment of Acute UTI
children are more likely to report urinary symp-
toms such as dysuria, urgency, frequency, and Timely antibiotic administration is the corner-
suprapubic abdominal pain. A recent meta- stone of treatment for acute UTIs, although there
analysis identified the following risk factors has been some disagreement regarding the choice
as the most relevant in identifying children of antibiotic, mode of administration, and dura-
<24 months with UTIs: suprapubic tenderness tion of therapy. All febrile neonates should be
(likelihood ratio [LR] 4.4), temperature > 40 °C treated with parenteral antibiotics pending urine,
(LR 3.2), uncircumcised (LR 2.8), history of UTI blood, and cerebrospinal fluid culture results.
(LR 2.3), and fever >24 h (LR 2.0) (Shaikh et al. American Academy of Pediatrics (AAP) and
2007). Pyelonephritis should be considered when (British) National Institute for Health and Clinical
patients demonstrate fever, chills, flank pain, or Excellence (NICE) guidelines emphasize that
costovertebral angle tenderness. Parental report oral and parenteral antibiotic treatment is as
of malodorous urine is not a reliable indicator equally efficacious for most children. The choice
(Gauthier et al. 2012). of antibiotics should depend on local resistance
patterns, although cephalosporins and
amoxicillin-clavulanic acid are frequently used
Diagnosis empirically (Montini et al. 2011). NICE recom-
mends 10 days of treatment, whereas the AAP
The diagnosis of UTI should be based on a uri- acknowledges that there is insufficient scientific
nalysis demonstrating pyuria (urine dipstick evidence to state whether 7, 10, or 14 days is
positive for leukocyte esterase, with or without preferred.
nitrite positivity, or urine microscopy demon-
strating the presence of white blood cells) and a
positive urine culture. Recent guidelines empha- Urinary Tract Imaging
size the importance of a non-contaminated urine
culture. Due to the unacceptably high false posi- The evolution of urinary tract imaging technol-
tive urine culture rate of urine bags applied to ogy over the past decades has influenced UTI
the perineum in non-toilet trained children, management and become part of the controversy
urine culture should be obtained by either supra- in this field. Traditionally, it was recommended
pubic bladder aspiration or urethral catheteriza- that all patients undergo renal and bladder ultra-
tion (Subcommittee on Urinary Tract Infection sound and voiding cystourethrography (VCUG),
SCoQI, Management and Roberts 2011). For often complemented by nuclear renal scan to
toilet-trained children, a midstream urine col- assess for parenchymal scarring. The aim of
lection is acceptable although appropriate these, often repeated diagnostic investigations
cleansing of the perineal region is critical to was to identify children with vesicoureteral reflux
avoid contamination. The diagnostic cut-off (VUR), treat them with long-term antibiotic pro-
level for a UTI is the growth of more than 105 phylaxis regardless of the VUR grade, and moni-
colony forming units (CFU) per mL. Lower tor longitudinally. Surgical correction of VUR
thresholds of >104 CFU/mL are accepted for was considered standard of care. However, recent
catheter specimens, acknowledging that this can AAP and NICE guidelines recommend a more
increase the sensitivity while decreasing speci- conservative approach for the imaging of children

with febrile UTI under the age 2–3 years. AAP most widely used nomenclature of the
recommends renal and bladder ultrasound in all International Reflux Study in Children defines
young children with febrile UTIs, but reserves five grades of reflux, where grade I corresponds
VCUG for children with recurrent febrile UTIs to reflux of contrast medium into the distal ureter,
or ultrasonographically detected anatomic abnor- and (maximal) grade V reflects gross dilation and
malities (Subcommittee on Urinary Tract tortuosity of the ureter and renal pelvis with
Infection SCoQI, Management and Roberts blunting of the calyces (Lebowitz et al. 1985).
2011). NICE recommends renal and bladder The prevalence of VUR in the general pediatric
ultrasound and VCUGs for infants <6 months population is estimated at 1–2% (Chand et al.
and older children if they have atypical or recur- 2003). Positive family history is an important risk
rent UTIs (Mori et al. 2007). NICE recommends factor for VUR with a prevalence of 27.4% in
nuclear imaging such as dimercaptosuccininc asymptomatic siblings and 35.7% in offspring
acid (DMSA) scans 4–6 months after an acute (Skoog et al. 2010). However, routine screening
infection in children <3 years with recurrent or of asymptomatic siblings is no longer practiced
atypical infections. Neither guideline recom- (MacNeily and Afshar 2006).
mends DMSA renal scan as part of routine clini-
cal evaluation of first, uncomplicated UTIs.
The role of routine VCUG in the evaluation of Diagnosis
UTIs remains contentious. Advocates generally
cite a strong association between the severity of VCUG involves the instillation of a radiopaque
VUR and the presence of renal scarring (Shaikh or radioactive contrast medium into the bladder
et al. 2010; Coulthard 2009), and argue that early via urethral catheterization followed by serial
detection of reflux remains important given the imaging during filling and voiding, and remains
ability to provide medical or surgical intervention the gold standard imaging test for the diagnosis
to prevent adverse outcomes (Wan et al. 2012; of VUR. Widespread adoption of prenatal ultra-
Hoberman et al. 2003). Opponents who argue for sound screening has led to the emergence of
a more selective approach argue that VCUG is an another population of individuals at risk for
invasive procedure with exposure to unnecessary VUR, infants with prenatally diagnosed urinary
radiation and risk of iatrogenic UTI due to ure- tract dilation (UTD). 12–38% of children with
thral catheterization (Roberts et al. 2012), and prenatally diagnosed UTD and approximately
that detection of lower grades of reflux with 40% with postnatal UTD have VUR by VCUG
VCUG is not essential (Hannula et al. 2011). A (Lee et al. 2006; Passerotti et al. 2011; Ismaili
review of the yield, economic, and radiation costs et al. 2002).
of five different guideline algorithms concluded Multiple classification schemes exist for the
that more aggressive protocols have a high sensi- grading of UTD, which include descriptive
tivity for detection of VUR and scarring but at the (mild—moderate—severe hydronephrosis) and
expense of increased radiation and financial costs quantitative, such as the anterior-posterior renal
with uncertain benefit (La Scola et al. 2013). pelvic diameter (Grignon et al. 1986) or semi-
quantitative such as the Society for Fetal
Ultrasound SFU (grade 0–4) (Fernbach et al.
Update in Vesicoureteral Reflux 1993). In 2014 a multidisciplinary consensus
panel devised a uniform classification system
Introduction with standard terminology for the diagnosis and
management of prenatal and postnatal UTD
Vesicoureteral reflux is defined as the abnormal (Nguyen et al. 2014). A management scheme was
backflow of urine from the urinary bladder into proposed, stratifying ultrasound results as UTD
one or both ureters and/or the renal pelvis. The P1: low risk, UTD P2: intermediate risk, and

UTD P3: high risk, based on size of the presented with a febrile UTI. The “Prevention of
anterior-posterior renal pelvic diameter, central Recurrent Urinary Tract Infection in Children
or peripheral calyceal dilatation, and appearance with Vesicoureteric Reflux and Normal Renal
of ureters, bladder, and renal parenchyma. VCUG Tracts” (PRIVENT) trial (Craig et al. 2009) and
is recommended only for infants with UTD P3, the Swedish reflux trial (Brandstrom et al. 2010)
and the choice to proceed with VCUG for UTD both demonstrated modest benefit of CAP in
P1 and P2 is left to the discretion of the reducing the risk of UTI recurrence. A Swedish
clinician. study demonstrated that in girls >1 year of age
with dilating VUR (grade 3 and 4), CAP also
reduced new renal parenchymal damage com-
Antibiotic Prophylaxis pared with surveillance only, while endoscopic
injection (see below) reduced the risk of UTI
The stated main purpose of subjecting children recurrence but not of new renal scars (Brandstrom
with VUR to continuous antibiotic prophylaxis et al. 2011). In the current American Urological
(CAP) is to reduce the risk of UTI recurrence Association VUR clinical guidelines, CAP is
and of new or additional renal scarring. For recommended in high risk groups including chil-
decades, children with VUR have been treated dren <1 year of age, those with dilating VUR
with CAP, despite poor clinical evidence, (grades 3–5) and/or a history of febrile UTIs,
although the scientific justification for this prac- and those >1 year of age with BBD (Peters et al.
tice was largely based on anecdotal or small case 2010).
series demonstrating equivocal results (Tullus
2015), and this practice has come under close
scrutiny. Recent randomized controlled trials Surgical Intervention
failed to show that CAP is beneficial in children
with mild to moderate VUR (Garin et al. 2006; VUR tends to spontaneously improve or resolve
Pennesi et al. 2008; Montini et al. 2008a), and during childhood years, with the exception of
the 2012 Cochrane review of 20 randomized (rare) grade V reflux (McLorie et al. 1990).
controlled trials of 2324 children with VUR con- Indications for surgical correction of VUR vary
cluded that CAP did not significantly reduce the and need to be revised. A 2011 meta-analysis
risk of UTI recurrence and that it was associated concluded that surgical correction of VUR did
with a threefold increase in bacterial drug resis- not reduce the risk of symptomatic UTIs com-
tance (Nagler et al. 2011). The “Randomized pared with CAP (Nagler et al. 2011). Children
Intervention for Children with Vesicoureteral with high-grade VUR or recurrent break-through
Reflux” (RIVUR) trial (Investigators et al. 2014) infections while receiving CAP should be con-
was the largest multicenter randomized double sidered for surgical intervention (Peters et al.
blind placebo- controlled study involving low- 2010; Fonseca et al. 2012). Traditional open ure-
dose trimethoprim/sulfamethoxazole in 607 teral reimplantation with success rates of 95–98%
children ages 2–72 months with grades I–IV (Elder 2000) has been largely replaced by endo-
VUR and a first or second symptomatic UTI. The scopic injection of bulking agents (viscous gel of
study demonstrated a 50% reduced risk of UTI dextranomer microspheres) as a minimally inva-
(hazard ratio 0.5, 95% CI 0.34–0.74) although sive alternative. The Food and Drug
no difference in the development of renal scar- Administration approved the dextranomer hyal-
ring (12% versus 10%) and a significantly uronic acid polymer Deflux® in 2001 for endo-
increased risk of antibiotic resistance of bacteria scopic correction of VUR grades II–IV VUR,
isolated during subsequent UTIs. The greatest and has reported success rates of 60–90% which
benefit was observed in children with underlying are dependent on degree of VUR and the absence
bowel and bladder dysfunction and those who of BBD (Lendvay et al. 2006).

Glomerular Diseases in Children nephritis, IgA vasculitis (IgAV; previously

Henoch-Schönlein Purpura (HSP)), lupus
Introduction nephritis, and vasculitides such as microscopic
polyangiitis and granulomatosis with polyangi-
Glomerulonephritis (GN) is a generic term to itis (formerly known as Wegener’s granuloma-
denote non-infectious inflammatory lesions and tosis). Important chronic glomerulonephritides
glomerular injury. The pathogenesis of glomer- include membranoproliferative glomerulone-
ulonephritides is only partially understood. phritis (MPGN), membranous GN, and IgA
Most cases are thought to be due to aberrant nephropathy. Major clinical features of three
immunological responses of the host to a variety common forms of GN in children are outlined in
of etiological triggers. GN can be classified as Table 15.1. Focal segmental glomerulosclerosis
acute, chronic, and in a small, but important (FSGS) and minimal change disease (MCD) can
subset as rapidly progressive glomerulonephri- be characterized as chronic (or recurrent) glo-
tis (RPGN). The majority of cases of acute GN merulopathies with no apparent glomerular
in children is due to post-infectious glomerulo- inflammation.
Table 15.1 Comparison of clinical features, treatment, and prognosis common acute glomerulonephritides in
children
Clinical features Post-streptococcal GN IgA nephropathy HSP nephritis (IgA vasculitis)
Trigger Nephritogenic beta “Synpharyngitic Prodrome (often viral URI) seen
hemolytic streptococcal hematuria”: Viral URI often in majority of patients; clustering
infection 10–14 days seen 24–74 h prior to onset in fall/spring
preceding onset of symptoms of gross hematuria
Clinical Hypertension, hyperkalemia, Microscopic hematuria and/ Rash (lower extremity palpable
features oliguria, and mild azotemia or low-level proteinuria may purpura); arthralgias, abdominal
common; microscopic persist between episodes of pain (bloody stools,
hematuria can persist for up gross hematuria intussusception); renal
to one year after presentation manifestations can be noted
within a few days to ~6 weeks
after initial presentation
Serum Transiently reduced Normal Normal
complement C3
Kidney biopsy Enlarged hypercellular Mesangial cell and matrix proliferation, mesangial IgA deposits
findings glomeruli, “starry sky” on immunofluorescence, ± IgG and C3 deposits
granular deposits of C3 and Mesangial IgA, IgG, and C3 deposits
IgG on immunofluorescence; Histological features of IgAN and HSP nephritis are
sub-epithelial “humps”— indistinguishable
electron-dense deposits
Treatment Supportive (high-dose ACE-I/ARB; lack of Supportive; lack of evidence-
methylprednisolone may be evidence-based data based data but various
considered in rare cases of although immunotherapy immunotherapy considered in
RPGN), in addition to sometimes considered in severe cases (glucocorticoids,
diuretics and progressive disease, often cyclophosphamide, azathioprine,
antihypertensives with large proteinuria severe mycophenolate mofetil)
cases (glucocorticoids,
mycophenolate mofetil);
omega3 supplements
Prognosis Majority self-limited; Chronic illness with Many patients recover
excellent prognosis long-term risk of CKD and spontaneously but subset with
hypertension long-term risk of CKD and
hypertension

Epidemiology abdominal pain, arthritis, and renal disease

(nephritis) in up to 30–40% of cases (Davin and
The most common form of GN in children is Coppo 2014).
acute post-infectious (mainly: post streptococ-
cal) GN affecting as much as 472,000 patients
worldwide with 5000 deaths annually according Diagnosis
the World Health Organization estimates
(Carapetis et al. 2005). Although its incidence Laboratory evaluation for suspected APIGN
has been steadily declining in the United States includes measurements of serum C3 and C4, and
and Europe over the past 40–50 years, it remains anti-streptolysin O and anti-DNAse B titers.
a substantial cause of morbidity and mortality Serum C3 is usually profoundly depressed in the
particularly in both developed and under- presence of normal C4 levels. Renal biopsies are
resourced countries (Sims Sanyahumbi et al. not necessary in most children with suspected
2016). The incidence of IgAV/HSP is ~20.4 per APIGN and HSP nephritis, but should be per-
100,000 population per year (Gardner-Medwin formed in patients with rapidly progressive renal
et al. 2002), primarily in children <10 years of dysfunction (RPGN), the persistence of signifi-
age, and tends to cluster in the fall and spring. cant or progressive proteinuria, or non-resolving
As indicated by the new nomenclature, HSP dif- renal failure (Davin and Coppo 2014). The diag-
fers from classical IgA nephropathy by the nosis of IgA nephropathy requires a kidney
pathognomonic purpuric rash. They demon- biopsy, which demonstrates predominantly IgA
strate virtually indistinguishable lesions in kid- deposits by immunofluorescence; staging is
ney biopsies and may represent different according to the Oxford classification (Working
manifestations of the same underlying disease Group of the International Ig ANN et al. 2009)
process (Kamei et al. 2016). Recent population- which includes mesangial cellularity, segmental
based Medicaid claims data from the US estimate sclerosis, endocapillary hypercellularity, and
the incidence of lupus nephritis as 0.72 cases per tubulointerstitial atrophy. Renal biopsy is also
100,000 children per year, and a prevalence of considered essential in the diagnosis of lupus
3.6 cases per 100,000 children (Hiraki et al. nephritis (Weening et al. 2004), as treatment is
2012). largely dictated by histopathological features
demonstrated in the biopsy.
Clinical Manifestations
Management
Glomerulonephritis presents clinically with
hematuria, proteinuria, edema, renal dysfunction, The goals of therapy are to reduce glomerular
and occasionally hypertension and nephrotic syn- inflammation, minimize proteinuria, improve
drome. Acute post-infectious, usually post- kidney function (if decreased), as well as symp-
streptococcal GN (APIGN/APSGN) occurs tomatic control of complications of fluid over-
7–21 days after the onset of pharyngotonsillitis load, which can manifest as hypertension or
or Group A streptococcal impetigo, whereas IgA edema. Loop diuretics help decreasing serum
nephropathy presents with painless gross hema- potassium levels in patients with mild hyperkale-
turia within 1–3 days of an upper respiratory mia and/or fluid overload. Sodium restriction is
infection (synpharyngitic hematuria). IgAV/HSP often recommended, particularly if patients are
is a form of leukocytoclastic vasculitis, charac- hypertensive or treated with glucocorticoids. The
terized by palpable purpura classically over the treatment of (mild) post-streptococcal GN and
buttocks and lower extremities, but occasionally HSP nephritis is symptomatic and supportive.
extending to the trunk and upper extremities, Although antibiotics do not alter the clinical

course of APSGN, elimination of the nephrito- p rogression to ESRD by 20 years in 20–25% of

genic strain of group A beta-hemolytic strepto- pediatric cases (Wyatt and Julian 2013).
cocci may minimize further spread of the disease
in the community. Various degrees of immuno-
therapy have been trialed in many cases of mod- Acute Kidney Injury in Children
erate to severe GN, although high-quality
evidence-based data, in particular double-blind, Introduction
randomized, placebo-controlled trials, are lack-
ing. Glucocorticoids have shown no benefit in Acute Kidney Injury (AKI) is defined as the sud-
prevention of HSP nephritis (Ronkainen et al. den decrease in glomerular filtration rate (GFR)
2006) but may improve renal involvement in that compromises the normal regulation of fluid,
select patients (Ronkainen et al. 2006). A 2007 electrolyte, and acid-base homeostasis. The term
meta-analysis concluded that early glucocorti- AKI has largely replaced acute renal failure
coid therapy reduced the odds of developing per- (ARF). The new term emphasizes the continuum
sistent renal disease (OR = 0.43, 95% CI of renal dysfunction without overt organ failure,
0.19–0.96) (Weiss et al. 2007). Although there is which is clinically relevant and linked to morbid-
no clear consensus on the optimal treatment of ity and mortality. ARF now often implies the
IgA nephropathy, moderate to large proteinuria need for renal replacement therapy. In clinical
>0.5 g/1.73 m2 per day is associated with acceler- practice, AKI is defined by an elevation of serum
ated decline of kidney function and an indication creatinine concentrations over an individual’s
to initiate long-term ACE-I/ARB therapy (Reid baseline creatinine and/or the sustained reduction
et al. 2011). The use of glucocorticids is contro- in urine output. Despite its widespread use, serum
versial; some evidence exists that high-dose creatinine is a poor marker for kidney function in
short-term therapy favors long-term renal protec- AKI, which only correlates with the GFR in
tion while daily low-dose long-term prednisone steady state. Patients with acute, severe AKI with
use does not (Lv et al. 2012). Omega3 fatty acid a markedly reduced GFR may still show normal
supplementation (fish oil) may decrease protein- or mildly elevated creatinine concentrations due
uria in IgA nephropathy, although it has not been to insufficient time for creatinine accumulation in
shown to prevent kidney function decline (Chou the serum. The increase in serum creatinine may
et al. 2012). be delayed by up to 48 h after kidney damage has
occurred.
Prognosis
Definition
Long-term prognosis of post-streptococcal GN
is excellent. Hypertension and azotemia The described limitations of serum creatinine
resolve within the first 2 weeks of illness, and have hampered clinical studies in the field
microscopic hematuria and proteinuria resolve (Thomas et al. 2015; Ricci et al. 2008) and
in the majority of cases within the first resulted in a large variability in reported inci-
3–6 months. In a systemic review of 1133 chil- dence, morbidity, and mortality estimates. This
dren with HSP, hematuria/proteinuria were deficit was remedied, in part, by consensus defi-
seen in ~1/3 of cases, although almost 20% had nitions, known as RIFLE, AKI network (AKIN),
some evidence of long- term kidney impair- and Kidney Disease Improving Global Outcomes
ment (Narchi 2005). Spontaneous remission (KDIGO) Classifications (Sutherland et al. 2015)
has been well-documented in IgA nephropathy (Table 15.2). The RIFLE criteria were developed
(Shima et al. 2013; Hogg 1988); persistence by an international consensus panel in 2004 and
of proteinuria is considered a marker for were intended for use in critically ill adults

Table 15.2 Acute kidney injury definitions

pRIFLE AKIN KDIGO
Stage Criteria Stage Criteria Stage Criteria
Risk (R) eCrCl ↓ 25% 1 ↑ SCr ≥ 0.3 mg/dL 1 ↑ SCr ≥ 0.3 mg/dL
(26.5 μM) or ↑ SCr (26.5 μM) or ↑
SCr ≥ 1.5–2×b
UOP < 0.5 mL/ ≥1.5–2 × a UOP < 0.5 mL/kg/h × 8 h
kg/h × 8 h
UOP < 0.5 mL/kg/h × 6 h
Injury (I) eCrCl ↓ 50% 2 ↑ SCr ≥ 2–3× II ↑ SCr ≥2–3×
UOP < 0.5 mL/ UOP < 0.5 mL/kg/h × 12 h UOP < 0.5 mL/
kg/h × 16 h kg/h × 16 h
Failure (F) eCrCl ↓ 75% or CrCl 3 ↑ SCr ≥ 3–4× or SCr > 4 III ↑ SCr ≥ 3–4× or SCr > 4
<35 mL/min/1.73 m2 (within 0.5 in 48 h) or (and meets criteria for
RRT initiated AKI) or RRT initiated or
eGFR < 35 in patients
<18 years old
UOP < 0.5 mL/ UOP < 0.5 mL/kg/h × 24 h UOP < 0.5 mL/
kg/h × 24 h or anuria or anuria × 12 h kg/h × 24 h or
for 12 h anuria × 12 h
Loss (L) Failure >4 weeks N/A N/A
End stage Failure >3 months N/A N/A
kidney
disease (E)
UOP: urine output awithin 48 h; bwithin 7 days
(Bellomo et al. 2004). RIFLE classifies increas- exists as to the preferred pediatric AKI definition
ing severity of AKI into five different categories: (Sutherland et al. 2015; Lafrance and Levin
(R) Risk, (I) Injury, (F) Failure, (L) Loss of kid- 2013). An area of active research is the study of
ney function, and (E) End stage renal disease, novel biomarkers with the goal of identifying
based on magnitude and duration of change in kidney injury in critically ill children before
creatinine/GFR, urine output, and the length of changes in serum creatinine occur and of allow-
renal replacement therapy (RRT). This classifica- ing prevention and possibly earlier intervention.
tion system was subsequently modified for chil- Biomarkers under investigation and validation
dren (pRIFLE), which also uses changes in the include urinary neutrophil gelatinase-associated
estimated creatinine clearance as a measure of lipocalin (NGAL), serum cystatin C, urinary kid-
GFR (Akcan-Arikan et al. 2007). The AKIN cri- ney injury molecule (KIM)-1, urinary interleukin
teria were developed next and are based on (IL)-18, and urinary liver-type fatty acid binding
changes in serum creatinine; AKIN stage 1 protein (L-FABP) (Schiffl and Lang 2012;
describes patients who experience a ≥0.3 mg/dL Vanmassenhove et al. 2013). Apart from cystatin
(26.4 μM) increase in serum creatinine over a C, none of these markers has yet become part of
48 hour period (Mehta et al. 2007). Although routine clinical practice.
AKIN was not adjusted for children, it has been
used in research in pediatric AKI, as has the most
recent KDIGO definition (Workgroup 2012), Etiology
which utilizes a more flexible timeline than
AKIN and has a specific modification for chil- Kidney function becomes impaired when ade-
dren. Although each new definition has refined quate blood supply and oxygenation, parenchy-
prior classifications, no universal consensus mal integrity and patency of the urinary tract are

interrupted. Consequently, AKI can be viewed as ing volume repletion (i.e. early goal-directed
caused primarily by prerenal, intrinsic renal and therapy in children with sepsis), and careful
postrenal factors. Despite substantial overlap, readjustment of nephrotoxic medications based
analysis of the likely cause is essential for reme- on close monitoring of drug levels and renal
diation and treatment. function. Several pharmacological agents includ-
ing mannitol, loop diuretics, low-dose dopamine,
fenoldopam, and N-acetylcysteine have been
Epidemiology studied in pediatric AKI with no convincing evi-
dence of benefit, but potential adverse side
The epidemiology of AKI has evolved signifi- effects; none is routinely recommended to pre-
cantly over the years. Common etiologies, such vent AKI or its progression.
as infections and sepsis, volume depletion, and Management of AKI includes judicious fluid
primary renal diseases (acute glomerulonephritis, administration to maintain euvolemia, treatment
hemolytic uremic syndrome) (Lameire et al. of electrolyte disarray including hyperkalemia,
2016) experience a shift to frequently multifacto- metabolic acidosis, hyperphosphatemia, and
rial events and complications of advanced tech- hypocalcemia, and treatment of coexistent hyper-
nological procedures, such as cardiac surgeries, tension if present. Loop diuretics are often used
exposure to nephrotoxic drugs, etc. (Hui-Stickle to induce diuresis in the setting of volume over-
et al. 2005). Nephrotoxic agents contribute to at load or for hyperkalemia, but have not been
least 25% of AKI in the intensive care unit shown to prevent AKI or substantially alter the
(Mehta et al. 2004). AKI is common in preterm natural history of AKI other than enhancing urine
infants, seen in up to 50% of neonates with output in the few nephrons that remain func-
asphyxia (Aggarwal et al. 2005), children under- tional. Restriction of sodium, potassium, and
going cardiac surgery (around 30–50%) (Bucholz phosphate delivery may be indicated, as may
et al. 2015; Mishra et al. 2005) and after bone sodium polystyrene sulfonate for hyperkalemia
marrow transplantation (Kist-van Holthe et al. and oral phosphate binders for hyperphosphate-
1998). The overall incidence of AKI in pediatric mia. Metabolic acidosis should be corrected care-
intensive care units is around 5% (Bailey et al. fully; the exchange of plasma protein-bound
2007), although a more recent retrospective anal- hydrogen ions with calcium can result in a
ysis of PICU discharges estimates the incidence decrease in available ionized calcium and result
of pediatric AKI in the intensive care unit in tetany. Frequent dose adjustments of renally
between 25% and 50% (Sutherland et al. 2015; eliminated or potentially nephrotoxic medica-
Selewski et al. 2014). AKI has been shown to be tions are necessary, and a multidisciplinary
an independent risk factor for mortality in chil- approach with intensivists, nephrologists, and
dren in the ICU. A large international prospective specialized pharmacists is recommended.
observational study, “Assessment of Worldwide
Acute Kidney Injury, Renal Angina, and
Epidemiology” (AWARE) (Basu et al. 2015) was Indications and Timing of RRT
launched in 2014 and aims to follow more than
5,000 critically-ill children worldwide. Renal replacement therapy (RRT) is considered
early when conservative measures fail. Typical
indications include fluid overload (10–20%
Treatment excess), hyperkalemia or severe acidosis unre-
sponsive to pharmacological therapy, uremia
General measures to prevent AKI include resto- (typically blood urea nitrogen [BUN] > 100 mg/
ration of intravascular volume, avoidance of dL (30 mM) or symptomatic), or an inability to
hypotension and renal ischemia by providing provide adequate nutrition (Selewski and Symons
inotropic support in critically ill children follow- 2014). Volume overload has been recognized as a

predictor of unfavorable outcome, and the degree of albuminuria and/or GFR <60 mL/min/1.73 m2,
of volume overload at RRT initiation is indepen- and nearly 50% were classified as at risk of CKD
dently associated with increased mortality—spe- (mildly decreased GFR of 60–90 mL/
cifically fluid overload greater than 20% min/1.73 m2, hypertension, and/or hyperfiltra-
(Sutherland et al. 2010), leading to an overall tion) (Mammen et al. 2012).
trend in many centers towards earlier initiation of
RRT (Basu et al. 2011). RRT modalities include
peritoneal dialysis (PD), hemodialysis (HD), and Chronic Kidney Disease in Children
continuous renal replacement therapy (CRRT);
their choice is dictated largely by the patient’s Introduction
clinical aspects as well as the availability of
equipment and expertise (Walters et al. 2009). As of 2015 estimates, chronic kidney disease
The Prospective Pediatric CRRT (ppCRRT) reg- (CKD) is currently estimated to affect 14% of the
istry demonstrated no difference in overall out- U.S. population (Saran et al. 2016). CKD is
comes based on modality or dose of CRRT used defined as abnormal kidney function based on
(Flores et al. 2008) in bone marrow transplant laboratory, urinalysis and/or imaging tests.
recipients. Peritoneal dialysis is advantageous in Although children comprise only a small propor-
younger children and neonates and in resource- tion of the total CKD population, pediatric kid-
limited countries, with no requirements for sys- ney function decline appears to be more rapid
temic/regional anticoagulation, vascular access, compared with adults. Extra-renal manifestations
or specialized equipment or personnel. and long-term outcome are uniquely different
Hemodialysis offers the advantage of rapidly cor- between pediatric and adulthood CKD due to the
recting fluid or electrolyte imbalances but essential role of normal kidney and related organ
requires patients to tolerate a large extracorporeal functions on the child’s physical and brain devel-
volume, and therefore CRRT may be preferred in opment. Young adults with ESKD suffer signifi-
children with multisystem organ dysfunction or cant comorbidities, with as much as a 10- to
hemodynamic instability: it permits gentler fluid 100-fold increased risk of coronary artery calcifi-
removal rates with less dynamic fluid shifts than cations, left ventricular hypertrophy, carotid arte-
HD while allowing full total enteral or parenteral riopathy, infectious complications, and metabolic
nutrition. bone disease (Goodman et al. 2000; Groothoff
et al. 2005; McDonald and Craig 2004; Oh et al.
2002). Age-specific mortality rates of dialyzed
Prognosis children are more than 130-fold higher than of
the general US population (Saran et al. 2015).
The overall mortality for AKI in the U.S. is There is a growing awareness of the impact of
around 15% (Sutherland et al. 2013); it is lower cardiovascular disease in children with CKD. The
in non-ICU compared with ICU settings ranging cardiovascular mortality of children with ESKD
from 1.5% to 9.5% (Sutherland et al. 2013, is 1000-fold higher than that of the general pedi-
2015). The ppCRRT registry of patients requiring atric population (Parekh et al. 2002). The overall
RRT reports a mortality of 42%. Survival was burden of ESKD on the US healthcare system is
lowest in patients <10 kg and those with liver dis- staggering, with over $31 billion in Medicare
ease/transplant (31%), pulmonary disease/trans- spending in 2013, representing over 7% of the
plant (45%), and bone marrow transplant (45%) entire annual budget (Saran et al. 2016).
(Symons et al. 2007). Patients who survive AKI Improvement of early diagnosis, intervention,
have an increased risk for hypertension, CKD, and long-term outcomes of patients, including
and ESRD. A prospective cohort study of pediat- children with CKD is a major goal of the
ric AKI survivors demonstrated that more than International Society of Nephrology, the National
10% had CKD after 3 years, defined as presence Kidney Foundation and other organizations.

Multi-center prospective studies and ongoing Table 15.3 CKD classification in children
reports of retrospective registry data have con- GFR (mL/min/1.73 m2)
tributed significantly to the CKD literature over Stage K/DOQI definition KDIGO definition
the last several years. 1 ≥90 ≥90
2 60–89 60–89
3 30–59 3a: 45–59
Definition 3b: 30–44
4 15–29 15–29
In 2003 the National Kidney Foundation pro- 5 <15 <15
posed a new definition and staging or CKD in
children (Table 15.3) (Hogg et al. 2003) which
was slightly adapted in 2013 by the Kidney nephritis, HSP), ciliopathies (nephronophthisis,
Disease Improving Global Outcomes (KDIGO) autosomal recessive polycystic kidney disease),
workgroup (Andrassy 2013). Chronic kidney dis- hemolytic uremic syndrome, cystinosis, and
ease is defined as functional or structural damage Alport’s syndrome.
to the kidneys or decrease in glomerular filtration
rate (GFR) to less than 60 mL/min/1.73 m2 for at
least three months. Importantly, the GFR may be New Equations to Estimate GFR
normal or near-normal in the early stages of CKD
when it is most important to prevent progression The original Schwartz formula to estimate GFR
and adequately treat comorbidities frequently in children was developed in the mid-1970s using
encountered with pediatric CKD. Although dia- serum creatinine, height, and an empiric constant
betes and hypertension account for the vast for age and gender. However, the serum creati-
majority of CKD in adults, approximately two nine assay has changed from the Jaffe chromogen
thirds of childhood CKD are attributed to con- reaction to the enzymatic method, requiring a
genital abnormalities of the kidney and urinary refinement of pediatric GFR estimating formulas.
tract (CAKUT) including renal dysplasia/hypo- The equation was updated in 2009 based on
plasia and various cause of obstructive uropathy results from the prospective observational multi-
(Harambat et al. 2012). Other common causes center study Chronic Kidney Disease in Children
include focal segmental glomerulosclerosis (CKiD), which measured GFR through the
(FSGS), chronic GN (lupus nephritis, IgA plasma disappearance of iohexol (Schwartz et al.
nephropathy, membranoproliferative glomerulo- 2009):
eGFR = 39.1 × [ height / SCr ] × [1.8 / cystatin C] × [30 / BUN ] × [1.099] × [ height / 1.4]
0.516 0.294 0.169 Male 0.188
Additionally, a simplified estimating equation min/1.73 m2 (Staples et al. 2010). Further studies
was derived—the so-called bedside CKiD equa- are planned in children and adolescents with nor-
tion—which included an updated constant of mal kidney function and earlier stages of CKD.
0.413: eGFR = 0.413 × height (cm)/serum creati-
nine (in mg/dL); for SI units, the constant is 36.5:
eGFR = 36.5 × height/serum [μmol/L]. Although dvances in Markers of CKD
A
the equation has been shown to perform reason- Progression
ably well in children with moderate CKD with
88% of the estimated GFR values falling within Several advances have been made in the recog-
30% of measured iohexol GFR (Schwartz et al. nition of modifiable risk factors to delay CKD
2009), the bedside CKiD equation underesti- progression. Hypertension is frequently present
mates GFR particularly in male adolescents and and often poorly controlled; the CKiD study has
children with a true GFR greater than 90 mL/ shown that over half of children had a systolic

or diastolic blood pressure ≥95percentile or use Education Program Working Group on High
of a current antihypertensive medication at Blood Pressure in C, Adolescents 2004). The
enrollment (Flynn et al. 2008). More recent epidemiology, diagnosis, and management of

investigations have demonstrated a prevalence childhood hypertension has changed greatly in
of masked hypertension in 35% (Samuels et al. the last decade, in part fueled by the rising obe-
2012). Twenty percentage of these children with sity epidemic. The current fourth report guide-
masked hypertension had left ventricular hyper- lines are in the process of revision with the
trophy (LVH) compared with 34% of children intention to reflect the changing trends in pediat-
with confirmed hypertension (Mitsnefes et al. ric hypertension management with expectation of
2010). The ESCAPE trial (Group et al. 2009), final guideline publication in 2017.
published in 2009, demonstrated that achieving
50th percentile blood pressure targets from an
intensified blood pressure regimen with ACE-I Epidemiology
delayed CKD progression. Proteinuria is another
recognized and potentially modifiable risk fac- Historically, hypertension in children was
tor for CKD progression in children; in a recent thought to be rare, and when present usually sec-
longitudinal analysis of CKiD data, nephrotic- ondary to an underlying condition, most com-
range proteinuria (urine protein to creatinine monly renal parenchymal disease. However, the
ratio >2 mg/mg) was shown to be one of the worldwide obesity epidemic has had a dramatic
strongest risk factors for CKD progression impact on obesity-related conditions including
(Warady et al. 2015). Therefore, renin-angioten- hypertension, and essential hypertension is now
sin-aldosterone system blockade with ACE-I or thought to be the most common form of hyper-
ARB is considered first-line therapy for hypertension during children and adolescence (Lurbe
tension or proteinuria in children with et al. 2010). Using data from the US National
CKD. Other novel risk factors for CKD progres- Health and Nutrition Examination Survey
sion which have recently been explored include (NHANES), an increase in the prevalence of pre-
low birth weight and prematurity (Carmody and hypertension by 2.3% and hypertension by 1%
Charlton 2013), exposure to secondhand smoke was observed from 1963 to 1999 (Din-Dzietham
(Omoloja et al. 2013), oxidative stress et al. 2007). Prehypertension progresses to hyper-
(Cachofeiro et al. 2008), and hyperuricemia tension at the rate of 7% per year (Expert Panel
(Rodenbach et al. 2015). on Integrated Guidelines for Cardiovascular H,
Risk Reduction in C, Adolescents, National
Heart L, Blood I 2011). More recent and alarm-
Update in Pediatric Hypertension ing analysis of NHANES survey data from 1999–
2008 revealed that 14% of adolescents ages
Introduction 12–19 years have pre-hypertension or hyperten-
sion, in addition to several other metabolic risk
Hypertension in children is defined as a sustained factors with 22% elevated low-density lipopro-
systolic or diastolic blood pressure ≥95%ile for tein cholesterol and 15% with impaired glucose
age, gender, and height according to normative tolerance (May et al. 2012). The entire distribu-
data derived from large databases of blood pres- tion of childhood blood pressure trends has
sure readings obtained in healthy children. One shifted upward by 1.4 mmHg for systolic BP and
of the most commonly used sources for normal 3.3 mmHg for diastolic blood pressure from 1988
blood pressure tables is the National High Blood to 2000 (Muntner et al. 2004). The most current
Pressure Education Program Working Group on estimates suggest that the prevalence of pre-
High Blood Pressure in Children and Adolescents hypertension has reached around 10% and hyper-
Fourth Report on the diagnosis, evaluation, and tension 4% in all children, with hypertension
treatment of high blood pressure in children and prevalence in obese children reported at 11–47%
adolescents (National High Blood Pressure (Flynn 2013).

Diagnosis the detection of a left ventricular mass index

(LVMI) >95% is considered an indication for ini-
Blood pressure is usually measured via indirect tiation of antihypertensive pharmacological ther-
methods, either through auscultation or oscillo- apy (Garin and Araya 2009; Daniels et al. 1998).
metric devices. Auscultative blood pressure However, the complex relationship between heart
assessment is considered the gold standard and is and body growth during development requires
what is used for all pediatric normative data. normalization of LV mass to body size, which led
Oscillometric devices calculate blood pressure by to the development and recent proposal of new
proprietary unpublished formulas, and are known reference centiles (Foster et al. 2016). Other
to overestimate blood pressure in children by as advances, predominantly used in research set-
much as 5–10 mmHg (Clark et al. 2002). Although tings, include pulse wave velocity to measure
the use of oscillometric blood pressure assessment central arterial stiffness, augmentation index to
has become widespread, caution should be used measure peripheral arterial stiffness, and radial
when diagnosing hypertension with an automated artery applanation tonometry which measures
device in children and elevated readings should be central vascular pressures and has been shown to
confirmed by manual auscultation. be a more accurate predictor of cardiovascular
Twenty-four hour ambulatory blood pressure disease outcomes than peripheral blood pressure
monitoring (ABPM) is increasingly used in the (O'Rourke and Adji 2010).
diagnosis of hypertension in children. In adults
ABPM has been shown to be superior to clinical
BP monitoring in predicting cardiovascular mor- Treatment
bidity and mortality (Metoki et al. 2006). In chil-
dren, APBM offers the advantages of For most patients with essential hypertension, a
distinguishing white coat from true hypertension, 6–12 month trial of nonpharmacological inter-
evaluating for the presence of masked hyperten- ventions should be recommended which include
sion, and of more precisely characterizing the DASH diet (Dietary Approaches to Stop
changes in blood pressure during daily activities Hypertension, a low sodium plant-based diet
and while asleep (Graves and Althaf 2006). In with whole grains, low-fat dairy and lean meats),
2014 the American Heart Association published moderate to vigorous exercise most days of the
a Scientific Statement regarding the use of APBM week, achievement and maintenance of normal
in children, affirming its utility in the diagnosis body mass index, and limited screen time (Expert
and management of hypertension in children Panel on Integrated Guidelines for Cardiovascular
(Flynn et al. 2014). ABPM should be considered H, Risk Reduction in C, Adolescents, National
for the confirmation of the diagnosis of HTN Heart L, Blood I 2011). Pharmacological therapy
(and exclusion of white coat HTN), evaluation is indicated for hypertension that persists despite
for the presence of masked HTN, assessing BP lifestyle changes, secondary hypertension, hyper-
variability, determining nocturnal dipping status, tension associated with end-organ damage such
and evaluation of the severity and persistence of as left ventricular hypertrophy, and hypertension
chronic diseases associated with HTN. associated with chronic diseases such as diabetes
or chronic kidney disease. In part due to the Best
Pharmaceuticals for Children Act, enacted by the
Evaluation of Target Organ Damage FDA in 2002, the number of antihypertensive
medications with pediatric-specific indications
Recent developments in the field of pediatric has increased considerably over the past decade,
HTN include an improved ability to identify tar- and includes angiotensin-converting enzyme
get organ damage. The use of echocardiography (ACE) inhibitors, angiotensin-receptor blockers,
to evaluate for the presence of left ventricular beta blockers, calcium channel blockers, and
hypertrophy is routine in clinical practice, and diuretics (Welch et al. 2012).

Genetics and the Kidney transcription factor) (Hinkes et al. 2007).

Systematic screening of all putative disease-
Introduction causing genes by next-generation sequencing can
now identify single gene defects in up to 30% of
The genetics of renal diseases have seen ground- cases of glucocorticoid-resistant nephrotic syn-
breaking changes over the last two decades with drome (Sadowski et al. 2015). Importantly, 1% of
direct effects on diagnosis and clinic practice. these mutations lead to defects in the mitochon-
Ever since the gene for Autosomal Dominant drial coenzyme Q10 biosynthesis pathway
Polycystic Kidney Disease (ADPKD) was (COQ2, COQ6, ADCK4) and are thought to com-
mapped to the short arm of chromosome 16 in promise podocyte energy metabolism. Early clin-
1985 (Reeders et al. 1985), the number of genes ical evidence indicates that proteinuria may be at
associated with renal disease has increased expo- least partially responsive to treatment with coen-
nentially. Such progress has led to a clearer zyme Q10 (Montini et al. 2008b; Heeringa et al.
understanding of the pathophysiology of pediat- 2011), a widely available nutritional supplement.
ric kidney disease, transformed the diagnostic Early identification of children with a monogenic
workup and in some cases offers the possibility glomerulopathy is vital, not only because patients
of a diagnosis without the need for a kidney may be spared exposure to immunosuppressive
biopsy, and enhanced the ability to provide prog- medications, which are unlikely to have any ben-
nostic information for patients and their families. efit, but also is also important for prognostic
Although only a tantalizing promise at present, information;” genetic” forms of nephrotic syn-
the identification of specific gene mutations holds drome are unlikely to recur after kidney
the possibility of curative treatment through gene transplantation.
therapy. Known or suspected ethnic disparities in the
epidemiology of CKD and ESRD have been
linked to genetic factors that contribute to disease
Glomerular Diseases susceptibility and increased risk of accelerated
disease progression. APOL1 polymorphisms are
Glucocorticoid (steroid)-resistant nephrotic syn- found almost exclusively among individuals of
drome is a challenging disease in childhood. African descent and are believed to confer resis-
Histologically, patients with glucocorticoid- tance to disease-causing trypanosomes. The
resistant nephrotic syndrome often demonstrate APOL1 risk variant confers tenfold higher risk of
focal segmental glomerulosclerosis (FSGS); ESRD due to FSGS and sevenfold higher risk of
FSGS is the 2nd common cause of ESRD in the ESRD due to hypertension in adults (Parsa et al.
pediatric age group. Principally, glucocorticoid 2013); the lifetime risk of kidney disease due to
resistant nephrotic syndrome can be divided into dual-risk APOL1 risk alleles is estimated at least
(1) congenital forms, the majority of which mani- 15% (Dummer et al. 2015). Two pediatric cohorts
fest during the first 3 months of life, (2) FSGS in of children with CKD, the CKiD cohort and
childhood with identifiable genetic mutations, (3) NEPTUNE cohort, have also identified high-risk
FSGS without identifiable mutation, but presence APOL1 risk variants to be associated with faster
of a circulating FSGS factor, and (4) adult onset/ CKD progression and more aggressive glomeru-
familial forms of FSGS. Up to 85% of cases pre- lar disease (Ng et al. 2017).
senting in the first 3 months and 66% of those Progress has also been made in the last decade
presenting in the first year of life have identifi- in the pathophysiology and treatment of atypical
able, disease-causing mutations in one of the hemolytic uremic syndrome (aHUS). Discovery
following four loci: NPHS1 (encoding nephrin, of multiple genes involved in the alternative path-
in the podocyte slit diaphragm), NPHS2 (podo- way of complement activation has led to the
cin), LAMB2 (laminin beta 2 in the glomerular emergence of aHUS largely as a disease of com-
basement membrane), or WT1 (Wilms tumor 1, a plement dysregulation. About 60% of patients

with aHUS carry currently identifiable mutations affecting cilial functions or downstream effect
in complement genes (CFH, CFI, MCP, C3, have been identified (Table 15.4) (Vivante and
CFB, THBD, and DGKE) or anti-CFH antibod- Hildebrandt 2016). A unifying paradigm to cystic
ies, and clinical genetic testing is available in sev- kidney disease was developed after the discovery
eral laboratories, by direct or next generation that the gene products of many of the mutated
sequencing (Loirat et al. 2016; Bajracharya et al. genes are expressed at the primary cilia and cen-
2016). Until recently, plasma therapy (preferably trosome complex (Hildebrandt and Otto 2005).
plasma exchange) was considered the therapy of Centrosomes play an important role in
choice for presumed aHUS (Ariceta et al. 2009). maintaining polarity in the cell-cycle regulation
However, long-term outcomes were generally of sensory cilia and cell-matrix signaling. This
poor, particularly for HUS due to CFH muta- has led to much interest in novel therapeutics tar-
tions, with mortality in excess of 8%, frequent geted at the cell signaling process, and in particu-
relapses with a risk of 50–80% progression to lar the relationship between vasopressin and
ESRD within a year, and almost universal risk of cyclic AMP in the development of cyst growth.
recurrence in renal allografts (Sellier-Leclerc In 2014, Japan was the first country to approve
et al. 2007). The publication of a pair of articles tolvaptan, a vasopressin 2 receptor antagonist for
in 2009 (Nurnberger et al. 2009; Gruppo and the treatment of ADPKD which showed signifi-
Rother 2009) demonstrating the remarkable suc- cant ability to retard cyst growth in the TEMPO
cess in treatment of aHUS with blockade of the 3:4 trial (Torres et al. 2012). This was followed
terminal complement cascade by eculizumab has closely by Europe and Canada in 2015, although
revolutionized the treatment of this disease. approval in the U.S. was denied due to concerns
Eculizumab is a humanized monoclonal antibody over potential hepatotoxicity.
that binds C5 and blocks the terminal pathway of
complement activation by preventing the genera-
tion of the cytotoxic membrane attack complex Renal Tubular Disorders
C5b-9 as well as the chemokine C5a. In 2015
consensus clinical practice recommendations on Renal tubules govern the homeostasis of solute
the management of aHUS in children were pub- and water regulation by modifying the quantity
lished, stressing the importance of eculizumab as and composition of the glomerular filtrate. Many
first-line therapy, and initiating treatment within tubulopathies are now recognized as single-gene
the first 24–48 h (Loirat et al. 2016). Although disorders. In most instances, the primary genetic
eculizumab has transformed the outlook of aHUS defect causes a loss or gain of function of a spe-
from a dismal prognosis to a now treatable condi- cific renal tubular transport protein, often a com-
tion, this comes at a high financial cost, with an ponent of a complex channel or a signaling
estimated annual price for eculizumab in 2015 of molecule. Because many transport systems are
nearly $400,000 USD (Blackwell 2015). preferentially expressed in specific tubule seg-
ments, such defects can result in recognizable
clinical syndromes with characteristic diagnostic
Ciliopathies features. Genetically determined proximal tubu-
lar abnormalities can result in glucosuria,
Hereditary renal cystic disease is a broad term phosphaturia, aminoaciduria, and/or proximal

encompassing a diverse array of disease pro- renal tubular acidosis. Generalized proximal
cesses including autosomal dominant (ADPKD) tubular dysfunction is known as renal Fanconi
and autosomal recessive polycystic kidney syndrome and a feature of several genetic disor-
disease (ARPKD), nephronophthisis, medullary ders, generally with multisystemic (extrarenal)
cystic kidney disease, and a variety of syndromic involvement. Examples are cystinosis (caused by
conditions including Bardet-Biedl, Joubert, and autosomal recessive mutations of CTNS that
Meckel syndrome; to date more than 95 genes encodes cystinosin), and the X-linked disorders,

Table 15.4 Hereditary cystic kidney disease

Disease Gene/protein MOI Comment
ADPKD
Type 1 PKD1/polycystin 2 AD Polycystic kidneys with large cysts, liver
Type 2 PKD2, polycystin 2 AD cysts, brain aneurysms, CKD
ARPKD PKHD1/fibrocystin and AR Polycystic kidney disease, liver fibrosis,
polyductin CKD
Nephronophthisis NPHP1 to NPHP9/nephrocystin AR Polyuria, polydipsia, anemia, CKD
types 1–9 Senior-Loken syndrome associated with
retinal lesions (retinal dystrophy, retinitis
pigmentosa)
Medullary cystic kidney UMOD/Tamm-Horsfall protein AD CKD (adult-onset), familial juvenile
disease (uromodulin) hyperuricemic nephropathy
Orofacial digital syndrome OFD1/OFD1 XLD Bilateral kidney cysts, CNS
malformations (agenesis of corpus
callosum, cerebellar agenesis),
micrognathia, malformations of digits of
hand
Meckel-Gruber syndrome MKS1;MKS3/meckelin AR Polycystic kidneys, multiple-organ
dysplasia, perinatal lethal
Bardet-Biedel syndrome BBS1 to BBS12/Bardet-Biedl’s AR Retinitis pigmentosa, polydactyly, mental
1–12 syndrome proteins retardation, hypogonadism, obesity
Jeune Syndrome IFD80/intraflagellar transport AR Bilateral cystic kidneys, skeletal
protein 80 homolog abnormalities including narrow chest,
DYNC2H1/dynein brachydactyly, short stature
Tuberous sclerosis TSC1/hamartin AD Renal angiomyolipomas, seizures,
TSC2/tuberin cardiac rhabdomyomas, skin lesions,
ADPKD (contiguous gene syndrome)
von-Hippel-Lindau VHL/tumor suppressor gene AD Increased risk for tumors: retinal
(G7 protein) angiomatosis, pheochromocytoma,
hemangioblastoma, renal cell carcinoma,
pancreatic cysts
WAGR complex WT1/WT suppressor gene 1 AD Wilm tumor, aniridia, genitourinary
anomalies, growth retardation
Papillary renal cell MET/hepatocyte growth factor AD Papillary renal cell carcinoma (subtype of
carcinoma receptor renal cell carcinoma)
MOI mode of inheritance, AD autosomal dominant, AR autosomal recessive, XLD X-linked dominant
o culocerebrorenal (or Lowe) syndrome (caused (NKCC2) (neonatal Bartter type 1), or physiolog-
by mutations of OCRL1 that encodes an inositol ically related proteins, including the potassium
polyphosphate- 5-
phosphatase) and Dent’s dis- channel ROMK/KCNJ1 (neonatal Bartter type 2),
ease (caused by mutations of CLCN5 that encodes and other channels or their subunits. Defects of
a renal-specific chloride/proton antiporter (Dent the distal convoluted tubule cause Gitelman syn-
1), or—infrequently—by mutations in the drome—due to mutations of the sodium-chloride
OCRL1 gene (Dent 2), the same gene that is symporter SLC12A3 (NCCT)—and other forms
responsible for Lowe syndrome. Other forms of hypomagnesemia. Defects in the collecting
are being identified. Dysfunctional solute duct impair reabsorption of water, sodium, potas-
reabsorption in the thick ascending limb of the sium, and hydrogen ions resulting in type IV
loop of Henle results in Bartter syndrome and its renal tubular acidosis. Nephrogenic diabetes
variants and secondary hypokalemic metabolic insipidus is caused by mutations in the aquapo-
alkalosis, caused by mutations in SLC12A2 that rin-2 water channel (Deen et al. 1994) or the
encodes the renal-specific Na-K-Cl cotransporter vasopressin-2-receptor (Rosenthal et al. 1992).

ongenital Anomalies of the Kidney

C References
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sion of glomerular and nonglomerular kidney disease

Update in Neonatology
16
Faiza Khurshid and Imtiaz Ahmad
Background then the practice has made rapid progress. One

example is the survival of extremely premature
The field of neonatology or neonatal-perinatal infants and the age of viability. In 1960s, a pre-
medicine is a pediatric subspecialty where the term infant was defined as an infant born at
practitioner manages medically sick infants during 30 weeks’ gestation. Now, the threshold of viabil-
early postnatal life. The most common patients are ity has reached to be 22- to 25-week gestation,
newborns who are premature, low birth weight, or depending upon the region of the world. This
who suffer from sepsis, hypoxic ischemic enceph- progress was initially supported by fluid and elec-
alopathy (HIE), congenital malformations or trolyte regulation, total parenteral nutrition,
respiratory distress. It is a hospital-based specialty, mechanical ventilation and minimizing blood
commonly practiced in Neonatal Intensive Care sampling. During the early 1990s, the use of ante-
Units (NICUs). However, the spectrum of care is natal steroids and surfactant for respiratory dis-
not limited to sick infants and includes routine tress syndrome were a breakthrough in decreasing
immediate care of a healthy newborn. the mortality of preterm infants. During the same
Distinct care for the newborns first appeared dur- period, the importance of regionalization of care
ing the early 1920s. As J.W. Ballantyne (1923) wrote: was realized. NICUs were distinguished as pri-
“There is a need for specialization in neonatal medi- mary (Level 1) to tertiary (level 3) units, and
cine, this applies to doctors and nurses as well as trained transport teams were developed to transfer
teaching and construction of hospitals” (Philip 2005). babies from one hospital to another depending
However, it took another half century for the upon the care required. Some other successful
specialty to achieve formal recognition. The first recent advancements are the use of the therapeutic
meeting of the American Academy of Pediatrics hypothermia in infants born with hypoxic isch-
(AAP), including a perinatal section was planned emic encephalopathy, the use of extracorporeal
in 1975 and the first neonatal board exam was membrane oxygenation (ECMO) in newborns
conducted in same year (Hodge et al. 2006). Since with respiratory failure, non-invasive ventilation
for preterm infants, the use of donor breast milk
and expanded newborn screening programs.
F. Khurshid, M.D., F.C.P.S., M.Sc. (H.Q.) (*)
Department of Pediatrics, Queen’s University, In parallel to the clinical successes, attitudes
Kingston, ON, Canada towards neonatal care also changed. In the1960s,
e-mail: khurshif@kgh.kari.net parents were only allowed to observe their babies
I. Ahmad, M.B.B.S., M.Sc. through glass windows (Baker 1999). Now, with
Department of Biomedical and Molecular Sciences, the emphasis on family-centered care, parents are
Queen’s University, Kingston, ON, Canada involved in decision-making. The infant-parent
e-mail: imtiaz_dr@hotmail.com


416 F. Khurshid and I. Ahmad
interaction is not limited to visiting at the side of mula was prevalent. In the last 20 years, as the
the incubator or bed, but parents are encouraged benefits of breast milk have become evident, ini-
to touch, hold, engage with their infants and pro- tiatives such as baby friendly hospitals, and orga-
vide expressed breast milk (Ramezani et al. 2014). nizations such as the World Health Organization
The increased survival of NICU patients is (WHO), The Academy of breastfeeding medi-
also related to progress in the fields of early pre- cine and others are working towards creating
natal detection, minimally invasive fetal surger- awareness of breastfeeding and setting targets to
ies, in utero blood transfusion performed by establish exclusive breast feeding in first
maternal fetal medicine specialists, the ex utero 6 months of life.
intrapartum treatment (EXIT) procedure for air- The American Academy of Pediatrics (AAP)
way related congenital abnormalities and new and WHO recommend the use of exclusive breast
surgical techniques for congenital heart disease. milk for at least 6 months and up to 12 months in
The future of neonatology in the next few a healthy term infant.
years is moving towards whole genome sequenc- Table 16.1 provides a summary of short- and
ing, artificial placentae, gene therapy and simu- long-term benefits published by WHO and agency
lated nurseries for teaching and learning. of the health care research report, related to breast
feeding (Horta and Victora 2013; Horta et al.
2013; Ip et al. 2009). While reading the summa-
Normal Newborn Care rized evidence, it should be kept in mind that the
results are synthesized from observational studies
Birth is the commonest reason for hospitalization. as conduction of a trial for breastfeeding would be
An adequate transition from intrauterine life to subjected to ethical justification.
the extra-uterine environment depends on the suc-
cessful adaptation of the cardiac, hemodynamic, ontraindications to Breastfeeding
C
and respiratory systems. Most newborns success- Human Immunodeficiency virus (HIV) infection
fully adapt to this change. However, about 10% of in mothers is a contraindication to breast feeding.
newborns require resuscitative measures just after However, the Centers of Disease control and
birth. Once the initial transition is achieved, rou- Prevention (CDC) suggests that in areas where
tine immediate care for healthy infants consists of there is a high prevalence of diarrhea and respira-
the establishment of feeding, early bonding cord tory illness leading to high infant mortality, exclu-
care, and the prevention of hypothermia, hypogly- sive breastfeeding for six months by mothers with
cemia, hemorrhagic disease of the newborn and HIV may outweigh the risks. Therefore, consider-
eye infection. Family education and assessment ation should be made on an individual basis (CDC
of readiness for discharge is also included within 2017). Other contraindications include type 1
routine management. galactosemia in the newborn, maternal infection
with human T-cell lymphotrophic virus type I or
type II, herpes simplex virus with active lesions
Neonatal Nutrition on the breast, and active tuberculosis not being
treated. The use of some illicit drugs and thera-
Current evidence has demonstrated that early peutic medications like antimetabolites, chemo-
nutrition plays an important role on later neurotherapeutics and radioisotopes may also preclude
development outcome and adult metabolic health breastfeeding (Hauk 2015).
(Robinson and Fall 2012).
upplements with Breastfeeding
S
enefits of Breastfeeding
B Although exclusive breast milk provides all nec-
Breastfeeding is now considered the optimal essary nutrients, it is found to be deficient in
feeding strategy for newborns. However, a few Vitamin D. Therefore, Vitamin D supplementation
decades ago, breastfeeding was considered as a of 400 IU/day is required in all breastfeeding
stigma of lower social class, and the use of for- babies. It can be started within the first few days

16 Update in Neonatology 417
Table 16.1 Benefits of breastfeeding regular standard infant formula is 20 calories per
Short-term benefits to Short-term benefits to ounce, which is equivalent to the average caloric
infant mother content of breast milk. However, the nutrient
– Protection against diarrhea – Sustained weight composition of formulas may have subtle differ-
and gastroenteritis loss
ences from breast milk composition. For exam-
– Protection against – Decreased
respiratory tract infection postpartum ple, protein contents are higher in formulas, and
and recurrent otitis media depression low and high iron containing formulas are avail-
– Reduction in asthma, atopic – Increased infant able. Some manufacturers have introduced very
dermatitis bonding
long-chain polyunsaturated fatty acids as evi-
– Reduction in sudden infant
death syndrome dence is promising for its effects on brain devel-
– Reduction in necrotizing opment. Some new generation formulas also
enterocolitis contain nucleotides, oligosaccharides (prebiot-
– Childhood leukemia
ics) and probiotics to promote healthy gut flora.
Long-term benefits to Long-term benefits to
At present, there is no evidence that one formula
infants mother
– Reduction of systolic blood – Decreased risk of
is better than another (Denne 2015). Soy formula
pressure (less than 1 mmHg) Type 2 diabetes and extensively hydrolyzed protein formula are
– Substantial protection – Decreased risk of not recommended for infants except in specific
against diabetes was noted breast and ovarian conditions.
in the pooled analysis (34% cancer
reduction) However – Decreased risk of
randomized trials did not hypertension, and astroesophageal Reflux (GER)
G
present results of these cardiovascular and Gastroesophageal Reflux Disease
outcomes diseases (GERD)
– 24% reduction in
overweight and/or obesity
GER is one of the most common conditions seen
– An increase in 3.5 points in in healthy newborns during the first two months
normalized test scores in the of life. Most are ‘happy spitters’ and require no
pooled analyses treatment. However, it is necessary to identify the
– Breastfeeding does not small proportion of infants, suffering from
seem to protect against
hyperlipidemia
GERD.
– No effect on diastolic An approach suggested by the North American
pressure Society for Gastroenterology, Hepatology, and
Nutrition describes several steps in managing
newborns with GERD (Vandenplas et al. 2009).
of life and should to be continued until the infant The first step is to take a good history and per-
is receiving 1 L/day or 1 quart/day of vitamin form a physical examination to ascertain ade-
D-fortified formula or whole milk. Breastfeeding quate caloric intake and to exclude any concerning
infants also require iron in a dose of 1 mg/kg/day signs such as bilious vomiting, GI bleeding, etc.
from 4 months of age which should be continued As a first step, dietary changes are used to address
until the infant consumes adequate oral iron from the concern of milk protein allergy. Breastfeeding
foods (Kirby and Noel 2007). mothers are advised to avoid the use of dairy and
egg products while formula-fed infants can be
Infant Formula given a trial of hydrolyzed formula. Thickened
Although the trends towards breastfeeding are formulas are also available; their use is contrain-
encouraging. It will not be possible for every dicated in preterm neonates due to the risk of
infant and therefore the use of infant formula is necrotizing enterocolitis. If no response is
still required. Infant formulas are available in dif- achieved than consultation with a pediatric
ferent forms including ready to feed, concen- gastroenterologist and the use of acid suppres-
trated liquid, and powder. It is essential to guide sion therapy should be considered. An upper gas-
parents in the proper preparation of the liquid trointestinal series can be performed in the
concentrate and powder. The caloric content of presence of any concerning symptoms or signs.

Newborn Skin and Umbilical Cord Care irst Newborn Cleaning

F
The importance of vernix caseosa has finally
The skin provides an effective barrier, and a been recognized as a protective moisturizer
breach of this barrier can create means of intro- (Visscher et al. 2015). Also, an immediate clean-
ducing bacteria which could potentially lead to ing with water or wet wipe can interfere with the
systemic infection. Over the last decade, new- thermoregulation and therefore skin to skin care
born skin care practices, cord care and meth- is preferred (Darmstadt and Dinulos 2000).
ods of bathing have changed considerably Newborn babies should be wiped off with a dry
which has created confusion among health care towel after birth. The first bath should be consid-
providers and parents. With emerging evidence ered only when the temperature has stabilized.
of the association of initial skin care with The use of gloves for the first bath is also required
development of atopy in later life, it is neces- in hospital settings (Blume-Peytavi et al. 2016).
sary to adopt practices for healthier skin (Cork
et al. 2006). Routine Bathing
The European group (Blume-Peytavi et al. 2016)
mbilical Cord Care
U have clarified some controversial issues related to
The umbilical cord is a unique structure present routine bathing. Based on available data, new-
in newborns. It provides a route whereby bacteria born infants should be bathed for 5–10 min at
may gain direct access to the systemic circula- least 2–3 times a week; it can be started even
tion. Infection of the cord can present as ompha- when the cord is not yet separated. The benefits
litis, thrombophlebitis, cellulitis or necrotizing include tactile stimulation, infant bonding, and
fasciitis. improved sleep (Bryanton et al. 2004; Mindell
The common risk factor in developed coun- et al. 2009). However, the benefits of bathing ver-
tries include umbilical catheterization, prematu- sus sponging is not yet clear. For bathing either
rity, chorioamnionitis, prolonged rupture of water or liquid cleaner with a neutral or slightly
membrane (PROM) (Mason et al. 1989). The acidic pH is preferable (Hachem et al. 2003).
incidence of umbilical cord -related infections is
highly variable and is dependent upon the place Diaper Care
of delivery (home vs. hospital) and cord care Diaper dermatitis is one of the common problem
practices. One published study from Canada seen in the initial months of life. The skin barrier
reported only three cases among 3518 infants is broken by the occlusive diaper environment,
(Dore et al. 1998) while in developing countries, with alkaline urine disrupting the epidermis
this could be as high 17% (Mir et al. 2011). along with fecal enzymes causing further dam-
The controversy over the use of chlorhexidine age. Several studies have suggested that the dia-
vs. dry care is long standing. However, in recent per area should be cleaned with washcloths
years the WHO has released evidence-based dipped in water or if available, particular wipes
guidelines for cord care. Due to the difference in which maintain a slight acidotic environment
incidence, WHO guidelines suggest dry cord care (Lavender et al. 2012).
for infants born within low incidence countries
and use of chlorhexidine solution in high inci-
dence setting (WHO 2014). Newborn Screening
In a statement released by the AAP, high
importance was placed on the promotion of skin Newborn screening is a practice whereby a single
to skin with mother to increase colonization test in apparently healthy babies at birth can detect
with non-pathogenic bacteria and considered a fatal disorder, which otherwise might not be diag-
dry cord care as another step towards reducing nosed at birth. Newborn screening began in 1960
resistant bacterial growth (Stewart and Benitz when Robert Guthrie developed a blood test to
2016). detect phenylketonuria (Guthrie and Susi 1963).

This has evolved from a blood or urine test to detect nodeficiencies and cystic fibrosis. A list is pro-
a single disease to a three-part screen. Now, one vided in Table 16.2.
drop of blood can be used to screen for as many as The Secretary of Health and Human Services’
50 diseases. Hearing screen at birth and pulse Advisory Committee on Heritable Disorders in
oximetry to detect critical congenital heart disease Newborns and Children (SACHDNC) in the
are also component of newborn screening. United States of America (USA) is the organiza-
To increase the number of disorders in the tion which oversees regulations regarding new-
screening program, the method of laboratory born screening program across the country. This
techniques to carry out screening tests have also centralization has helped to develop a
changed. The method introduced by Guthrie was Recommended Uniform Screening Panel (RUSP)
a bacterial inhibition assay, while currently, tan- in the USA. Initially, RUSP had 29 core condi-
dem mass spectrometry can allow rapid and tion. In 2015 four additional conditions were
accurate analysis for multiple conditions simulta- included on the panel list. [severe combined
neously (Chace and Naylor 1999). immunodeficiency disease (SCID), Pompe dis-
In most developed countries, screening is a ease, and Mucopolysaccharidosis type I (MPS I)]
public health service. However, there is a huge along with 1 secondary target, T-cell lymphocyte
variation in the number of diseases available on deficiencies.
the screening panel of different countries or even
different states/provinces of the same country earing Screening Program
H
(Therrell et al. 2015). Hearing loss is another common disorder with the
It is important to remember that screening prevalence being as high as 1–3/1000 births
cannot confirm the disease. It identifies newborns (Hyde 2005). Hearing loss may be sensorineural,
who require further follow-up testing to confirm conductive or mixed type. Initially, screening was
the diagnosis. It is always hard to set the thresh- only offered to high-risk populations (premature,
old level for screening tests. If it is too high, the neonates with persistent pulmonary hypertension,
false negative number will be high, and a certain hyperbilirubinemia, newborns requiring mechani-
number of infants who have the disorder will go cal ventilation or ECMO, congenital infections,
undetected. If it is set too low, the false positivity meningitis, family history of hearing impair-
rate will be higher. ment). However, as risk factors are only present in
For instance, data extracted from the National 50% of infants who develop hearing impairment
Newborn Screening Information System revealed during infancy, the practice of universal hearing
that 3,364,612 infants were tested for maple screening for every newborn has been adopted in
syrup urine disease (MSUD) in the United States many countries (Patel and Feldman 2011). The
during 2007. The initial reports were positive for two methods used in screening programs are the
1249 among all tested, but after further testing, auditory brainstem response (ABR) and
only 18 newborns were eventually confirmed as Otoacoustic emissions (OAEs).
having the disease (The President's Council on The effectiveness of universal screening pro-
Bioethics 2017). grams has been demonstrated in systematic
reviews. A recent meta- analysis based on 17
ewborn Blood Spot Screening
N studies concluded that studies comparing screen-
Typically, blood is taken from a heel stick to be ing versus no screening showed an improvement
absorbed on a special filter paper and sent to des- in speech development in the screening group
ignated laboratories. Most countries have devel- (Wolff et al. 2010).
oped a central laboratory system where tests are The effectiveness of prompt interventions
performed. based on early detection is also well studied.
The conditions that could be screened for There is a clear evidence that infants who receive
newborns include inborn errors of metabolism, intervention before 6 months of age score higher
endocrine disorders, hemoglobinopathies, immu- on school-related measure (Korver et al. 2010).

420
Table 16.2 Diseases available on screening panels for newborn screening program
Lysosomal
Metabolic disorder disorder Endocrine disorder Hemoglobinopathies/hematology related Miscellaneous Infections
Six core amino acid Krabbe Hypothyroidism Beta thalassemia SCID Toxoplasmosis
disorders
Eight secondary Pompe Congenital adrenal Hemoglobin S-C disease X-Linked Human immuno-
amino acid disorders hyperplasia Adrenoleuko- deficiency virus (HIV)
dystrophy (X-ALD)
Five core fatty acid Fabry Sickle cell disease Cystic fibrosis
oxidation disorders
Eight secondary fatty Gaucher Glucose-6-phosphate dehydrogenase
acid disorders deficiency (G6PD) deficiency
Nine core organic acid Niemann pick Other Hb variant
disorders
Six secondary organic MPS-I
acid disorders
Biotinidase deficiency MPS-II

Galactosemia
F. Khurshid and I. Ahmad
ongenital Cardiac Disease

C tilation (PPV) should be present at each delivery
Critical congenital heart defects (CCHD) are (Wyckoff et al. 2015).
serious congenital conditions that require treat- The international Liaison Committee on
ment right after birth or need surgery within the Resuscitation (ILCOR) is responsible for devel-
first year of life. These conditions include oping recommendations based on currently avail-
hypoplastic left heart syndrome, pulmonary able evidence.
atresia, tetralogy of Fallot, total anomalous pul- These recommendations are then adapted by
monary venous return, transposition of the regional organizations with some subtle differ-
great arteries, tricuspid atresia, and truncus ences. (Neo-Resus in Australia and New Zealand,
arteriosus. The reported incidence of these con- Newborn Life support in Europe, Neonatal
ditions in the United States is approximately Resuscitation Provider (NRP) in North America).
7200 babies per year (Oster et al. 2013). Pulse Recent updates were published in 2015 introduc-
oximetry screening at 24 h of age or later could ing some significant changes from the previous
detect these seven critical diseases. Pulse oxim- 2010 edition (Perlman et al. 2015). Since then,
etry is widely available as an accurate method local organizations have released their updated
of measuring oxygen saturation. The sensitivity version with provisions of timeline within which
of this screening method has been shown to to start new practices.
range from 60% to 100% specificity being The basic principle of neonatal resuscitation
≥94% in most studies (Narayen et al. 2016). In has remained unchanged. This includes emphasis
2011, the Secretary of Health and Human on the establishment of effective ventilation, syn-
Services recommended adding screening for chronized chest compression with a ratio of three
CCHD using pulse oximetry before hospital compression per one breath (3:1), and the use of
discharge to RUSP (Mahle et al. 2012). The blended oxygen to target oxygen saturation.
screening has also been adopted in most of the Below is a summary of significant changes
European countries and USA. suggested by ILCOR.
Future Perspective 1. Management of meconium

In upcoming years, newborn screening programs The long-standing practice of routine tracheal
are expected to expand. intubation and suction of non-vigorous infants
Research is ongoing to include fragile X syn- born through meconium stained amniotic fluid
drome, spinal muscular atrophy, Wilsons disease, is no longer recommended. There was insuffi-
guanidinoacetate methyl transferase deficiency cient published human evidence to suggest any
(Therrell et al. 2015). DNA-based testing to con- benefit of intubation for suctioning. As ventila-
firm results when newborn tests are positive for a tion is the most important aspect of newborn
disorder, the use of nanotechnology (a lab on a resuscitation, tracheal suction can delay the
chip) to save and screen mass samples are exam- establishment of effective ventilation.
ples of work in progress. 2. Cord clamping
In recent publications, delayed cord clamping
has demonstrated a decreased incidence of
Neonatal Resuscitation intraventricular hemorrhage in preterm infants
and anemia in later infancy. Based on this evi-
Although the risk of requiring resuscitation at dence, it is suggested that cord clamping be
birth is small with only 1–3 per 1000 term new- delayed for at least 1 min after birth in uncom-
borns requiring chest compressions or emergency promised term and preterm infants. The evi-
medications, it is strongly advised that even in dence is not clear to guide timing of cord
the absence of anticipated risk factors, at least clamping in non-vigorous infants who require
one qualified individual, skilled in the initial resuscitation. Another similar approach is cord
steps of newborn care and positive-pressure ven- milking. At this time, ILCOR r ecommendations

do not support this practice in the infants born mon for a newborn to undergo painful proce-
at or less than 28 weeks’ gestation. dures. Until the early 1990s, a common belief
3. Assessment of heart rate was that infants do not feel pain. Now it is well
The traditional approach to assess heart rate was known that premature infants as young as this
the use of umbilical cord palpation as well as age and repeated noxious stimulus can cause
auscultation. Now ILCOR suggests that electro- increased excitability in nociceptive neurons,
cardiographic monitoring (ECG) should be resulting in sensitization and future hyperin-
used to provide a rapid, accurate estimation of tense response to pain (Ingram et al. 2008).
heart rate in newborns requiring resuscitation. Repeated painful procedures or even routine
4. Temperature control heel puncture or tape removal can affect future
ILCOR recommends that an infant should be pain perception (Bellieni et al. 2009). Pain and
maintained between 36.5 and 37.5 °C after stress in neonatal life also impact long-term
birth and during stabilization. A combination neurodevelopment.
of interventions including the use of plastic It is widely recommended by the AAP (Keels
wrap, warming mattresses, hats and raising of et al. 2016) and Canadian Pediatric Society
the environmental temperature to 23.0–25.0 °C (CPS) (Batton et al. 2006) that every facility
should be used to achieve target temperatures. involved in newborn care should develop a stan-
5. Oxygen concentration for preterm infants dard to evaluate/assess pain as well as a pain
In the previous ILCOR version, the use of prevention program. Since these recommenda-
room air during the resuscitation of full-term tions were published there has been a significant
infants was recommended. In the current drop in the number of procedures and increased
update, ILCOR recommends against initiating use of pain management strategies to control
resuscitation of preterm newborns <35 weeks’ pain. In a recent report from the USA, the num-
gestation with high concentrations of oxygen ber of painful procedures declined from 14.3
(65–100%). This change was translated in the procedure per infant per day in 2001 to 11.4 in
new edition of NRP as a recommendation to 2014. Similarly, use of analgesia increased from
initiate resuscitation of newborns <35 weeks’ 36.6% to 60.3% during the same period
gestation at 21–30% oxygen. (Roofthooft et al. 2014).
ILCOR found insufficient human evidence to Scoring System

inform the practice of oxygen concentration dur- The biggest challenge is to find an efficient scor-
ing CPR (cardiac compressions), suggesting, if ing system for assessment. The pain assessment
supplementary oxygen is used, should be weaned scores usually combine behavior and physiologi-
as soon as the heart rate has recovered. cal responses. There are many published scoring
The AAP and American Heart Association system, but only a few have undergone psycho-
(AHA) released a new NRP publication in the metric testing to prove validity (MEDICINE
spring of 2016. Along with clinical changes as COFANaSOAAP et al. 2016). The most common
suggested by ILCOR, emphasis was placed on score systems in use are the PIPP (premature
preparation for resuscitation and teamwork infant pain profile (Stevens et al. 1996), neonatal
including identification of role and debriefings. facial coding system (Grunau et al. 1998), and
Behavior Indicators of Infant Pain (Holsti and
Grunau 2007).
Common Neonatal Problems
Pain Management
revention and Management
P Pain management in neonates consists of envi-
of Procedural Pain in Neonates ronmental changes, nonpharmacological maneu-
vers and pharmacological measures.
Alleviation of pain is a fundamental right and Nonpharmacological maneuvers include breast-
ethical principal in medicine. It is not uncom- feeding, swaddling, rocking, and sensorial

s timulation. A 2012 Cochrane review of 20 stud- The most well studied pharmacological analge-
ies demonstrated that breastfeeding is effective as sia in newborns is oral sucrose. The effect is gener-
compared to other non-pharmacological methods ated through the release of possible endogenous
and has similar effectiveness as the administra- opiates (Shide and Blass 1989). It’s effect is well
tion of glucose solution in reducing pain scores described when used as a single dose in moderate
during heel lancet or venipuncture (Shah et al. painful procedures. Longer procedure may need
2012). repeated doses (Stevens et al. 2013). Topical anal-
Sensorial stimulation (SS) during painful pro- gesia can be used to relieve pain from local painful
cedures has recently been introduced as one of procedures. They are usually applied 30 min prior
the methods to reduce pain in newborns. SS to the procedure. The other commonly used anal-
could be as simple as looking and talking to an gesic agents are morphine, fentanyl, and acetamin-
infant and gentle massage of the back. However, ophen (Table. 16.3). Continuous use of opiate
it was found to be more effective when used analgesia for pain relief during prolonged intuba-
along with sucrose as an analgesia (Bellieni tion and ventilation is not recommended (Canadian
et al. 2012). Pediatric Society 2017a).
Table 16.3 Use of analgesia in procedural pain

Systemic/opiate
Name of procedure NNS Sucrose Topical anesthesia Acetaminophen based analgesia Regional block
Heel puncture Y Y N
Venipuncture, Y Y ± (EMLA)
arterial puncture,
percutaneous
central venous
catheter insertion
Intramuscular Or Y(EMLA)
subcutaneous
injection
Central venous Y Y Y (EMLA) Y
catheter insertion
by surgical
cut-down
Tracheal Y
intubation
Lumbar puncture Y Y Y (EMLA) ±
Chest tube Y Y
insertion LIDOCAINE
Chest tube Y Y
removal
Screening for Y Y Y
ROP Local anesthetic
drop
Laser therapy for Y
ROP
Circumcision Y Y (EMLA) Y (post Y (Dorsal penile
procedure) nerve block,
Subcutaneous
ring block)
Post-operative Y Y Y ±
Adapted from (Lago et al. 2009; Pediatrics and FaN 2006)
NNS non-nutritive sucking, Y recommended, N no recommendation, ± suggested

Neonatal Sepsis et al. 1996). Total white blood cell (WBC) count
is the most common test in clinical practice as it
Early-onset sepsis (EOS) is defined as sepsis occur- is low cost and readily available but the predica-
ring within first seven days of life. Vertical trans- tive value of WBC for diagnosis of EOS is poor.
mission of pathogens is considered as an important Few recent studies reported a high likelihood of
etiology, and Group B streptococcus (GBS) is the confirmed sepsis if the WBC count is performed
most common bacteria causing sepsis in full-term at 4–6 h of life or the absolute neutrophil count is
infants. In 2002, CDC recommended routine intra- low (Newman et al. 2010). The acute phase reac-
partum screening of GBS for all expectant mothers tant C-reactive protein is a marker of tissue injury
at 35–37 weeks of gestation and intrapartum antibi- or an infectious process. A single value of CRP
otics prophylaxis (IAP) for women with GBS vagi- should not be used to diagnose sepsis; however,
nal colonization, GBS bacteriuria, and previous serial levels of CRP could help in determination
child with invasive GBS disease (Di Renzo et al. of length of antibiotic therapy in cases of sus-
2015). A guide to manage newborn at risk of sepsis pected sepsis (Lacaze-Masmonteil et al. 2014).
due to perinatal factors was also implemented at
same time. The reported prevalence of Early onset anagement of Newborns >35-Weeks
M
GBS sepsis in USA decreased from 1.7 cases per of Gestation at Risk for Sepsis
1000 live births to 0.45/1000 cases after implemen- There are published practice guidelines available
tation of screening guidelines i.e. an approximate to manage full term infants born at risk for sepsis.
70% reduction (Schrag et al. 2002). Although these The recommendations to treat a newborn are
guidelines were effective to decrease the neonatal based on the presence of risk factors at delivery
disease burden due to EOS, they raised other con- and clinical signs in the newborn. Table 16.4
troversies like increased incidence of infection due presents a brief comparison of three commonly
to organisms other than GBS like EColi, excessive used guidelines in the North America (CDC
use of antibiotics, and increase in invasive testing in (CDC 2017), APA (Polin 2012), CPS (Canadian
newborns. Pediatric Society 2017b) and National Institute
for health care and Excellence (NICE) from the
iagnosis of Sepsis
D United Kingdom (NICE 2012).
Suspected sepsis is one of the commonest diag- Puopolo and colleagues developed a calcula-
noses in NICUs. Sepsis is diagnosed using a tor to predict the incidence of sepsis in a newborn
combination of strategies including perinatal risk based on a dose-dependent relationship of risk
factors, infants’ signs and symptoms, and labora- factors rather than on a dichotomous relation as
tory testing. It is challenging for physicians to in previous studies. Authors of the study demon-
decide when to perform invasive tests and start strated a significant decrease in the number of
antibiotics in a healthy-looking newborn based invasive tests and antibiotic usage without any
on risk factors only and, when to stop antibiotics missed cases with the use of their proposed cal-
in a low likelihood of infection before discharg- culator (Puopolo et al. 2011).
ing the baby home (Polin 2012). The major risk
factors for sepsis include chorioamnionitis, rup-
ture of membranes >18 h, maternal GBS coloni- Hypoxic Ischemic Encephalopathy
zation with inadequate prophylaxis, and
prematurity (Schuchat et al. 2000). Neonatal encephalopathy is characterized by dis-
At present, there is not a single test which turbed neurological function resulting in reduced
could safely confirm or rule out early onset sep- level of consciousness with or without seizures
sis. Blood culture is the gold standard to diagnose (Pediatrics AAo 2014). Hypoxia, ischemia or
EOS but use of maternal antibiotics and volume birth asphyxia, is the commonest cause of
of blood obtained to grow on culture media can encephalopathy in early days of life. In this
affect the sensitivity of the results (Schelonka instance, it is often accompanied with multisystem

Table 16.4 Managements of term newborn with risk of early onset sepsis
Limited evaluation and
Routine care Observation only observation Full evaluation with antibiotics
CPS – GBS + ve GBS + ve with Chorioamnionitis or Unwell/symptomatic infant at
with adequate adequate IAP and multiple risk factors birth
IAP no risk factors – Observation for 24 h
– GBS –ve/ – GBS –ve/GBS – Consider CBC at
GBS unknown with 4–6 h of age
unknown one risk factor
with one risk and inadequate
factor and IAP
adequate IAP
AAP – GBS +ve with Chorioamnionitis
inadequate IAP or risk – Unwell/symptomatic
factors infant at birth
– CBC with differential and
CRP at 6–12 h of age
– Observation 48 h
CDC GBS –ve with – GBS +ve with GBS + ve with Inadequate Chorioamnionitis
no risk factors adequate IAP and risk factors – Unwell/symptomatic
prophylaxis – CBC infant at birth
– GBS +ve with – Observation for 48 h
inadequate
prophylaxis but
>37 week and
ROM <18 h
NICE Babies with one – Maternal confirmed
risk factora bacterial infection
– monitor for 12 h – confirmed infection in
second twin
– Two or more risk factorsa
– Unwell babies
CPS Canadian Pediatric Society, AAP American Academy of Pediatrics, CDC Centers of disease control and preven-
tion, NICE National Institute for health care and Excellence, CBC Complete blood count, CRP C reactive protein, GBS
Group B streptococcus, IAP Intrapartum prophylaxis
Full evaluation = (CBC, blood Culture) chest x-ray and lumbar puncture if indicated
Risk Factor in CPS statement = Rupture of membrane >18 h, Maternal temperature > 380 °C
RISK factor * in NICE guidelines (Maternal GBS + ve in current pregnancy, invasive disease in previous baby, GBS
bacteriuria, pre-labor rupture of membranes, Intrapartum fever or confirmed Chorioamnionitis)
organ failure including difficulty in maintaining cental blood flow results in compromised blood
respiration, myocardial depression, liver and supply to the fetal heart and brain leading to the
acute kidney injury, and disseminated intravascu- initiation of a hypoxic cascade. Hypoxic injury to
lar coagulation. the brain is a staged process. Initially, neurons
Hypoxic Ischemic Encephalopathy (HIE) is suffer with energy failure and anaerobic metabo-
historically associated with high mortality and lism is used to generate energy. This primary
morbidity. The incidence ranges from 1 in 8/1000 phase enters into latent and secondary phases
live births in developed countries to 26/1000 live characterized by inflammation, cytotoxic edema,
birth in other parts of world (Kurinczuk et al. and continuation of the apoptotic cascade
2010). (Douglas-Escobar and Weiss 2015) (Fig. 16.1).
athophysiology of HIE
P iagnosis of HIE
D
Adequate blood supply is needed to provide oxy- The diagnosis of HIE is based on the presence of
gen and nutrient to the brain. Disruption of pla- abnormal neurological signs and sentinel events

Oxidative Inflammation
stress
Secondary Chronic
Pro–
Hypoxia –ischemia
mitochondrial inflammation
Excitotoxicity apoptotic failure
Reperfusion
signal
insult
Loss of trophic
Cell swelling
Cell swelling support
NMDA
receptor hyper Cell death
Primary cell excitability
Late Cell
death Seizures death
Primary Latent Secondary Tertiary
30–60 min 6–12 hours 72 hours Months
Fig. 16.1 Pathophysiological features of hypoxic ischemic encephalopathy (adapted from Davidson (Davidson et al.
2014))
in proximity to labor and delivery. The sentinel Other areas involved in hypoxic injury are the
hypoxic events are ruptured uterus, placental watershed cortex and the posterior limb of the
abruption, umbilical cord prolapse, maternal car- internal capsule, while global injury affecting
diovascular collapse, and massive fetal blood both grey and white matter is seen in cases of per-
loss. Perinatal hypoxia is recognized before birth sistent severe hypoxia (Rutherford et al. 2010).
with characteristic fetal heart rate patterns (cate- The diffusion-weighted images (DWI) performed
gory III pattern, tachycardia with recurrent decel- as early as 48–72 h of life have shown predictive
eration, and persistent minimal variability with value in cases of neonatal HIE. These findings
recurrent deceleration). After birth, umbilical help the physician in decision-making for con-
artery acidemia, poor Apgar scores, and resusci- tinuing management and the counseling of
tation at birth will identify newborn at risk of parents. However, a word of caution should be
developing HIE (Nelson et al. 2012). The Sarnat used while predicting prognosis with a normal
scoring staging system assesses the severity of MRI. Rollins and colleagues have shown that as
encephalopathy. It is a bedside clinical tool based many as 26% who receive hypothermia could
on the following: level of consciousness, motor have a normal MRI with later abnormal develop-
tone, reflexes, and autonomic dysfunction. It ment (Rollins et al. 2014).
grades neurological dysfunction into mild, mod- Electroencephalogram (EEG) is another com-
erate, and severe encephalopathy (Sarnat and mon investigation used for HIE infants. It is used
Sarnat 1976). in the diagnosis of neurological abnormalities
Besides the clinical examination and a history and the management of associated seizures. Also,
of perinatal risk factors, neuroradiology findings pattern and recovery time of amplitude-integrated
are diagnostic in cases of HIE. Magnetic reso- EEG (aEEG) has a predictive value for later
nance imaging (MRI) and Magnetic spectros- prognosis (van Laerhoven et al. 2013).
copy (MS) provide characteristic features of
timing and type of hypoxic brain injury. Deep Management
grey nuclear matter (basal ganglia) injury is a Previously, only supportive management was
feature of an acute severe asphyxiated insult. offered to newborns with HIE. After successful

clinical trials of therapeutic hypothermia within obtained within the first hour after birth, in
the last year, it has been adopted as the treatment addition to any one of following: Apgar score
of choice in HIE. <5 at 10 min, and the need for resuscitation
after 10 min of life. In some centers, aEEG
1. Supportive management changes have also been included within eligi-
• Maintenance of adequate ventilation. bility criteria (Papile et al. 2014).
Newborns with a moderate to severe brain 3. Emerging therapies
injury require ventilatory support. A criti- Although therapeutic hypothermia has signifi-
cal approach to prevent hypocapnia and cantly improved the prognosis in HIE patients.
hyperoxia, to maintain normal cerebral There is still a search underway to develop
perfusion, and to reduce oxidative stress therapies that can act synergistically with
should be adopted to minimize secondary hypothermia to improve outcomes. Some of
brain injury (Lingappan et al. 2016; Klinger these agents include Xenon, allopurinol,
et al. 2005). erythropoietin and stem cell therapy.
• Maintenance of organ perfusion. Cardiac
dysfunction is common in newborns with Prognosis
HIE as documented by elevated troponin Neurological sequelae depend upon brain dam-
levels. Normal systemic blood pressure is age and the degree of encephalopathy. Most
required to maintain cerebral blood perfu- infants with mild HIE will have normal develop-
sion. New advances in functional echocar- mental outcomes. Children with moderate to
diography, and organ-specific regional severe encephalopathy are likely to develop per-
oximetry will help guide treatment in the manent neurological outcomes later. These can
future (Howlett et al. 2013). range from mild learning difficulties to severe
• Maintenance of normal metabolic status cerebral palsy (Van Handel et al. 2007).
(glucose, calcium, magnesium, pH).
• Maintenance of fluid and electrolyte bal-
ance. Acute kidney injury is often accom- Neonatal Hypoglycemia
panied with HIE, and fluid overload can
worsen brain edema. During normal physiological transition to extra-
• Control of seizures. Seizures are common uterine life, blood glucose concentrations fall
in moderate to severe encephalopathy. after delivery. It can take two hours to overcome
Timely control of seizures is necessary to the lowest nadir of glucose levels and to reach
prevent further brain injury. normal physiological levels. However, some
2. Therapeutic hypothermia high-risk newborns will not be able to maintain
Moderate hypothermia (33.5–34.5 °C) for normal glucose levels, which will result in persis-
72 h started within 6 h of birth is the only tent or recurrent hypoglycemia. A study showed
effective neuroprotective therapy available to that almost 50% of high risk infants can develop
infants with HIE. Currently, it is offered only hypoglycemia in first 24 h of life and within this
in regional tertiary care centers to eligible group 20% had blood glucose levels less than
patients (Takenouchi et al. 2012). 2 mmol/L (Harris et al. 2012). Adequate treat-
The eligibility criteria are based on major ment of hypoglycemia is required to prevent neu-
published trials and generally include the fol- rological injury and developmental sequelae.
lowing criteria: Infants >36 weeks of gesta- Currently, infants born at risk for hypoglycemia
tion and less than 6 hours of age with moderate are offered frequent feedings and blood glucose
to severe encephalopathy. The presence of checks. High risk infants include those who are
intrapartum hypoxia is demonstrated by a pH born preterm, small for gestational age (SGA),
of ≤7.0 or a base deficit of ≥16 mmol/L in a large for gestational age (LGA), and infants of
sample of umbilical cord blood or any blood the diabetic mothers. If frequent feeding is unable

to maintain sugar levels than an intravenous infu- promising way to prevent separation of mother
sion is offered (Aziz and Dancey 2004). In the and baby; however, a potential delay in definitive
case of symptomatic hypoglycemia, or when fre- treatment might occur. It is necessary to establish
quent feeding cannot maintain normal glycemic long-term safety of this new treatment. The Sugar
levels, a bolus of 200 mg/kg dextrose water is Babies Study group recently published two-year
required before starting a continuous infusion of outcomes of the study cohort with no difference
glucose. This results in painful intravenous inser- between placebo and the gel group (Harris et al.
tion, admission in neonatal intensive care, and 2016). However, before adopting the practice of
interruption to normal breastfeeding and skin to glucose gel, it is important to note the following
skin care. limitations in this study: this was a single center
study with a high rate of breast feeding, defini-
efinition of Hypoglycemia
D tion and screening procedures can be different
A threshold level of blood glucose requiring treat- from other practice groups, and only asymptom-
ment and when neuroglycopenia will occur is con- atic neonates were eligible to enroll for interven-
troversial. However, a plasma glucose level of tion. Protocols using dextrose gel should be
47 mg/dL (2.6 mmol/L) was used in multiple stud- created as per current practices in that respective
ies and management guidelines as the cut off value center. The reports after implementation of the
(Rozance and Hay 2016). In 2015, the Pediatric new protocol are very promising (Bennett et al.
Endocrine Society released a new guideline with 2016).
the goal to identify newborns at risk for developing
pathological and persistent hypoglycemia. The ontinuous Glucose Monitoring
C
guideline suggests 50 mg/dL (2.8 mmol/L) as a tar- Point of care whole blood analyzers and labora-
get threshold of treatment in newborns. Further, the tory plasma levels are current standards to moni-
guideline advises to set different blood glucose tar- tor glucose levels. The use of the bedside
gets in a subset of patients with different risk fac- glucometer provides rapid and easy access for
tors. For high risk newborns, maintaining plasma measuring glucose levels; however, sensitivity in
glucose level >50 mg/dL (2.8 mmol/L) at less than relation to lab values is variable. Once hypogly-
48 h of age and more than >60 mg/dL (>3.3 mmol/L) cemia is detected on a point of care testing device,
after 48 h of age is recommended. In contrast, the confirmation from the laboratory could take time
suggested target goals are higher >70 mg/dL and can cause treatment delays. Notwithstanding,
(3.9 mmol/L) in newborns with a suspected con- low glucose levels can cause neuroglycopenia
genital hypoglycemia disorder (Thornton et al. and require urgent treatment, thus showing the
2015). need to develop an accurate bedside tool for
timely detection and management of low glucose
se of Dextrose Gel
U levels. So far, the role of continuous interstitial
Harris et al. introduced a new intervention to treat monitoring is limited to research studies.
asymptomatic newborns at risk of hypoglycemia. Continuous interstitial monitoring was well toler-
In the Sugar Babies Study, 40% Dextrose gel ated in newborns during research trials. The
(200 mg/kg) was rubbed into the baby’s buccal results indicated that almost 80% of the time, low
mucosa followed by breast feeding. The results interstitial glucose values on continuous monitor-
were significant for reducing treatment failure in ing were not detected with a spot blood glucose
comparison to placebo without any serious side measurement (Harris et al. 2010).
effects (Harris et al. 2014). A recently published
Cochrane systematic review also supported
safety of dextrose gel in high-risk newborns; the Neonatal Abstinence Syndrome
number of newborns needed to treat were eight to
prevent one admission to the NICU for hypogly- Maternal use of opioids during pregnancy can
cemia (Weston et al. 2016). Dextrose gel offers a cause drug withdrawal in exposed newborns after

birth. The clinical presentation is referred as neo- (Herzlinger et al. 1977). The time to manifest
natal abstinence syndrome (NAS). In addition to clinical symptoms is variable. Timing depends
this specific group, newborns who are treated upon the type, dose, and pharmacokinetics of the
with long-term opioids used as analgesia or seda- drug in use. Heroin withdrawal symptoms pres-
tion can also develop similar signs and symp- ents within 24 h due to its short half-life, while
toms. Although NAS is generally related to the long-acting methadone withdrawal might not
use of opioids, use of other substances like nico- appear until 5 days of age (Hudak and Tan 2012).
tine, cigarettes, benzodiazepines, and selective
serotonin reuptake inhibitors (SSRI) can also Management
manifest with similar symptoms. The mother-infant dyad is cared for by a multi-
A sudden rise of NAS has been observed in disciplinary team, which includes a health care
last 20 years which is attributed to increased provider and a social worker. The goal is to allow
maternal use of opioid as pain medication. The the successful integration of the infant into the
NICU admission rate across the USA for new- environment, and the establishment of weight
borns diagnosed as NAS has climbed from 7 to gain and adequate sleep. Both supportive non-
27 cases per 1000 admissions from 2004 to 2013. pharmacological and pharmacological therapies
There is also an observed increase in the length of play an important role. Supportive care should be
hospital stays from 13 to 19 days in the same offered to all exposed infants regardless of the
population (Tolia et al. 2015). presence of clinical symptoms. Although it is not
an alternative to drug therapy, it can avoid and
athophysiology of NAS
P reduce the need for drugs. Breastfeeding is
NAS is a complex and ill-defined spectrum of encouraged in women whereby the urine toxicol-
behaviour dysregulation which is not completely ogy at delivery is negative except for prescribed
understood yet. Changes in the levels of different medications, and there is no other contraindica-
neurotransmitters like dopamine, serotonin, and tion to breastfeeding (e.g., HIV status).
norepinephrine are thought to be responsible for Appropriate skin care is necessary to prevent
most of the clinical manifestations (Kocherlakota excoriation. Routine skin care includes keeping
2014). The new discovery of genetic influences the skin dry, clean, and open to the air, and the
on the need for pharmacotherapy and length of application of barrier creams if necessary. Non-
stay in patients exposed to opioids has opened pharmacological support of infants is
new doors that may change the future manage- individualized based upon behavioral observa-
ment of these infants. The two genes currently tion. Swaddling, vertical rocking, and side lying
under research are mu-opioid receptor and in the C position reduce motor hyperactivity.
catechol-
o-methyltransferase (Wachman et al. Reduction in tactile, auditory, and visual stimuli
2013). helps to down regulate sensory disintegration.
The need to start pharmacological therapy is
Clinical Manifestation based upon assessment using the NAS scoring
NAS is diagnosed based on the clinical presenta- system. The Finnegan neonatal abstinence scor-
tion and a positive prenatal history of drug expo- ing system is most commonly used in clinical
sure. The characteristic signs of NAS include practice (Finnegan et al. 1974). The Lipsitz tool
high-pitched cry/irritability, sleep and wake dis- and the neonatal withdrawal inventory are other
turbances, alteration in the tone usually hyperto- scoring systems to name.
nicity and tremors, and gastrointestinal symptoms Opioids are used as first-line pharmacological
including vomiting, diarrhea, and difficulty in therapy. Oral morphine is the most common drug
feeding. Overall, these symptoms reflect dys- used for NAS. Buprenorphine has been used in
function of the nervous system related to motor, small cohort studies but there is no randomized
autonomic, attention, and sensory integration. control trial available to compare efficacy (Kraft
Seizures have been reported in 2–11% infants et al. 2011). The addition of a second drug is

required as an adjunct when symptoms are not scoring system for this population are not avail-
controlled with a single agent. Oral clonidine is able (Liu et al. 2010).
currently used as the drug of choice as second
line agent (Agthe et al. 2009). Phenobarbitone cquired Opioid or Benzodiazepam
A
has also been used in resistant cases. Dependency in Infants
Physical dependency results when sick neonates
Long-Term Management require analgesia and sedation, which cannot be
Available data about developmental outcomes is stopped within few days. Cumulative exposure
conflicting. A systematic review based on case- and development of drug tolerance also contrib-
control studies found trends toward a poor out- utes towards drug withdrawal. Infants with long-
come, but the difference was not significant term exposure should be weaned by a defined
among exposed and non-exposed groups protocol. Signs and symptoms of withdrawal
(Baldacchino et al. 2014). A recent longitudinal should be observed in these patients. If with-
study showed lower intelligence quotient (IQ) drawal signs and symptoms develop during the
scores in exposed neonates (Nygaard et al. 2015). tapering opioids, methadone can be used as a res-
cue approach. For midazolam withdrawal, the
Other Drugs infusion can be substituted with enteral
Fetal and neonatal exposure to marijuana usually Lorazepam (Hudak and Tan 2012).
does not result in any withdrawal symptoms in
neonates, but it can effect long-term neurobehav-
ioral outcome (Campolongo et al. 2009). CNS Prematurity
stimulants like cocaine and amphetamine expo-
sure cause symptoms similar to opioid with- A birth prior to 37 completed weeks (less than
drawal, but reports are controversial. Fetal 259 days) is defined as premature birth. Premature
exposure to cocaine and methamphetamine leads infants are further divided into three categories
to increased risk of prematurity and intrauterine per gestational age at birth.
growth restriction. Extremely preterm infants (EPT) are new-
SSRIs are frequently used antidepressant borns born at or below 28 weeks of gestation,
drugs. Exposure to SSRIs during pregnancy, very Preterm infant (VPT) are born at or below
especially in the third trimester, results in neona- 32 weeks of gestation, and late preterm infants
tal symptoms. The manifestation can be due to are born between 34 weeks and 36 weeks and
either serotonin syndrome (increased serotonin 6 days of gestation (Blencowe et al. 2013).
concentration in the inter-synaptic cleft) or with- Another method to classify babies who are
drawal effects of drug. The current recommenda- born small is based on birth weight. Newborns
tion is to continue SSRIs on lowest effective dose are categorized as extremely low birth weight
during pregnancy. However neonatal practitio- (ELBW) when birthweight is less than 1000 g.
ners should be aware of the possibility of toxic- Similarly, very low birth infants (VLBW) are
ity/withdrawal symptoms, and should ensure below 1500 g and low birth weight (LBW) are
close follow up for neonates exposed to SSRIs in below 2500 g at birth (Fig. 16.2).
pregnancy.
AS in Preterm Infants
N I ncidence and Risk Factors
Preterm infants manifest fewer symptoms as of Prematurity
compared to their term peers. The lower gesta-
tional age decreases the severity of withdrawal. In 2010, a total of 14.9 million babies were
This relates to immaturity of the brain and lower born before 37 week of gestation. The true inci-
fat depots of the drug. It is also more difficult to dence is variable in different parts of world; it
identify symptoms in preterm infants; dedicated ranges from 5% in some European countries to

Grey zone
First late Preterm

day of
LMP Extreme preterm Early term Late term
Full term Post term
0/7 20 0/7 25 0/7 32 34 0/7 41 6/7

28 36 6/7 38 6/7 40 6/7
Very preterm
Preterm term
Fig. 16.2 Classification of newborns at different gestation
18% in Africa (Blencowe et al. 2012). In the black ethnicity, previous history of preterm
North America, it is estimated around 11% birth, and life style issues like stress, substance
(Hamilton et al. 2013). The burden of disease abuse, smoking, diet, and weight (Behrman and
can be estimated from the fact that prematurity Butler 2007).
is a direct cause of 50% neonatal deaths
worldwide.
Spontaneous onset of preterm labor or prema- Grey Zone or Limit of Viability
ture rupture of membranes accounts for 80% of
premature births. Factors associated with the Viability is defined as a gestational age (GA)
spontaneous onset of preterm labor include infec- when a fetus reaches an anatomical threshold that
tion, pathological uterine distension, hypotha- critical organs, such as the lungs and kidneys, can
lamic–pituitary adrenal axis activation, and sustain life’ (Seri and Evans 2008). With increased
decidual hemorrhage The remaining 20% are survival and decreased morbidities of extremely
medically indicated preterm births due to various premature infants, the age of viability where neo-
maternal or fetal conditions. Fetal indications of natal resuscitation is offered has been pushed
early delivery are congenital abnormalities, back in last 20 years. In the 1960s, a newborn at
infection, growth restriction and fetal distress. 30 weeks of gestation was considered to have a
Maternal indications of early delivery include 50% chance of survival. In 2000, perinatal guide-
antepartum hemorrhage (placenta previa, pla- lines suggested management and resuscitation at
centa accreta), hypertensive disorder of preg- 24 weeks of gestation. Currently in some coun-
nancy (preeclampsia), and maternal chronic tries, resuscitation is offered as low as 22 weeks
health conditions. of gestation. In a meta-analysis review for perina-
The advancement in assisted reproductive tal guidelines at the threshold of viability, authors
techniques (ART) is considered to be an impor- reported a summary of 34 guidelines from 23
tant factor in the increased incidence of prema- countries and four international groups. Sixty-
ture babies; ART is related to an increase in eight percent of the guidelines supported comfort
multiparity and infants of multiple gestation are care at 22-week gestation. However, variation
prone to deliver as preterm. Many socioeco- was observed for 23 and 24 weeks GA, with the
nomic factors have been identified as risk fac- majority recommending parental involvement in
tors for preterm births. These factors include decision making for active care at that gestation
maternal age (<16 and >35 years), non-Hispanic (Guillén et al. 2015).

I nitial Stabilization and Short-Term these preterm babies will be discharged around

Morbidities their term gestational age, the medical needs are
higher in this group than healthy term infants and
The initial stabilization is very important for pre- require special attention. Effective communica-
term infants and proper management can reduce tion between the neonatologist and primary care
the risk of later complications. Perinatal care of provider is required for continuity of care in the
an anticipated delivery includes maternal trans- community after discharge from the NICU.
port to a high-risk center, antenatal steroids, toco- Outpatient care of this high-risk population
lytics to enhance latency for potential benefit includes evaluation of growth and neurodevelop-
from steroids, magnesium sulfate (Mg So4) for ment, hearing and vision assessments, and immu-
neuroprotection, antibiotics for premature rup- nization. Some prematurity related complications
ture of membranes, and continuous fetal monitor- like bronchopulmonary dysplasia, anemia of pre-
ing. Delivery room management comprises maturity, metabolic bone disease, apnea of pre-
establishment and maintenance of respiratory maturity, gastroesophageal reflux, and hernias
support, hemodynamic stability, prevention of might be present at discharge and require con-
hypothermia, avoidance of hypoglycemia, early tinuous monitoring and care. Depending upon
start of parenteral nutrition and minimal handling their medical need, the initial visit should be
strategies to prevent neurological injury. scheduled within first week following hospital
Short-term complications observed within the discharge to ensure safe transition to home and
neonatal period are linked to a high rate of mor- the provision of social supports to the parents.
tality and long-term sequelae, which occur in Following the initial visit, subsequent visits
patients who survive and are discharged home should occur every month in first 6–9 months
from NICU. The risk of complications increases (Andrews et al. 2014).
with decreasing gestational age. Preterm infants should receive all recom-
The Neonatal Research Network published mended childhood vaccinations as per chrono-
data for common complications in a cohort of logical age with the same schedules and doses
9575 infants born at an extremely low gestational recommended for term infants (Saari 2003).
age between 2003 and 2007. The common prob- Prophylactic administration of Palivizumab
lems observed in decreasing order were respira- (respiratory syncytial virus {RSV} antibody)
tory distress syndrome (93%), retinopathy of during RSV season is recommended especially in
prematurity (59%), Patent ductus arteriosus infants with chronic lung disease. The risk of
(46%), late onset sepsis (36%), severe intraven- readmission in ex-preterm infants is twice as high
tricular hemorrhage (16%), and necrotizing in comparison to term infants during first year of
enterocolitis (11%). The rate of survival to dis- life. Re-admissions are usually related to infec-
charge in this cohort was 6% at 22 weeks and tions, respiratory problems, surgery, and gastro-
92% at 28 weeks (Stoll et al. 2010). The rates of intestinal issues (Houweling et al. 2013).
complications and morbidities are highly vari- Extrauterine growth failure is very common
able among centers and regions of the world, ulti- among preterm infants. During the NICU stay,
mately reflecting practice variation in the fortification of milk helps to maintain growth, but
management of these infants. the risk of a faltering growth pattern remains high
after discharge. In part, this is attributed to by an
increased caloric requirement for catch up growth
ost-discharge Care of NICU
P in preterm babies and in patients with broncho-
Graduate pulmonary dysplasia. However, feeding prob-
lems associated with prematurity also play an
With the increase in survival rates of premature important role, such as oral aversion, GERD, oral
infants, the number of NICU graduates being dis- motor dysfunction, and hypersensitivity. These
charged home is increasing. Although most of feeding issues require special attention and the

collaboration of various specialties including pressure, insulin sensitivity, and increased adi-
occupational therapy and feeding experts for posity), chronic kidney conditions, asthma and
management (Samara et al. 2010). Premature pulmonary abnormalities, psychological disor-
infants who are below the 10th centile at dis- ders, and poor social adaptation. Due to the life-
charge should continue to use nutrient enriched long impact of prematurity, it is now considered
formulas or preterm discharge formulas to main- as a chronic disease condition (Raju et al. 2016).
tain optimal growth. Iron and vit. D should also
be continued until foods enriched with both are
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Update in Pediatric Neurology
17
Andrea Andrade and Asuri N. Prasad
Introduction 1. Epileptic seizures—when the clinical parox-

ysmal event is the result of abnormal hyper-
Repetitive, stereotyped paroxysmal events account synchronized electrical activity in the brain
for a significant number of pediatric consultations cortex, and is commonly associated with elec-
and pediatric ER visits. These events can affect troencephalogram (EEG) abnormalities.
children of all ages. Paroxysmal events that affect These usually respond to anticonvulsant med-
young infants are different from those affecting ications. Epileptic seizures represent the prin-
older children and adolescents. Variability in clini- cipal symptom of epilepsy.
cal features and age-dependent expression pose a 2. Non epileptic—these events are divided into
diagnostic challenge. Accurate and early recogni- psychogenic (conversion disorder) and non-
tion of these events is important for the implemen- psychogenic or physiologic events that are
tion of appropriate therapeutic measures and for caused by the following etiologies: cardiac,
the provision of reassurance to families. autonomic, behavioral, and movement
Paroxysmal events in children can be divided disorders.
in two major groups: epileptic and non-epileptic
events. In the following sections, we will review
the classification, differential diagnosis, and pileptic Seizures and Epilepsy:
E
treatment of paroxysmal events in children, with Definitions and Current Concepts
a focus on events most frequently encountered by
the pediatrician. Seizures—Seizures are paroxysmal, episodic
events that result from underlying neuronal dys-
function. Seizures cause a sudden and transient
Definitions and Classifications occurrence in behavioral, somatosensory, motor,
or visual signs and/or symptoms depending on
Pediatric paroxysmal events can be divided in the location in the cerebral cortex where the sei-
two major groups: zure is generated (Fig. 17.1). Seizures can be pro-
voked by certain triggers (i.e. trauma, infection, a
A. Andrade (*) • A.N. Prasad brain hemorrhage, metabolic abnormalities, or a
Department of Pediatriacs, Schulich School of drug exposure) or unprovoked if there is no an
Medicine and Dentistry, Neurology Division LHSC,
identifiable or reversible trigger (Berg et al.
London, Ontario Canada
e-mail: Andrea.Andrade@lhsc.on.ca; 2010).
narayan.prasad@lhsc.on.ca


440 A. Andrade and A.N. Prasad
FRONTAL LOBE SEIZURES

-MOTOR, NOCTURNAL, ASYMETRIC
TONIC, HYPERMOTOR
BIZARRE FEATURES
PARIETAL LOBE SEIZURES

Somatosensory: “tingling”,
“pins and needles”, numbness
TEMPORAL LOBE SEIZURE:

-Epigastric aura, focal dyscognitive
OCCIPITAL LOBE SEIZURES:

-Visual phenomena, illusions
-Ocular phenomena: nystagmus
Fig. 17.1 Seizure semiology and anatomical correlation: red circle = frontal lobe, blue square = parietal lobe, yellow
oval = temporal lobe, green circle = occipital lobe
Epilepsy—The current ILAE (International newly develop epilepsy each year (Berg et al.
League Against Epilepsy) definition of epi- 2010; St Louis and Cascino 2016).
lepsy refers to epilepsy as either a disease The principal clinical symptoms of epilepsy
characterized by one or more seizures with a can be divided in: ictal—during the seizure; post-
relatively high risk of recurrence (60% risk or ictal—immediately following seizure termina-
more, given clinical, EEG and/or MRI find- tion; and interictal—in between seizure episodes
ings) or recurrent unprovoked seizures (two or (St Louis and Cascino 2016).
more unprovoked seizures occurring at least The constellation of ictal phenomena can
24 h apart). The implication of this definition is range from subjective symptoms reported by the
that antiepileptic therapy can be initiated fol- patient to objectively witnessed events of invol-
lowing the first seizure in certain situations untary motor activity, behavioral arrest, etc.
(Berg et al. 2010). The prognosis and management of epilepsy
Epilepsy affects an estimated 50 million people are directed by the diagnosis of a specific epi-
worldwide. The prevalence of epilepsy in child- lepsy syndrome. Seizure type and epilepsy syn-
hood is approximately 0.5%. In developed coun- drome diagnoses are based on a description of the
tries, an average of about 50 per 100,000 children ictal phenomena in addition to the EEG findings;

17 Update in Pediatric Neurology 441
neuroimaging and genetic studies can be comple- Other clues to the diagnosis include the pres-
mentary findings (Berg et al. 2010). ence of an aura (such as epigastric sensation),
The classification of epileptic seizures has sensory phenomena, visual disturbances, and
changed over time, which is also the result of fur- psychic and experiential phenomena (“deja-vu”
ther advances in genetics and neuroimaging and “jamais vu”). During the post-ictal state, def-
technology. icits (motor, sensory, visual, etc.) are highly sug-
The revised classification by the ILAE in 2010 gestive of focal epilepsy and should direct the
proposed that seizures should be divided into clinician to consider early neuroimaging.
focal (formerly partial) and generalized seizures. Focal epilepsy should be suspected in children
Focal seizures are subdivided into focal dyscog- with seizures and pre-existing focal neurological
nitive seizures (formerly complex partial) and deficits on history (early hand preference or gaze
focal seizures with loss of awareness. Although preference) and neurological exam (hemiparesis,
the terminology refers to the same seizures, the monoparesis, even subtle asymmetries on rapid
reader should be familiar with the different terms alternating movements and tests of coordination).
used to define and classify seizures (Berg et al. Stressed gait manoevres can be clues to the pres-
2010). ence of a structural abnormality.
In Fig. 17.1 we describe different seizure
semiologies and their anatomical correlates.
Focal Epilepsies in Children Epileptogenic lesions refer to structural brain
abnormalities that are responsible for causing
Approximately 50% of childhood epilepsies have epileptic seizures. These can be very diverse and
a focal onset. Focal epilepsies originate in the include the following: focal encephalomalacia
neuronal network confined to a regional or hemi- secondary to remote brain lesions (such as peri-
spheric distribution. The seizure type will depend natal or neonatal stroke), cerebral infections,
on the area of the brain that is affected, the age of malformations of cortical development that can
the child, and the presence of a cerebral structural affect the entire hemisphere (hemimegalenceph-
lesion. Pediatric patients with focal epilepsies aly), focal cortical dysplasia, low grade CNS
usually present a bigger challenge due to their tumors, mesial temporal sclerosis, Rasmussen
unpredictable age of onset, the presence of subtle encephalithis, and Sturge Weber Syndrome. In
and under recognized phenomena with or with- Fig. 17.2 we present examples of common epi-
out dyscognitive symptoms. The evolution in sei- leptogenic lesions in children (Moosa and Wyllie
zure semiology as children get older and access 2013).
challenges to appropriate high resolution neuro- The diagnosis of epilepsy should made on the
imaging techniques and epilepsy protocols for basis of the history, physical exam, neurological
infants and young children are added challenges electroencephalogram, and MRI of the brain.
(Moosa and Wyllie 2013). These factors often Added investigations are dependent on the nature
lead to a delay in the diagnosis and treatment in of the epilepsy and the suspected etiology.
childhood epilepsies. Initial treatment with antiepileptic medica-
A very accurate and detailed description of tions targeting focal seizures such as carbamaze-
the seizure sequence is key to the diagnosis of pine is warranted. When a patient continues
focal epilepsies in infants and children. It is having seizures despite an appropriate dose of an
important to elicit historical details of the fol- anticonvulsant and subsequently fails to respond
lowing focal features: forced eye deviation, to two anticonvulsants in monotherapy or in
asymmetric or unilateral motor activity, head combination (Kwan et al. 2010), an early referral
deviation, focal dyscognitive seizures (presence to an paediatric epilepsy center should be made.
of ictal speech/recollection of the seizure), Such a referral will help facilitate the evaluation
asymmetric tonic posturing, and hypermotor for other therapeutic strategies, such as epilepsy
nocturnal seizures. surgery.

a b c
d e f g
Fig. 17.2 Examples of focal epileptogenic lesions com- Right focal cortical dysplasia (e) Right hemisphere
monly seen in children: (a) Sturge Weber, right hemi- Rasmussen’s encephalitis, (f) Right hemimegalencephaly,
sphere leptomeningeal angioma (b) Right mesial temporal (g) Left remote MCA stroke
sclerosis (c) Left mesial temporal low grade tumor (d)
pilepsy Syndromes in the Neonatal

E 2. Typically, these seizures remit spontaneously
Period and in Infancy after a few weeks to months, and respond well
to conventional antiepileptic drugs.
Epilepsy syndromes in children can be divided 3. These infants are neurologically normal on
into focal epilepsy syndromes and generalized examination, and tend to have normal
epilepsy syndromes. In this section we will developmental outcomes for the most part
review the most common benign epilepsy syn- (Cross 2013).
dromes encountered by the general pediatrician.
In this section, we discuss several types of early
onset epilepsies beginning in the neonatal stage or Benign Familial Neonatal Seizures
in infancy. Three following familial focal epilepsy
syndromes are most notable: benign familial neo- Benign familial neonatal seizures (BFNS) are
natal seizures (BFNS), benign familial neonatal- caused by dominant mutations in the potassium
infantile seizures (BFNIS), and benign familial voltage-gated channel KQT-like subfamily
infantile seizures (BFIS). genes: KCNQ2 and KCNQ3. There is a higher
incidence of patients carrying KCNQ2 mutations.
These genes code for corresponding subunits of
Inheritance the potassium channel. Fixed genetic deficits in
channel structure lead only to intermittent sei-
All three syndromes show autosomal dominant zures in early life that tend to remit over time.
inheritance with variable penetrance. The reason for this may be related to time locked
changes in the expression of different channel
eizure Semiology and Evolution
S genes and their component subunits and physio-
1. Focal motor phenomena that can evolve into logical changes in gating effects of channel
generalized seizures, with apnea, cyanosis dependent currents during brain development.
and staring. Rarely, KCNQ2 mutations have also been

reported in association with early life seizures Several epileptic encephalopathies have been
and an epileptic encephalopathy eventually lead- described in infancy based on their electroclinical
ing to intellectual disability (Cross 2013). The features (age of onset, seizure type, and EEG pat-
remaining two entities less frequently encoun- tern). Epileptic encephalopathy syndromes in
tered are listed below. infancy can be further classified into:
1. Early infantile epileptic encephalopathy (EIEE

enign Familial Neonatal-Infantile
B or Ohtahara syndrome)
Seizures (BFNIS) 2. Early myoclonic encephalopathy (EME)
3. Infantile spasms (West syndrome)
Among families described with benign familial 4. Malignant epilepsy with migrating partial sei-
neonatal convulsions, there exist families with an zures in infancy (MMPS)
age of onset intermediate between classic BFNS 5. Severe myoclonic epilepsy in infancy (SMEI)
and BFIS (i.e. onset predominantly after
1 month). The seizures are partial onset with sec- The etiologies of epileptic encephalopathies
ondary generalization beginning between 2 and are heterogeneous and a significant proportion of
7 months and carry a good prognosis. A missense cases are attributable to structural brain defects
mutation in the alpha2 subunit of the voltage- and inherited metabolic disorders. This is an
gated sodium channel (SCN2A) has been identi- evolving field, genotype-phenotype correlations
fied (Cross 2013). are not completely well understood, and there is
considerable phenotypic variability within the
same genetic defect.
enign Familial Infantile
B There is recognition of both locus heterogeneity
Seizures (BFIS) and genetic heterogeneity. In locus heterogeneity,
mutations in the sodium channel genes cause Dravet
A less commonly encountered syndrome, with syndrome as well as generalized epilepsy with
age of onset between 3 and 8 months and sponta- febrile seizures plus (GEFS+). In genetic heteroge-
neous remission by age 3 years, has been neity, a particular electroclinical syndrome may be
described in some families. This condition, caused by multiple gene defects. In the latter for
benign familial infantile seizures, has been example, Ohtahara syndrome may be caused by
described to cosegregate with a movement disor- mutations in syntaxin binding protein-1 (STXBP1),
der (choreoathetosis) as well as hemiplegic potassium channel mutations (KCNQ2), Aristaless
migraine. The condition is genetically heteroge- related homeobox (ARX), solute carrier family 25,
neous (Cross 2013). and member 22 (SLC25A22) encoding a mitochon-
drial glutamate carrier. Currently, as many as 35 dif-
ferent genes have been identified as being associated
Epileptic Encephalopathy with an early onset epileptic encephalopathy and it
is likely that the list will grow longer each year
In 2001, the international league against epilepsy (Pisani et al. 2015).
(ILAE) identified epileptic encephalopathy as a
distinct group encompassing disorders in which a
progressive disturbance in cerebral function was Early Infantile Epileptic Encephalopathy
the result of a combination of frequent and severe
seizures and continuous unremitting interictal par- Early infantile epileptic encephalopathy (EIEE),
oxysmal epileptiform activity. Epileptic encepha- more commonly known as Ohtahara syndrome,
lopathy can be further divided into two main was first described by Japanese neurologist
categories: (1) Epileptic encephalopathy syn- Shunsuke Ohtahara in 1976 and is one of the ear-
dromes in infancy and (2) Epileptic encephalopa- liest and most severe forms of age-related epilep-
thy syndromes in childhood (Berg et al. 2010). tic enecephalopathies.

Seizure Semiology pilepsy of Infancy with Migrating

E
1. The major seizure type is tonic spasms but can Focal Seizures (Malignant Migrating
vary to include tonic/clonic, clonic, myoclonic, Partial Seizures of Infancy (MMPSI)
atonic, absences, partial, complex partial,
gelastic seizures, and seizures with Jacksonian This condition is characterized by normal early
features (motor activity that marches along development, refractory focal seizures arising
the body mimicking spread across the independently from either hemisphere, severe
Rolandic motor strip). psychomotor retardation, and a poor prognosis.
2. Seizure onset is within the first 10 days or up While the electroclinical features of this condi-
to 3 months of life eventually leading to psy- tion are being better recognized owing to typical
chomotor impairment and death. seizure semiology and EEG findings, the condi-
tion appears to be genetically heterogeneous with
Inheritance pathogenic mutations in SCN1A, KCNT1, SCN8
The majority of cases arise from sporadic de identified.
novo mutations (no mutational change identified
in either parent). However, in rare cases, autoso- Inheritance
mal and X-linked recessive inheritance patterns Mutations of de novo origin are mostly consid-
have been observed (Pisani et al. 2015; Prasad ered responsible (Sharma and Prasad 2013).
and Hoffmann 2010).
Infantile Spasms (IS)

arly Myoclonic Encephalopathy
E
(EME) Infantile spasms represent a specific syndrome of
generalized epileptic seizures associated with a
Early myoclonic encephalopathy is a neonatal characteristic EEG pattern of hypsarrhythmia
onset disorder beginning typically within the first (Fig. 17.3). Both genetic (tuberous sclerosis,
month of life. inborn errors of metabolism, Down syndrome),
and nongenetic (perinatal hypoxic ischemic
eizure Semiology and Evolution
S encephalopathy) conditions are associated with
Early myoclonic encephalopathy is characterized this epilepsy syndrome.(Prasad and Hoffmann
clinically by erratic, fragmentary or massive 2010; Sharma and Prasad 2013).
myoclonus, partial seizures, and late tonic spasms.
Early myoclonic encephalopathy shares many eizure Semiology and Evolution
S
clinical and pathological features with Ohtahara West syndrome is characterized by the occurrence
syndrome. However, the etiology of EME is highly of infantile spasms, the EEG finding of hypsar-
variable and typically associated with an inborn rhythmia, and developmental delay or regression.
error of metabolism (glycine encephalopathy, Infantile spasms typically occur between 3 and
organic acidemias, Menke’s disease, Zellweger 12 months of age. Spasms usually occur in clusters
syndrome, and molybdenum cofactor deficiency). comprising of tonic contractions of limb and axial
The prognosis and outcome are generally poor and muscles, and may be flexor, extensor or mixed.
dependent on the underlying disorder. The spasms typically occur in relation to the sleep
wake cycle; they occur when the child wakes up
Inheritance from sleep, or is going to sleep. Often the onset of
Inborn errors of metabolism are inherited as spasms may be preceded by loss of ocular pursuit,
Mendelian recessive conditions with a few excep- and be associated with development arrest.
tions, where de-novo mutations, and/or com-
pound heterozygosity may be responsible for a Etiology
severe phenotype.(Prasad and Hoffmann 2010; The etiology is diverse and heterogeneous. An
Sharma and Prasad 2013). insult to the developing brain (intra-uterine

Fig. 17.3 EEG of a 6 month old infant diagnosed with infantile spasms. The EEG epoch shows the typical, chaotic,
disorganized interictal pattern of hypsarrhythmia
infections), inherited metabolic disorders, brain Australian kindred. A variety of dominantly

malformations, or post-natal acquired brain inherited epilepsy phenotypes occurred in these
insults (e.g. meningoencephalitis, hypoxic brain families, and they proposed a syndrome desig-
injury) during a critically vulnerable window of nated as “generalized epilepsy with FS plus”
time can also lead to West syndrome. In as many (GEFS+) (Sharma and Prasad 2013).
as 30% of the affected children, previously no
cause could be identified, and in these cases NGS Semiology
technologies are identifying pathogenic gene The most common phenotype, termed “febrile
mutations that seem to arise de-novo (Sharma seizures plus” (FSP), consists of multiple FS
and Prasad 2013). with onset in infancy and the continued occur-
rence of afebrile seizures beyond 6 years of age.
All seizures remit by adolescence. Other pheno-
Epilepsies of Early Childhood types identified in this family include FS plus
absences, FS plus myoclonic seizures, and FS
Febrile seizures are common and present a plus atonic seizures.
different situation and are not dealt with in this
discussion. Inheritance
The mode of inheritance in GEFS+ remains a
matter of debate; in some a dominant pattern is
eneralized Epilepsy with Febrile
G observed. In others, an oligogenic effect accounts
Seizures Plus (GEFS+) for a wide variation in the clinical phenotype. So
far, only a single gene defect has been identified
Scheffer and Berkovic reported on an expanding in each family with a GEFS+ phenotype.
clinical phenotype of febrile seizures (FS) in an Mutations appear to involve subunits of voltage

gated sodium channels and subunits of the ligand most of these mutations occur de novo, and the
gated GABAergic receptors. An overlap is noted absence of a family history or a Mendelian pat-
between the clinical features and genetic basis of tern of inheritance is not a necessary prerequisite
GEFS+ and SMEI (Dravet syndrome described for testing.
below), exemplifying the enormous complexity Mutations associated with PCDH19 encoding
of genotype-phenotype correlations in the epilep- Protocadherin 19 have also been associated with
sies (McTague et al. 2016). a Dravet-like syndrome in girls. Mutations of
PCDH19 were originally described with the
disorder called ‘epilepsy with mental retardation
Severe Myoclonic Epilepsy of Infancy limited to females’ (EFMR). This disorder is
(SMEI, Dravet Syndrome) characterized by seizure onset in infancy or early
childhood (6–36 months) and cognitive impair-
This condition can begin in developmentally nor- ment. The disorder is X-linked with an unusual
mal infants with an onset similar to febrile expression pattern and with the phenotype being
seizures. restricted to females; carrier males remain appar-
ently unaffected, with normal cognitive function.
Seizure Semiology and Evolution The PCDH19 mutation-affected patients how-
Dravet syndrome described by Charlotte Dravet, ever, present with a later mean age of onset
is characterized by the occurrence of generalized (9 months compared with 6 months), fewer
or unilateral/hemibody clonic or tonic–clonic sei- absence and myoclonic seizures, and the condi-
zures, usually triggered by fever, in the first year tion carries a slightly better developmental
of life. Later, other types of seizures are reported, outcome. Also photosensitivity, which is very
including myoclonus, atypical absences and par- common in Dravet syndrome, is unusual in
tial seizures. Development slows in the second PCDH19 patients.
year of life after the onset of seizures. Cognitive The appropriate diagnosis of Dravet syndrome
decline and behavioral disturbances are fre- is important as it has therapeutic implications.
quently noted. Lamotrigine, phenytoin, carbamazepine, and
Neurological signs consisting of hypotonia, vigabatrin may worsen the seizures, and their use
ataxia, pyramidal signs, and motor in-should be avoided. Treatments with a beneficial
coordination may also be seen. A positive family effect include sodium valproate, stiripentol, topi-
history is noted in 25–71% of patients. The inter- ramate, benzodiazepines, and the ketogenic diet
ictal EEG is usually normal in the first year of (Sharma and Prasad 2013; McTague et al. 2016).
life. Between the second and the fifth years of
life, a progressive increase in paroxysmal epilep-
tiform abnormalities with background slowing is Acquired Epileptic Aphasia
evident in more than 50% of the cases on the
EEG. Paroxysmal EEG abnormalities are consti- Epileptic aphasias include the following condi-
tuted by generalized spike wave and polyspike tions; Landau-Kleffner syndrome (LKS, also
wave discharges. Focal and multifocal abnormal- known as acquired epileptic aphasia) and epilep-
ities such as fast spikes or polyspikes are also tic encephalopathy with continuous spike and
described. wave during slow-wave sleep (CSWS).
Inheritance Semiology
Mutations in the SCN1A gene encoding the Seizures typically have their origins in the tem-
alpha-1 subunit of the sodium channel are detect- poral lobe, or rolandic regions around the oper-
able in 70–80% of patients with Dravet syndrome. cular region of the brain affecting speech and
Rarely mutations have been identified in the language; therefore, one of the first symptoms
GABARG2 and SCN1B genes. The most signifi- of LKS is developmental regression particularly
cant aspect of the molecular genetic basis is that affecting language in otherwise normal chil-

dren. This is initially not coupled with any other are seen in male infants. However, recently
neurological abnormalities or cognitive impair- mutations in the CDKL5 gene have been
ment; however, a distinct EEG pattern of nearly described in epileptic encephalopathy in boys as
continuous generalized spike and wave pattern well. The developmental history prior to the
occupying more than 80% NREM sleep emerges onset of seizures (normal or pre-existing devel-
over time. With unremitting electrical changes in opmental delay) and the parental report of devel-
sleep, gradual regression occurs in speech (verbal opmental arrest or regression carries added
auditory agnosia), leading eventually to complete significance. The presence of other neurological
mutism, behavioral and psychomotor regression. problems such as abnormal muscle tone and,
Eventually the epileptiform activity may cease vision, and hearing problems must be screened
as seizures remit with age; residual neurological for. A detailed family history and a three-gener-
deficits are often not reversible. ation pedigree should be constructed. A history
of seizures triggered by fever is characteristic in
Treatment patients with Dravet syndrome and PCDH19
Timely diagnosis and early institution of treat- related mutations.
ment with nocturnal administration of high dose A general physical examination must be
diazepam, and steroids can be of help in amelio- performed to look for craniofacial dysmorphic
rating the situation. The condition requires features (chromosomal abnormalities, peroxi-
expert management under the supervision of a somal disorders, abnormal fat pads in congenital
neurologist. disorders of glycosylation), and neurocutane-
Mutations in the glutamate receptor, iono- ous markers such as ash leaf macules, which
tropic, N-methyl-d-aspartate, subunit 2A gene are characteristic of tuberous sclerosis.
(GRIN2A), which encodes an N-methyl-d- Visceromegaly is a feature of metabolic storage
aspartate (NMDA) receptor subunit, have been disorders. The presence of ambiguous genitalia
linked to LKS. NMDA receptors are postsynaptic in a child with infantile spasms is an indication
glutamate receptors that facilitate sodium and to screen for ARX mutations. The neurological
calcium influx to promote transmission of neuro- examination is conducted to identify abnormali-
nal activity. They also play a crucial role in main- ties of muscle tone, and gait abnormalities
taining synaptic plasticity, which is important for (ataxia) associated movement disorders such as
learning and memory (McTague et al. 2016). dystonia, choreoathetosis, and motor stereoty-
pies. The presence of dystonias and progressive
spasticity in a child with infantile spasms may be
Clinical and Laboratory Evaluation a clue towards an underlying ARX mutation. The
of an Infant with Epileptic ocular fundi must be examined for the presence
Encephalopathy of chorioretinitis and/or changes of a pigmentary
retinopathy or optic atrophy, which may point
The evaluation begins with a detailed history, towards the presence of infantile neuronal ceroid
which should include details of the pregnancy, lipofuscinosis and mitochondrial disorders
delivery, and postnatal factors. History of exces- (Prasad and Hoffmann 2010; Sharma and Prasad
sive fetal movements could signify the presence 2013; McTague et al. 2016).
of fetal seizures, which are seen in pyridoxine
dependency and in KCNQ2 epileptic encepha-
lopathy. History of excessive irritability, vomit- Investigations
ing, and multisystem symptoms are also
frequently reported in pyridoxine dependency. A Investigations of an infant or child with an epilep-
gender predisposition is seen in epileptic enceph- tic encephalopathy must be conducted in consul-
alopathies associated with CDKL5 mutations, tation with a pediatric neurologist and a clinical
and PCDH19 mutations are reported in females, and biochemical geneticist. The investigation
while the ones associated with ARX mutations process can be complex and time consuming and

a final diagnosis at present may still prove elusive. should be done to look for the following: low
The role of next generation sequencing technolo- glucose levels and a low CSF to serum glucose
gies is continually expanding and proving indis- ratio (glucose transporter defect); elevated lac-
pensable to the diagnostic process. tate (mitochondriopathies); elevated glycine
An EEG and often video EEG to provide clin- (nonketotic hyperglycinemia), serine (serine
ical and EEG correlation are often the first step. biosynthesis defects), or pipecolic acid (pyri-
A discussion of the EEG abnormalities encoun- doxine dependency); and neurotransmitters
tered is beyond the scope of the present discus- (abnormalities seen in Pyridoxal phosphate
sion. Suffice it to say that EEG abnormalities, dependency, Folic acid transport defects).
which are often present in waking and sleep, tend Again, consultation with a biochemical geneti-
to be persistent in the established phase of the cisit should prove invaluable.
condition. A neuroimaging study, preferably an Some authorities recommend that a sequential
MRI of brain, must be performed in all children therapeutic trial with vitamin B6, pyridoxal phos-
with epileptic encephalopathy. MRI is often diag- phate, and folinic acid should be instituted early
nostic for brain malformations, tuberous sclero- in all babies with epileptic encephalopathy and a
sis, perinatal insult sequelae such as asphyxia, poor response to antiepileptic treatment. There
while an MR spectroscopy performed simultane- are numerous other metabolic conditions that are
ously can be of diagnostic value in patients with associated with epilepsy and the reader is referred
inborn errors of metabolism (glycine encepha- to a recent article on the metabolic evaluation and
lopathy, creatine deficiency syndromes) and management of PDE (antiquitin deficiency) for
mitochondrial disorders (elevated lactate). In the rationale and additional details (Gallager et al.
majority of the genetic epileptic encephalopa- 2009; Sharma and Prasad 2017).
thies, the MRI is normal or may show non-spe- There is a debate as to whether molecular
cific features such as cerebral atrophy or delayed genetic testing should precede screening for met-
myelination. The presence of a cortical dysgene- abolic disorders. The costs of molecular diagnos-
sis does not however, preclude a genetic or meta- tics under current conditions are rapidly changing.
bolic etiology as the two may coexist. Currently, special approval from the provincial
Chromosomal karyotyping must be performed ministry of health has to be sought before of out
if dysmorphic features and a genetic syndrome is of country testing is sought. Where no definite
suspected. Chromosomal microarray (array- syndromic diagnosis is evident, genetic heteroge-
CGH) is now recommended as a first-tier test in neity is high, and targeted testing excludes the
patients with epilepsy associated with unex- known gene defects, the value of further genetic
plained developmental delay, intellectual disabil- testing and its diagnostic yield remains unclear
ity, autism spectrum disorders, or multiple (Sharma and Prasad 2013).
congenital anomalies. As discussed earlier, there
are emerging data on the role of copy number
variations in epileptic encephalopathies, which he Role of Emerging Genetic
T
can be detected through microarrays. Technologies
When the clinical evaluation and imaging
studies are not informative, a metabolic etiology In addition, the availability of next-generation
must be excluded, even though the diagnostic sequencing methods, via exome-wide sequenc-
yield for inborn errors of metabolism is pres- ing or an epilepsy specific gene panel approach
ently around 5% of total cases in case registries. can have clinical utility in the field of epileptic
The initial metabolic investigations in most encephalopathies. This field is rapidly evolving
practice settings should exclude hypoglycemia, and will continue to generate additional suscepti-
hypocalcemia, hypomagnesemia, and elevations bility genes of interest that are hitherto undiscov-
of lactate and ammonia. The focus of the inves- ered in epilepsy research. NGS technologies is a
tigation should prioritize a search for treatable broad umbrella term for technologies that allow
epileptic encephalopathies. A CSF examination for rapid, efficient sequencing of multiple human

genomes by facilitating millions of reactions clinical phenotype is evident and the genetic het-
simultaneously leading to high throughput of erogeneity is low (restricted to a single or a few
data. The advent of NGS technologies has accel- known genes), a targeted mutation analysis would
erated gene discoveries for both simple and com- carry great clinical utility as pointed out in the
plex epilepsies and has also been widely used in commission document.
virtually all diseases. There are three main types Currently the commercial availability of gene
of NGS applications including (1) whole-genome panels has made this task easier. These gene pan-
sequencing (WGS); (2) whole-exome sequencing els screen for known gene mutations and can lead
(WES); and (3) targeted gene panels.(Prasad and to a rapid molecular diagnosis if the affected indi-
Hoffmann 2010; Sharma and Prasad 2013; vidual carries a common or known pathogenic
McTague et al. 2016). mutation. Thus potentially treatable disorders
WGS is an indiscriminate approach that can be screened for with a rapid turnaround time.
decodes the genetic information in an individu- A negative test does not however rule out the
al’s entire genome. In contrast, WES targets only existence of a genetic etiology. It is conceivable
the protein-coding regions or the “exome” of the in these situations that the patient may carry an
genome by designing probes that are unique to previously unreported pathogenic mutation in a
the exons. Targeting only the protein-coding known gene, or in a gene hitherto not known to
regions of the genome stems from the trend that be associated with a clinical phenotype.
nearly 85% of human genetic diseases are caused For further information on available genetic
by non-synonymous mutations in evolutionarily testing methods, the reader is directed to www.
considered protein-coding genes. Moreover, the genetests.org and www.genereviews.org (Prasad
difference in cost between the two methods and Hoffmann 2010; Sharma and Prasad 2013).
(WGS ~$7000 USD; WES ~$1000 USD); and
the computational power necessary to reassemble
the human exome (1–2% of the human genome) Conclusion
is significantly less resource intensive. Notably
however, while NGS has led to the discovery of Epileptic encephalopathies in infants and young
mutations in genes not previously implicated in children are caused by structural brain malforma-
human diseases, the majority of findings are tions, acquired brain insults, and inborn errors of
novel mutations in known disease-causing genes. metabolism in the majority of the affected patients.
These trends have consequently led to the devel- However, no cause may be identified in a signifi-
opment of custom designed NGS gene panels cant number of children under present conditions.
where disease-specific genes are preselected and Recent advances in molecular diagnostics have led
are screened for without sequencing other regions to the discovery of a number of genetic defects that
of the genome. This prioritized approach pro- may be causative in many epileptic encephalopa-
vides an economical, focused, and rapid diagnos- thies. Most of these disorders are relatively rare
tic method without the burden of incidental and it will be a while before sufficient testing and
findings in known disease causing genes not rel- experience will be available to formulate evidence-
evant to the disease of interest. based guidelines. Identification of the causative
A protocol for targeted and selective genetic mutation is important for prognostication and
testing can be developed based on the clinical genetic counseling, and as has been discussed,
characteristics of the epileptic encephalopathy, provides a sound basis of treatment decisions, and
the seizure phenotype, and a syndromic diagno- symptom management. Knowledge of the clinical
sis. In this context, the decision and selection of profile, seizure types, and EEG features of the dis-
genetic testing is guided by several principles that ease phenotype associated with the specific muta-
take into account the many variables of the clini- tion help the clinician improve diagnostic precision
cal presentation. These principles have been dis- and management. Over time, large scale studies
cussed in the document produced by the ILAE involving multicenter databases and rare disorder
genetics commission. Where a distinct electro- registries may capture the relative prevalence of

these rare disorders in populations to provide evi- spikes on EEG, the child should be considered
dence based data to make informed decisions. for further investigations such as neuroimaging
(preferentially MRI) and should be referred to a
pediatric neurologist.
pileptic Syndromes in the Pre-school
E
and School Age Child Treatment
Treatment with daily anticonvulsants is often not
enign Epilepsy with Centro
B necessary, as seizures are brief and self-limited,
Temporal Spikes (BECTS) occur mainly during sleep and minimally inter-
fere activities of daily living.
Benign epilepsy with centro temporal spikes
(BECTS) is the most common childhood idio- Prognosis
pathic focal epilepsy. Its benign nature is related The prognosis is usually excellent. Epilepsy
to the lack of effect on neurological development, remission occurs within 2–4 years from onset
lack of focal neurological deficits, high rates of and before the age of 16 in the majority of cases
spontaneous remission in its natural history and (Park et al. 2015; Panayiotopoulos et al. 2008).
good response to first line anticonvulsant medica-
tion. BECTS accounts for around 15% of chil-
dren diagnosed with epilepsy. The typical onset Childhood Absence Epilepsy (CAE)
is around 7–9 years and before the age 13.
The age of onset is around 5–6 years of age
Seizure Semiology (4–10 years). CAE accounts for 8–15% of all
The classic seizures occur during sleep and childhood epilepsies.
involve the oro-facial muscles with rhythmic
clonic movements that usually interfere with Seizure Semiology
speech and phonation (dysarthria). During the Typical absence seizures are described as brief
seizures, children retain awareness and may (4–20 s), periods of loss of awareness, that can
appear fearful (30%). Other symptoms include occur frequently through the day (10 to
oropharyngo-laryngeal paresis (53%), speech >100 day−1), with an abrupt “onset and offset”.
arrest (40%) and drooling (30%). Progression to There is no postictal state and the child resumes
a secondary generalized tonic-clonic seizure his/her activity immediately after the absence
occurs in around 50% of affected children. Post- seizure. Other associated ictal findings include
ictal paresis is rare and should be consider an the following: rapid eye blinking; lip smacking
atypical feature for BECTS that might prompt and twitching of the eyelids, eyebrows or mouth;
further investigations such as neuroimaging. simple motor and/or oroalimentary automatisms
(in up to two-thirds of cases); and incontinence
Diagnosis (unusual). At times slumping of posture may be
The diagnosis is made on the clinical grounds seen due to a reduction in axial muscle tone, but
and supported by a routine EEG, that typically falls associated with atonic seizures do not occur
shows bihemispharic, independent, centro- in CAE and if present the patient should be
temporal spikes that are exacerbated in sleep. referred to a pediatric neurologist. Around 35%
Neuroimaging is typically normal, therefore MRI of these children may present with one general-
is not indicated in classic cases. ized tonic-clonic seizure.
Rarely, patients with other more complex epi-
lepsies may have similar clinical patterns. When Diagnosis
atypical features are present; i.e. post-ictal pare- In around 80% of cases, absence seizures can be
sis, status epilepticus, abnormal neurological reproduced by hyperventilation. This manoeuvre
exam, persistent unilateral centro-temporal is part of the routine EEG when CAE is suspected

Fig. 17.4 The figure represents one epoch of an EEG in a 5 year old child with typical absence seizures. The EEG
demostrates the typical generalized 3 Hz per second spike and wave discharges
and can be also applied in the office to provoke pileptic Encephalopathies in School
E
an absence seizure for anticipation of the diagno- Age Child
sis and management. The findings on EEG are
usually diagnostic with monomorphic general- ennox Gastaut Syndrome
L
ized 3 Hz spike and waves (Fig. 17.4) or frag- Lennox Gastaut Syndrome is considered an epi-
ments of these epileptiform discharges occur in leptic encephalopathy based on a triad of multiple
association with absences or on interictal records. seizure types, usually refractory to conventional
antiepileptic drugs, severe developmental psycho-
Treatment motor retardation, and typical EEG findings.
Seizures usually respond well to ethosuximide, The usual onset is between 1 and 8 years of
valproate, and lamotrigine. First line therapy is life with a peak between 3 and 5 years. Lennox
ethosuximide given its efficacy controlling Gastaut syndrome accounts for 3–10% of pediat-
absence seizures in 70% of cases without signifi- ric epilepsies.
cant side effects. Beyond the age of 10 years,
children may also develop generalized tonic Seizure Semiology
clonic seizures, and in that instance the choice Typically tonic seizures involving different mus-
of lamotrigine, valproic acid or levetiracetam cle groups such as axial (head and trunk mus-
may be considered. Prognosis is excellent cles), axorhizomelic (arms predominantly), and
with complete remission in 56–84% of cases global (the whole body) are essential to diagno-
within 2–5 years from onset (Park et al. 2015; sis. Tonic seizures can be accompanied by
Panayiotopoulos 2008). autonomic symptoms including loss of bladder

control, respiratory changes, tachycardia, facial (79%) and absence seizures (33%) might be
flushing and dilated pupils. Other seizures present. Seizures appear frequently upon awak-
include the following: atypical absence (which ening in the morning, and patients find them-
are of longer duration than typical absence sei- selves dropping objects or with morning
zures and the EEG shows generalized slow spike “clumsiness” due myoclonic jerks. Many seizure
and wave) and drop attacks (which include myo- precipitants were described including sleep
clonic or atonic seizures). deprivation, flashing lights, alcohol c onsumption,
Up to 60% of children with LGS have a previ- anxiety, stress, and menstruation. JME is consid-
ous diagnosis of epileptic encephalopathy such ered a genetic epilepsy.
as infantile spasms.
Diagnosis
Diagnosis Made on the basis of clinical history, age of onset
LGS can be divided in symptomatic (a clear and seizure types. The EEG abnormalities are
cause for the epilepsy can be identified) or cryp- usually supportive for JME, showing generalized
togenic (a clear cause cannot be established). 4–6 Hz (fast) polyspike and wave (Fig. 17.5) and
Among the symptomatic cases are children with a photoparoxysmal response.
severe/diffuse brain injury including hypoxic-
ischemic encephalopathy, post-meningitis, tuber- Treatment
ous sclerosis, diffuse malformations of cortical JME patients respond very well to sodium valpro-
development (lissencephaly), and genetic syn- ate, rendering at least 80% with seizure freedom.
dromes (Aicardi syndrome, trisomy 21), etc. However, sodium valproate may not be the drug
The diagnosis is made on the basis of the sei- of choice for an adolescent girl due to gynaeco-
zure description, global developmental delays logical (polycystic ovarian syndrome), cosmetic
and classic EEG findings of generalized slow (acne and gain weight) and teratogenic side
spike and wave and paroxysmal fast activity. effects. In female patients, other broad spectrum
antiepileptics should be considered, including
Treatment levetiracetam, topiramate and clobazam.
Seizure control is difficult to achieve with typi- Lamotrigine can be effective at managing chil-
cal antiepileptic drugs, and at times palliative dren with JME with GTCs, however it can trigger
surgery (corpus callosotomy) for atonic drop or increase the frequency of the myoclonic jerks.
seizures, non-pharmacological therapies such as JME is a lifelong condition and seizure recur-
ketogenic diet, placement of a vagal nerve stim- rence occurs almost always when a wean-off of
ulator, and even cannabidiol can be considered AED is attempted (Park et al. 2015; Brodie
to ameliorate the severity of the seizures 2016).
(Arzimanoglou et al. 2009).
Progressive Myoclonic
Epileptic Syndromes Epilepsies (PME)
in the Adolescent Child
This is a rare group of conditions characterized by
J uvenile Myoclonic Epilepsy (JME) myoclonic seizures, progressive developmental
JME accounts for 5–10% of all epilepsy syn- regression, and cognitive decline. The differential
dromes, and affects mainly adolescents between diagnosis include: Baltic myoclonus, myoclonic
13 and 15 years of age. epilepsy with red ragged fibers (MERRF), storage
disorders such as sialidosis type 1, neuronal ceroid
Seizure Semiology lipofuscinosis and Lafora body disease. Further
The main seizure type is myoclonic seizures details on these disorders are beyond the scope of
(97%), but generalized tonic clonic seizures this book chapter (Shahwan et al. 2005).

Fig. 17.5 This figure demostrates an EEG epoch of a 15 year old girl with morning myoclonic seizures and one gen-
eralized-tonic-clonic seizure. The EEG findings are consistent of generalized polyspike and wave consistent with
Juvenile Myoclonic Epilepsy (JME)
Nonepileptic Paroxysmal Events leading to a drop in cerebral perfusion, is described

as a reflexive syncope. Syncope is most frequently
Other conditions different to epilepsy can also reported in the adolescent years and is twice as
cause paroxysmal events in children, some of common in females than males. The incidence of
which may involve alteration in level of con- syncope is considered to be around 0.5–3 per
sciousness and/or involve motor, visual, or sen- 1000 children (Anderson et al. 2016; Yeh 2015).
sory phenomena. A list of differential diagnoses A description of common types of syncope is
of non epileptic events are listed in (Tables 17.3)/ provided below.
Boxes 17.1 and 17.2.
Vasovagal Syncope
Syncope
Typically in a vasovagal (cardiogenic, cardiode-
One of the commonest occurrences involving an pressor, neurocardiogenic) syncope, there is
altered level of consciousness reported at extremes peripheral pooling of blood by arterial and/or
of age (young and old) is a “syncopal” event. venous dilatation followed by a bradycardia that
These events are the result of a transient reduction is profound and leads to hypotension and reduced
of cerebral perfusion below a critical threshold cerebral perfusion. Such an occurrence may fol-
required to maintain consciousness. Typically, a low a prolonged period of standing in a warm
trigger that induces, by direct or indirect path- environment (standing in a church choir, after
ways, a reduction of heart rate and blood pressure strenuous exercise on a hot day). At other times

Table 17.3 Clinical features and etiologies of common paroxysmal events in children
Paroxysmal event Features Etiology/comorbidities
Epileptic seizures Paroxysmal stereotyped, focal or Epilepsy, febrile seizures, metabolic
generalized. With and without loss of disturbances, traumatic brain injury,
awareness. Abnormal EEG and postictal stroke, CNS infections, CNS tumors, CNS
state malformations
Tics Sudden, rapid, non-rhythmic, motor or Tourette Syndrome, Tic Disorder
vocalizations, premonitory urge, can be OCD, oppositional and aggressive
suppressed transiently behavior, mood disorder
Dyskinesias Involuntary, focal, sudden onset, persistent Infection, medications reaction, Sydenham
chorea, Huntington disease
Stereotypies Repetitive, stereotyped, affecting arms, ASD, Intellectual disability
hands, trunk. Intermittent movements.
Usually experienced as pleasant
PNES Variable and bizarre motor features, waxing Conversion disorder/coexistence with
and waning, long duration (several minutes epileptic seizures, mood disorder, PTSD,
to hours), eyes closed, disappeared during anxiety disorder
sleep
Box 17.1 Differential Diagnosis of Seizures in Infants and Children

1. Epilepsy/epileptic seizures
2. Syncope
3. Movement disorders
(a) Tics
(b) Chorea/Dyskinesias
• Paroxysmal choreoathetosis
(c) Dystonia
(d) Ballism
(e) Ataxias
• Episodic ataxias
4. Transient ischemic attacks
5. Metabolic disturbance-hypoglycemia, hyperammonemia
6. Sleep related disorders-parasomnias-night terrors, REM sleep behavior disorders
7. Narcolepsy
8. Migraine and Migraine equivalents
9. Pyschiatric disturbances- Anxiety, panic attacks
10. Psychogenic non epileptic seizures (PNES)
Box 17.2 Triggers for Syncopal Events

1. Prolonged standing in crowded places, warm environments
2. Emotional events, pain
3. Sleep deprivation, fasting, febrile illness
4. Dehydration
5. Post tussive/coughing paroxysm
6. Straining at bowel movements
7. Sudden change in posture i.e. standing up from a squatting position
8. Post micturition
9. After a period of rapid weight loss i.e. anorexia nervosa
10. Drugs/medications
11. Psychogenic

the event may follow a specific trigger like vigor- eral regulatory mechanisms that maintain heart
ous brushing of one’s hair or using a toothbrush, rate and blood pressure becoming discordant.
or watching or reading about a painful or emo- Inappropriate cerebral vasoconstriction in the
tional scene on television. While most events face of normal blood pressure, excess venous
occur in a standing position, events are reported pooling, enhanced cardiac sympathetic respon-
even while sitting or during activities like walk- siveness, reduced peripheral sympathetic
ing, cycling, etc. responsiveness, and reflex sympathetic activa-
The individual may report prodromal symp- tion are some of the involved variables. The
toms such as a warm feeling, nausea, dizziness, diagnostic confirmation of this condition can
epigastric discomfort, palpitations, a graying and only be carried out in a specialized laboratory
constriction of the visual field, or the “dropping investigating autonomic dysfunction (Anderson
of the curtain” prior to a loss of consciousness. et al. 2016).
Observers or caregivers can also report pupillary
dilatation and sweating (Yeh 2015).
Stretch Syncope
Orthostatic Hypotension In stretch syncope, some teenagers show a ten-

and Postural Orthostatic Tachycardia dency to faint when they stretch themselves, a
Syndrome (POTS) movement associated with hyperextension of the
neck. There is often a family history of fainting in
Orthostatic hypotension is a transient sensation these individuals. A combination of valsalva
of dizziness and visual blurring that may accom- induced peripheral pooling, and reduction in
pany a rapid change in posture from supine or cerebral blood flow due to compression of blood
squatting position to standing. This phenomenon vessels in the neck may be involved (Anderson
occurs in young healthy adolescents, particularly et al. 2016; Yeh 2015).
in tall individuals with an asthenic build and poor
muscle mass. Typically, there is prompt recovery
from symptoms within 30 seconds. The cause of Self-Induced Syncope
this transient drop is not entirely well understood.
Such a drop may not be demonstrable on a tilt Some children may be able to induce syncope
table test. almost at will. They have taught themselves to
Postural orthostatic tachycardia syndrome hyperventilate while squatting, rapidly stand up
(POTS) is a condition characterized by symp- and straining that through a valasalva maneuver,
toms of cerebral and retinal hypoperfusion that is ultimately producing a combination of venous
accompanied by a dramatic rise in heart rate with pooling and cerebral vasoconstriction sufficient
a relatively normal blood pressure in the upright to induce loss of consciousness. This may be
posture. The symptoms of lightheadedness, used as an entertainment or has been reported as
fatigue, weakness, and blurring of vision are an avoidance measure to miss out unpleasant sit-
reported. It must be noted that in older children uations like a school examination (fainting lark)
and adolescents the change in heart rate that (Anderson et al. 2016; Yeh 2015).
accompanies a change in posture must be adjusted
for age, as an increase of 20 beats or more is not
uncommon in this age group. An increase of >35 Reflex Anoxic Seizure
beats/min and a heart rate above 135 beats/min,
two min after standing in an average adolescent, Towards the end of a syncopal episode, there
can be considered abnormal. may be enough hypoxia associated with cerebral
The pathophysiology underlying POTS is hypoperfusion to induce a brief “reflex anoxic”
attributable to a number of central and periph- seizure. Reflex anoxic seizures may take the

form of tonic posturing, clonic movements, and Psychogenic pseudosyncope is the appearance
myoclonic jerks. Typically, the seizure is self- of transient loss of consciousness (TLOC) in the
limited and often terminates with recovery of absence of a true loss of consciousness. The dis-
consciousness. In a reflex anoxic seizure, the order is under investigated in the unexplained
loss of consciousness is brief, urinary inconti- syncope population. Patients are more likely to
nence is uncommon, and post event confusion is be adolescent females reporting an increased fre-
short lived while fatigue can be prolonged. On quency of episodes over the past 6 months.
the other, in an epileptic seizure, the events are Affected individuals frequently experience
longer, and they are often associated with symptoms prior to their episodes including
incontinence and a prolonged postictal state of light-
headedness, shortness of breath and tin-
confusion. Reflex anoxic seizures are also noted gling. The events are prolonged often 10–30 min
in the context of breathholding spells described in duration and tend to continue despite a supine
below (Anderson et al. 2016; Yeh 2015). posture. The individual will maintain eyes closed
or eyelid fluttering. Unresponsiveness is rarely
maintained to painful stimuli. The passive lifting
Breathholding Spells and dropping of the arm and hand onto the face
may show an avoidance movement. The diagno-
This condition is extremely common in toddlers, sis may require the performance of transcranial
and is often a dramatic event causing alarm and doppler studies for blood flow, and a heads up tilt
anxiety for parents. Two types of spells are rec- table test which will not show the typical changes
ognized; the “pallid” and “cyanotic” type. The in terms of a drop in blood pressure and transcra-
events begin around 6 months to 2 years of age nial blood flow in patients with PPS (Anderson
begin to remit spontaneously by school entry. et al. 2016; Yeh 2015) There may be on careful
Both types are triggered following relatively history taking evidence to support psychiatric co-
minor trauma or pain following which, the child morbid features and environmental stressors.
begins a cry that may be short in the pallid type, This form of conversion disorder is associated
and prolonged in the cyanotic variety. The child with symptomatic chronicity, increased psychiat-
goes pale or becomes cyanosed and then loses ric and physical impairment, and diminished
posture; subsequently, the child may develop quality of life.
clonic and or myoclonic movements that are self-
limited, followed by recovery of consciousness.
The pathophysiology involved may invoke mech- pproach to the Investigation
A
anistic factors that are operative in other kinds of of Syncope
syncopal events discussed above. For instance,
the pallid attack may have a component of severe In all patients presenting with a single or recur-
bradycardia and even transient asystole. On the rent event suggestive of syncope, a detailed his-
other hand, the cyanotic type may depend on tory and physical examination must be performed.
hyperventilation associated with crying and The purpose of such an evaluation is to rule out
resulting vasoconstriction and valsalva induced any serious cardiac pathology that may present
venous pooling (Anderson et al. 2016; Yeh 2015). initially with such events. For instance, an under-
lying serious brady or tacharrythmia that may
carry with it the risk of sudden death must be
Pseudosyncope ruled out. Descriptions of the event obtained
directly from observers witnessing the event, to
Recurrent syncopal events in adolescents for identifying the temporal evolution of events, the
which no explanation is found despite thorough initiating triggers, and the environmental factors
evaluation and investigation should raise the sus- can be helpful. Every effort must be made to
picion of psychogenic pseudosyncope (PPS). directly talk to such individuals and obtain a

ritten description; a video recording on the cell-

w for status epilepticus if prolonged. It is charac-
phone can all be helpful. A family history of any terized by myoclonic jerks involving the limbs,
pacemaker placement, sudden death, cardiac most frequently generalized and symmetric, but
rhythm abnormalities, syncope, and/or epilepsy at times affecting only one limb or one side of
should be carefully sought and documented. the body. The paroxysmal movements only
If the description is typical and definite trig- occur during sleep, mainly in quiet sleep and
gers identifiable, then a diagnosis of syncope can they stop on arousal. Rocking or repetitive stim-
be offered with little need for major investiga- uli may provoke the motor phenomena. The
tions. If the presentation is atypical, then a care- onset of BNSM is usually during the first weeks
ful physical examination looking for any cardiac of life and resolution occurs spontaneously
abnormalities, measurement of vitals, including within six months of age. This phenomena may
supine and erect recordings after 2 min of stand- be the result of both immaturity of the networks
ing for both blood pressure and heart rate can be involved in motor control during sleep and
helpful to detect orthostatic changes. At the mini- genetic factors. The EEG and psychomotor
mum, an ECG with a rhythm strip (to exclude a development of affected newborns are both nor-
prolonged QTc interval and any other conduction mal (Facini et al. 2016).
abnormalities), and an EEG to rule out an epilep-
tiform abnormality may be considered in selected
cases where there may be a family history of sei- Tic Disorders
zures or heightened parental anxiety for their
young child. However, the evaluation may not Tics are “sudden, rapid, recurrent, but non-
yield clues in which case referral to a cardiologist rhythmic movements and/or vocalizations, gen-
to rule out structural heart disease, and arrhyth- erally preceded by premonitory sensory “urges”.
mias (echocardiogram and Holter recordings) They are experienced as purposeless and only
can be considered. Where the history gives a sus- partially suppressible.
picion of epileptic or non-epileptic events, refer- The age of onset for tic disorders is between 6
ral to a neurologist for EEG and/or video EEG and 7 years of age (3–11 years). In children,
recordings can be helpful. In recurrent cases, motor tics tend to appear a few years earlier than
when the work up does not yield any answers, vocal tics. Tics are divided into the following cat-
referral to a specialized centre for a tilt table test egories: simple (eye blinking, nose twitching,
can be considered. There are caveats to tilt testing jaw or neck movements, sniffing, grunting, throat
as there is often a high false positive rate in chil- clearing, and coughing) or complex (squatting,
dren. However, the test can be helpful when posi- touching, jumping, uttering words, or sentences).
tive to offer reassurance to the patient and family Some vocal tics (clearing throat and snuffling)
of a relatively benign form of syncope and if can be misdiagnosed as upper airway disease,
negative, provide support to the diagnosis of a asthma or allergies. Tics usually affect the facial
psychogenic pseudosyncope.(Anderson et al. and cephalic body areas and subsequently involve
2016; Yeh 2015). the shoulders and extremities. The severity of tics
usually peaks around 12 years of age. Tics could
be a transitory condition currently recognized by
enign Neonatal Sleep
B the DSMV as “provisional tic disorder”. When
Myoclonus (BNSM) tics persist longer than 12 months, a “persistent
tic disorder” is recognized. Tourette Syndrome is
Benign neonatal sleep myoclonus is a benign a childhood onset neurodevelopmental disorder
and common condition affecting 0.8–3/1000 characterized by motor and vocal tics lasting
full term and near-term neonates. BNSM may more than a year. Only a small proportion of chil-
occur in neurologically normal and healthy dren with tics (5–10%) will continue to have tics
infants. It can be mistaken for epilepsy and even in adulthood.

Tics occur in bouts and usually follow a wax- atric population consist of physiologic and organic
ing and waning pattern in frequency, intensity, disorders. The most common of these conditions
location and complexity. Most patients can sup- include inattention/daydreaming/staring, sleep
press their tics for a short period of time, but usu- myoclonus, stereotyped movements, hypnic jerks,
ally this is followed by a rebound effect and a tonic posture, parasomnias, and movement
transitory increase in its intensity and frequency. disorders.
Some children are able to suppress tics when at Of those with a psychogenic basis, psycho-
school or in the presence of peers, and later genic non epileptic seizures (PNES) are the most
relieve the urge for tics at home. Triggers that can common non epileptic events. The prevalence
exacerbate tics bouts include excitement, frustra- increases in older children.
tion, stress, fatigue, or boredom. There are also, PNES involve observable abrupt paroxysmal
situations that can help to suppress tics such as: changes in consciousness or behaviour that pres-
intense concentration (goal-directed attention) ent similarly to epileptic seizures but are not
and focused activities, such as playing an instru- accompanied by EEG changes associated with
ment or performing certain sports. epilepsy, and there is a strong suspicion of a psy-
Tics are more frequent in boys (4:1). Transient chogenic cause.
tic disorder affects around 3–20% of school age Some authors have reported that based on
children. They can be associated with attention video EEG children with PNES could be divided
deficit and hyperactivity disorder (ADHD), obses- into three groups: patients with prominent motor
sive compulsive disorder (OCD) and less fre- activity, patients with subtle motor activity, and
quently in children with oppositional and aggressive patients with both types of events. Subtle motor
behaviours, depression and parasomnias. activity was more prominent in those younger
Tics need to be differentiated from other child- than 13 years old, and prominent motor activity
hood movement disorders such as stereotypies, was found more consistently in children older
chorea and dyskinesia. These other type of motor than 13 (Sankhyan 2014).
phenomena are more common in children with The semiology of the PNES is variable, in
Autistic Spectrum Disorders (ASD), cerebral children with video EEG recordings, rhythmic
palsy (CP) and drug induced psychomotor disor- motor movements have been commonly
ders (Table 3) described. Complex motor PNES (ie. diverse and
The majority of tic disorders respond to cogni- bizarre motor activity such as pelvic thrusting,
tive behavioural therapy. Pharmacological treat- body shaking or bizarre body posturing) has been
ment is considered for severe and chronic cases. described in only 13% of the pediatric population
Indications for medication include the following: and mixed PNES in 4%. Dialeptic PNES (i.e.
if tics cause pain, emotional problems, or strong behavioral arrest, staring spells, “absence-like”
discomfort; or if they lead to social isolation, behavior) were found more frequently in children
stigmatization or bullying. In North America first (29%) than in adults. Children were unresponsive
line drugs include alpha-2 agonists such as guan- during 34% of the events. The most common
facine and clonidine. In Europe risperidone is the motor sign was a tremor (25%) involving the
first line drug (Dooley 2006; Ganos 2016). upper limbs more frequently than the lower
limbs. Emotional manifestations were observed
in approximately 43% of events, and the emo-
Non-epileptic Seizures tions were negative in almost all children.
When encountering a child or adolescent with
A significant minority of children referred because suspected PNES, a detail psychosocial history is
of suspected epileptic seizures may not actually key in identifying triggers. The main areas of pre-
have the condition. Non-epileptic seizures can be cipitating stressors in children are: school related
present in psychiatric and non-psychogenic disor- difficulties (academic difficulties and bullying),
ders. The non-psychogenic conditions in the pedi- family/interpersonal conflict, and physical/sexual

abuse. Studies suggest that a significant propor- agement requires the clinician to adopt a careful
tion of children with PNES have a psychiatric and systematic evaluation of the semiology of the
disorder as well as conversion disorder, such as event, its evolution, progression and termination.
a mood disorder, separation anxiety school pho- Clinical history taking combined with a complete
bia, and less frequently reactive psychosis or physical and neurological examination often can
schizophrenia. provide diagnostic clues that point toward an epi-
The diagnosis is based on a description of the leptic or non-epileptic etiology in the majority. If
events plus a history of a significant psychosocial an epilepsy-related diagnosis is suspected, the
component. Video-recording through smart diagnostic testing will involve electroencepha-
phones can be helpful to differentiate epileptic vs lography, neuroimaging, and further evaluation
non epileptic events. The diagnostic gold stan- by a pediatric neurologist. If a non-epileptic con-
dard is the video EEG. dition is suspected, an EEG study may still be
Delivering the diagnosis to families and part of the investigation. Assessment of cardiac
patients is important, and the importance of effec- function, if indicated, may necessitate referral for
tive communication of the diagnosis of PNES as a evaluation by a cardiologist in addition to routine
therapeutic measure is clearly established. Most studies of ECG, chest xray and Holter studies. By
authors emphasize that it is crucial to make it and large, a systematic process of evaluation and
explicit that the attacks are real and the certainty elimination of unlikely conditions in the differen-
of a psychogenic basis for the events should be tial diagnosis can establish a diagnosis. It is in the
clearly conveyed to the child and the family. A process that the above descriptions will be most
proportion of children with PNES will also have helpful.
epilepsy, and it is important that the manifesta- The clinician is well advised to consult sub-
tions of both events are made clear to the family. speciality services (pediatric neurologist and a
In the pediatric population most authors rec- cardiologist), where indicated in order to exclude
ommend a prompt intervention by a pediatric conditions that may require specialised diagnos-
mental health professional. Cognitive Behavioral tic and treatment interventions.
Therapy (CBT) has been shown to be effective in
adults with PNES.
The outcome of PNES in pediatric patients is References
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Update in Pediatric Oncology:
Section A-New Developments 18
in the Treatment of Pediatric
Acute Lymphoblastic Leukemia
Shannon L. Maude and Stephen P. Hunger
Immunophenotype genic event occurred at the developmental

stage the malignant lymphoblasts resembled by
ALL is a malignancy of lymphoid progenitors. immunophenotype; however, it is now under-

Early progenitors with transforming lesions sub- stood that transformation occurs in an earlier cell
sequently acquire additional mutational events. and that somatic mutations in ALL often block
The net result of these genetic events is patho- differentiation past a specific maturational stage
logic alteration of cell growth, differentiation, (Campos-Sanchez et al. 2011). It is not uncom-
proliferation, and survival. ALL is classified into mon for B-ALLs to express myeloid markers,
subtypes arising from the B and T cell lineages; such as CD13 and CD33. In addition, there is
however, this classification oversimplifies this considerable plasticity within the B cell lineage,
heterogeneous group of leukemias. B-ALL and allowing for the possibility that more mature
T-ALL are distinct not only in the cell of origin stages can de-differentiate or that less mature
and immunophenotype but also in the presenta- stages can acquire B cell markers (Campos-
tion and, historically, the prognosis. Sanchez et al. 2011).
Malignant B lymphoblasts are typically B-ALL is by far the more common form, com-
arrested at the precursor B or earlier stage of prising 85% of ALLs, although the frequency of
differentiation; therefore, they express many T-ALL begins to increase in adolescents
of the same cell surface markers as these early (Linabery and Ross 2008). B-ALL is a disease of
stages of development, including immature (i.e. the bone marrow, where B cell development
terminal deoxynucleotidyl transferase (TdT), occurs. Bone marrow replacement with leukemia
CD10), lymphoid (i.e. CD45), and B cell mark- leads to impaired hematopoiesis and cytopenias;
ers (i.e. CD19, CD22, CD79a) (LeBien 2000). therefore, B-ALL frequently presents with
Historically, it was thought that the leukemo- sequelae of anemia, thrombocytopenia, and neu-
tropenia, including pallor, fatigue, bruising, or
S.L. Maude (*) • S.P. Hunger infection. Other common presenting symptoms
Division of Oncology and Center and signs include bone pain, hepatosplenomeg-
for Childhood Cancer Research, The Children’s aly, and lymphadenopathy.
Hospital of Philadelphia, Philadelphia, PA, USA
Much of T cell differentiation occurs in the
Department of Pediatrics, Perelman School thymus; therefore, it is common for T-ALL to
of Medicine at the University of Pennsylvania,
present with a mediastinal mass that may cause
Philadelphia, PA, USA
e-mail: maude@email.chop.edu; respiratory distress in addition to other common
hungers@email.chop.edu presenting signs and symptoms noted above for


462 S.L. Maude and S.P. Hunger
B-ALL. Hyperleukocytosis and CNS involvement (WBC) count at diagnosis define initial risk
are more common in T-ALL compared to B-ALL allocation and therapy in B-ALL. An international
(Hunger and Mullighan 2015a). Furthermore, consensus conference established the National
T-ALL has a higher incidence in boys and older Cancer Institute (NCI)/Rome criteria which sepa-
children and adolescents, in contrast to B-ALL rate B-ALL into standard-risk (SR) and high-risk
with a peak incidence in the toddler age (Hunger (HR) (Smith et al. 1996). Age between 1 and
and Mullighan 2015a; Patrick and Vora 2015). 10 years and presenting WBC < 50,000 μL−1 are
Like B-ALL, T lymphoblasts display an both required for classification as SR, while
immunophenotype similar to early progenitor either age ≥ 10 years or presenting
counterparts in the T cell lineage. Markers of WBC ≥ 50,000 μL−1 are sufficient to classify as
immaturity, such as TdT, are expressed as well as HR B-ALL. Therapy intensification has nar-
T cell-specific markers, such as CD2, CD7, and rowed the gap between SR and HR B-ALL; how-
cytoplasmic CD3. A recently identified subtype ever, outcomes for HR B-ALL remain inferior
of T-ALL, termed early T cell precursor (ETP) despite more intensive therapy. Children with SR
ALL, is distinguished by a unique immunophe- B-ALL treated on Children’s Oncology Group
notype (Coustan-Smith et al. 2009). While ETP (COG) ALL clinical trials between 2000 and
ALL displays markers of the T cell lineage, it 2005 had a 5-year survival of 95.0% compared to
lacks some typical markers such as CD1a and 82.9% for those with HR B-ALL (Hunger et al.
CD8, and expresses stem cell or myeloid markers 2012). While the NCI/Rome risk criteria set a cut
such as CD13 and CD33. The genetic profile of point, the relationship between prognosis and
ETP ALL also differs from the majority of both age and presenting WBC count is linear,
T-ALLs in that it resembles myeloid or stem cell with increasing age and increasing WBC count
leukemias (Zhang et al. 2012). conferring a worse prognosis. Age and presenting
Historically, prognosis differed between WBC count have limited prognostic value in
B-ALL and T-ALL with T-ALL carrying a worse T-ALL and are not used to alter therapy (Patrick
prognosis (Hunger and Mullighan 2015a; and Vora 2015). Infants <1 year have significantly
Teachey and Hunger 2013). However, with cur- inferior outcomes, and for this group, age is
rent treatment regimens, survival rates for T-ALL, inversely related to outcome, with infants
although inferior, now approach those of B-ALL <3 months having the worst survival rates (Dreyer
(Hunger et al. 2012; Patrick and Vora 2015). ETP et al. 2015; Pieters et al. 2007). Survival rates
ALL, which comprises 10–15% of childhood have improved significantly over the past few
T-ALL, was originally reported to carry a dismal decades for all subgroups of ALL, except infants
prognosis, with a 19% 10-year overall survival (Hunger et al. 2012).
(Coustan-Smith et al. 2009). However, larger Extent of disease, including organ involve-
studies with modern risk-adapted therapy dem- ment, skin involvement, and lymphadenopathy, is
onstrate similar outcomes to T-ALL, with sur- neither prognostic nor therapy altering, for the
vival rates of approximately 80% (Wood et al. most part. However, two extramedullary sites of
2014). An important difference that remains is disease, the CNS and the testes, are important to
the intensity of treatment: children with T-ALL note as the presence of leukemia in these sites
require more intense therapy than the majority of requires consideration of directed therapy. Both
children with B-ALL to achieve these outcomes. the CNS and testes are considered sanctuary sites
where leukemia cells can evade standard therapy
and recur. Children with CNS involvement,
Prognostic Factors defined as WBC count ≥5 μL−1 with blasts pres-
ent in the cerebrospinal fluid or neurologic signs,
Clinical Features receive intensified CNS-directed therapy, includ-
ing augmented intrathecal chemotherapy with or
Several clinical features are prognostic of out- without cranial radiation therapy (discussed in
come in pediatric ALL. Age and white blood cell more detail in “CNS-directed Therapy” section).

18 Update in Pediatric Oncology 463
Boys with persistent testicular disease receive The BFM group has shown that PPR confers a
testicular irradiation. On COG protocols, both of significantly worse prognosis in both B-ALL and
these extramedullary sites up-risk patients to T-ALL (Schrappe et al. 2000; Lauten et al. 2012).
high-risk therapy. Despite intensified therapy, Prednisone response, therefore, has been incor-
patients with CNS involvement consistently have porated into risk allocation in BFM trials, with
worse outcomes (Vora et al. 2016). PPR being a high-risk feature, though this is
Other demographic features, such as race, evolving currently.
ethnicity, and sex, also appear to be prognostic MRD assessment of response to therapy is the
but have not been used to alter therapy, and NCI/ most important prognostic variable in pediatric
Rome risk group remains the most significant ALL, consistently demonstrating independent
clinical prognostic factor for B-ALL in com- prognostic value across studies. The assay used
bined models (Hunger et al. 2012). Despite to measure MRD varies amongst different coop-
improvements in outcome, males, blacks, and erative groups, but the power of this technology
Hispanics continue to have inferior survival to predict outcome is unchanged. The COG MRD
(Hunger et al. 2012; Kadan-Lottick et al. 2003). assay employs multiparameter flow cytometry to
Underlying biology and genetic determinants characterize the leukemic immunophenotype and
likely play a large role in these differences. can detect aberrant blasts at a level of 0.01%.
Males and blacks are disproportionately repre- MRD ≥ 0.01% at the end of the first block of
sented in T-ALL, which continues to carry a therapy (day 29 of induction) confers a signifi-
worse prognosis, and there is an increased rate of cantly worse outcome for patients with B-ALL
high-risk genetic features in the Hispanic popu- (Borowitz et al. 2008). More recent data indicates
lation (Harvey et al. 2010b). that these patients can be characterized further by
MRD measurement after the first 3 months of
therapy (at the end of consolidation): patients
Early Response to Therapy with persistent MRD ≥ 0.01% fare much worse,
with a 5-year disease-free survival (DFS) of 39%
Across cooperative groups, treatment protocols, compared to 79% for those with MRD <0.01% at
and response assays, early response to therapy end-consolidation (Borowitz et al. 2015). The
has proven to be the single most important pre- International BFM study group utilizes a PCR-
dictor of prognosis. For many years, bone mar- based MRD assay, which tracks immunoglobulin
row morphologic assessments during the first or T cell receptor (TCR) gene rearrangements in
month of therapy were used to stratify patients the leukemic blasts (Biondi et al. 2000). In a col-
into risk groups based on rapidity of response laborative prospective study of the Associazione
(Gaynon et al. 1997). Early bone marrow assess- Italiana di Ematologie Pediatrica (AIEOP) and
ments have largely been replaced with more sen- BFM study groups, patients treated on AEIOP-
sitive assays of minimal residual disease (MRD) BFM ALL 2000 were risk-stratified based on
at the end of the first month of therapy (Borowitz MRD at day 33 and day 78. Those B-ALL
et al. 2008; Coustan-Smith et al. 2000). patients with MRD ≥ 10−3 at day 78 had the
One very early assessment of response that is worst outcome, with a 5-year event-free (EFS)
still used widely is the peripheral blood morpho- survival of 50.1% (Conter et al. 2010). MRD is
logic response to a prednisone pre-phase. The also an important prognostic tool in T-ALL,
Berlin-Frankfurt-Munster (BFM) study group although the time point that is prognostic appears
assesses the response to 7 days of prednisone in to be different from B-ALL. The kinetics of blast
combination with one dose of intrathecal metho- clearance is slower in T-ALL. On AEIOP-BFM
trexate. A peripheral blast count <1000 μL−1 on ALL 2000, MRD ≥ 10−3 at the later time point
day 8 is classified as a good response, while a (day 78) was predictive of outcome, regardless of
peripheral blast count ≥1000 μL−1 on day 8 is MRD at day 33 (Schrappe et al. 2011). Lastly,
classified as a prednisone poor response (PPR). infant ALL can be stratified into the highest and

lowest risk groups by MRD. Once again, MRD at hyperdiploid ALL is common, accounting for
end-consolidation was highly predictive of out- 25–30% of pediatric B-ALL cases, and is typi-
come: all patients with MRD ≥ 10−4 at this time cally associated with other low-risk features,
point relapsed (Van der Velden et al. 2009). such as low presenting WBC count and
Conversely, infants who achieved MRD < 10−4 at age <10 years (Paulsson and Johansson 2009).
the end of induction fared well with a relapse rate The same chromosomes (4, 6, 10, 14, 17, 18, 21,
of 13%. and X) are frequently gained, suggesting this
Intensification of therapy based on response event is not random (Paulsson et al. 2015). The
measured by MRD has improved survival, yet gain of chromosomes 4, 10, and 17, termed triple
there remains a subset of ALL patients with per- trisomy, was demonstrated to confer a favorable
sistent MRD at later time points who continue to prognosis and historically used for risk allocation
have poor outcomes (Conter et al. 2010; Borowitz in COG treatment studies (Sutcliffe et al. 2005;
et al. 2015). These patients are likely chemo- Schultz et al. 2007). The COG now uses double
refractory and may require alternative treatment trisomy of chromosomes 4 and 10 to define low-
strategies. risk patients. Other groups have documented
favorable outcomes with the same or different
trisomies (Paulsson et al. 2013; Moorman et al.
Genetic Features 2010), but not all use trisomies or hyperdiploidy
in risk allocation. Little is known about the etiol-
Genetic alterations present in the leukemic blasts ogy of hyperdiploid ALL, but modern genomic
contribute to prognosis and likely influence other technologies are advancing our understanding.
prognostic factors, such as presenting WBC Whole genome and whole exome sequencing
count and response to therapy. Cytogenetic clas- identified the RAS pathway as frequently
sification of ALL offered the first look at the involved in hyperdiploid ALL (Paulsson et al.
impact of genetic abnormalities on outcome. 2015). Future work hopes to delineate risk within
Particularly in B-ALL, many cytogenetic fea- this favorable subset and identify targeted
tures were found to have such a major influence therapies.
on outcome that their presence alters therapy. In contrast to hyperdiploidy, hypodiploid
This is not the case for T-ALL. Recent advances subsets carry a poor prognosis and are uncom-
in technology provide a much deeper view of the mon (Harrison et al. 2004; Heerema et al. 1999;
diverse biology of ALL and may change the way Nachman et al. 2007; Raimondi et al. 2003; Pui
we treat ALL in the future (Hunger and Mullighan et al. 1990, 1987). Most hypodiploid ALL has 45
2015b). chromosomes, which does not portend an inferior
prognosis (Harrison et al. 2004; Raimondi et al.
Aneuploidy 2003). However, hypodiploidy with <44 chro-
Karyotype analysis is routinely performed at diag- mosomes comprises only 1–2% of B-ALL and
nosis and can easily detect changes in chromo- confers a dismal outcome (Nachman et al. 2007).
some number. The majority of ALL cases contain This group has been broken down further into low
whole chromosome gains or losses, and in many hypodiploid (~30–39 chromosomes) and near
cases, the ploidy of the blast population impacts haploid (24–29 chromosomes) (Harrison et al.
prognosis. Definitions of ploidy relate to the nor- 2004). Due to low incidence, it is unclear in most
mal diploid complement of 46 chromosomes. studies if absolute chromosome number influ-
Hyperdiploid cells contain >46 chromosomes, ences prognosis (Raimondi et al. 2003). A study
while hypodiploid cells contain <46 chromosomes. of 139 children with hypodiploid ALL treated
Several cooperative groups have found high on clinical trials of ten study groups found that
hyperdiploidy (>50 chromosomes) to be a favor- patients with 44 chromosomes fared better than
able prognostic feature (Sutcliffe et al. 2005; those with <44 chromosomes, but there was no
Paulsson et al. 2013; Moorman et al. 2010). High difference in outcome when the group was b roken

down further (Nachman et al. 2007). Recent chemotherapy regimens (Schultz et al. 2009;
genomic studies, however, demonstrate dis- Biondi et al. 2012). The COG reported a 5-year
tinct genomic profiles amongst these subgroups. DFS of 70% for children treated with imatinib in
Genomic profiling revealed lesions in recep- combination with an intensified chemotherapy
tor tyrosine kinase and RAS pathways in ALL backbone (Schultz et al. 2014).
cases with 24–31 chromosomes, while >90% of Translocations involving the mixed lineage
low hypodiploid (32–39 chromosomes) harbored leukemia (MLL) gene on chromosome 11q23 are
TP53 alterations and a striking 50% of these had present in about 75% of infant ALLs and are also
germline TP53 mutations (Holmfeldt et al. 2013). seen in 2–5% of childhood ALL (Dreyer et al.
2015; Schultz et al. 2007). MLL has numerous
Structural Alterations fusion partners, but three make up the majority of
Sentinel chromosome translocations have long cases: AF4 in t(4;11), AF9 in t(9;11), and MLLT1
been recognized in ALL. In recent years, numer- in t(11;19) (Krivtsov and Armstrong 2007). In
ous rare gene fusions have been identified through infants, MLL rearrangement unequivocally con-
next generation sequencing techniques. Many of fers a worse prognosis (Pieters et al. 2007; Dreyer
these inter- and intrachromosomal alterations et al. 2015). In children >1 year of age, the impact
have prognostic implications and some have is less clear, but MLL rearrangement has been
treatment implications as well. associated with inferior EFS in several studies
The ETV6-RUNX1 (TEL-AML1) gene fusion (Pui et al. 2003; Moorman et al. 2010; Schultz
resulting from the t(12;21), is the single most et al. 2007).
common translocation in pediatric ALL, account- Several translocations involving TCF3 (E2A)
ing for 20–25% of B-ALL in children (Harrison on chromosome 19 have been reported in ALL
et al. 2010). Screening for this translocation by including the t(1;19) resulting in TCF3-PBX1
fluorescence in situ hybridization (FISH) is rou- fusion and t(17;19) resulting in TCF3-HLF
tinely performed at diagnosis by many groups. A fusion (Hunger et al. 1991, 1992). While initially
study of newborn blood samples from children reported to be high-risk, t(1;19), identified in 5%
who later developed ALL demonstrated the pres- of pediatric B-ALL, is no longer considered an
ence of the ETV6-RUNX1 fusion at birth, indicat- independent risk factor with modern response-
ing that this is an initiating or early event and not based therapy (Moorman et al. 2010; Hunger
sufficient for leukemogenesis (Wiemels et al. 1996). In contrast, t(17;19) is quite rare, account-
1999). Survival rates for children with B-ALL ing for <1% of B-ALL, but is associated with dis-
carrying the ETV6-RUNX1 gene fusion are out- mal outcomes (Moorman et al. 2010; Minson
standing (Moorman et al. 2010; Harrison et al. et al. 2013).
2010; Schultz et al. 2007). Moreover, this trans- Intrachromosomal amplification of chromo-
location is associated with favorable prognosis some 21 (iAMP21) is defined by three or more
regardless of risk group (Forestier et al. 2008). extra copies of RUNX1 on a single chromosome
The Philadelphia chromosome (Ph) or t(9;22) 21 (Harewood et al. 2003; Soulier et al. 2003).
(q34;q11) is present in approximately 3% of Approximately 2% of childhood ALL harbors
childhood ALL and results in BCR-ABL1 gene iAMP21 (Heerema et al. 2013; Moorman et al.
fusion (Bernt and Hunger 2014). The BCR- 2013). Several studies showed inferior outcomes
ABL1 fusion protein functions as a leukemo- in patients with iAMP21, which may be over-
genic driver through aberrant ABL1 kinase come with intensified therapy (Heerema et al.
activity. Historically, Ph+ ALL had a dismal prog- 2013; Moorman et al. 2013; Harrison et al. 2014).
nosis, which was only modestly improved with Recent COG trials found that SR B-ALL patients
hematopoietic stem cell transplantation (HSCT) with iAMP21 fare particularly poorly with
(Aricò et al. 2000, 2010). Survival rates have standard- risk therapy; therefore, these patients
improved significantly with the introduction of are currently treated on HR treatment protocols
the tyrosine kinase inhibitor (TKI) imatinib into (Heerema et al. 2013).

Genomic Profile Ph-like ALL is common, comprising 10–15%

Next generation genomic technologies have dra- of childhood B-ALL, and carries a poor progno-
matically expanded our knowledge of the sis, with 4–5 year relapse-free survival rates of
genomic landscape of ALL beyond aneuploidy 21–63%, depending on the cohort examined (Loh
and sentinel chromosomal rearrangements. In et al. 2013; Den Boer et al. 2009; Harvey et al.
recent years, several groups identified a very 2010b). The incidence of Ph-like ALL increases
high-risk cohort of B-ALL whose gene expres- with age with upwards of 25% affected in the
sion profile resembles that of Ph+ ALL. This sub- 21–39 year age range (Roberts et al. 2014). Male
group, termed Ph-like or BCR-ABL1-like, does sex and Hispanic ethnicity are enriched in the
not harbor the BCR-ABL1 translocation but COG Ph-like ALL cohort (Harvey et al. 2010b).
appears to activate similar downstream signaling Patients with Ph-like ALL more frequently pres-
pathways to Ph+ ALL (Den Boer et al. 2009; ent with hyperleukocytosis and tend to be chemo-
Harvey et al. 2010b; Mullighan et al. 2009b). refractory, with a higher rate of induction failure
Deletion of the lymphoid transcription factor (failure to achieve morphologic complete remis-
gene IKZF1, commonly seen in Ph+ ALL, fre- sion (CR) at the end of the first month of therapy)
quently occurs in Ph-like ALL. Due to these sim- and positive MRD at the end of induction (Harvey
ilarities, an investigation into other kinase et al. 2010b; Loh et al. 2013).
pathways ensued, and several lesions affecting
kinase activity and cytokine signaling are impli- Genetics of T-ALL
cated in this high-risk cohort. Several common genetic lesions occur in T-ALL;
Approximately 50% of cases harbor rear- however, none are prognostic in isolation, and
rangements in CRLF2 (cytokine receptor-like therefore, none are currently used to stratify by
factor 2), leading to overexpression of this com- risk or alter therapy. The NOTCH signaling path-
ponent of the heterodimeric cytokine recep- way represents the most common family of
tor for thymic stromal lymphopoietin (TSLP) genetic lesions in childhood T-ALL, affecting
(Mullighan et al. 2009a; Russell et al. 2009). more than 50% of T-ALL (Weng et al. 2004).
About half of cases with CRLF2 rearrangements Additional genetic alterations in T-ALL involve
also have point mutations in genes encoding JAK LMO2, TAL1, TLX1, and HOX11 (Van
kinases (Russell et al. 2009; Harvey et al. 2010a; Vlierberghe and Ferrando 2012).
Mullighan et al. 2009c; Yoda et al. 2010), a family The ETP subtype of T-ALL is distinguished
of tyrosine kinases important for cytokine recep- not only by immunophenotype but also by gene
tor signaling, cell growth, survival, and differen- expression profiles resembling myeloid or stem
tiation in many cell types, particularly those of the cell leukemias (Coustan-Smith et al. 2009; Zhang
hematopoietic and immune systems. Moreover, et al. 2012). ETP ALL cases commonly harbor
CRLF2-overexpressing ALL cell lines and pri- lesions leading to dysregulation of the RAS path-
mary human leukemias demonstrate aberrant way as well as lesions affecting IL7R and the
JAK2 signaling through its downstream target, JAK/STAT pathway (Maude et al. 2015; Zhang
STAT5, in vitro (Tasian et al. 2012). Numerous et al. 2012). For all subtypes of T-ALL, however,
fusions involving kinases continue to be identi- response to therapy by MRD remains the most
fied in Ph-like ALL. Fusions or oncogenic altera- important prognostic factor.
tions of ABL1, ABL2, JAK2, PDGFRB, CSF1R,
EPOR, and IL7R have been identified by next-
generation sequencing technologies (Roberts Current Treatment for
et al. 2012, 2014). Approximately 20% of Ph-like Childhood ALL
ALL cases have no known lesion in the above-
named pathways but are suspected to harbor as With the introduction of chemotherapy, child-
yet unidentified genetic lesions affecting sig- hood ALL changed from a universally fatal dis-
naling pathways important for proliferation and ease a half century ago to one in which almost
transformation (Roberts et al. 2014). 90% of children are cured in the current era.

Pediatric ALL provides an example of the intensity is adjusted based on risk group. For
enormous impact cooperative group clinical tri- B-ALL, risk group is determined by a combina-
als can have on therapy and outcomes (Pui et al. tion of baseline clinical features, genetic features,
2015). In fact, childhood ALL was the first dis- and early response to therapy.
ease to be treated with chemotherapy, paving the For both B-ALL and T-ALL, the concept of
way for the future of cancer therapy (Farber et al. risk-adapted therapy, whereby therapy is inten-
1948). Through both major additions and itera- sified for patients at high risk of relapse, has
tive changes, the treatment for pediatric ALL has improved overall outcomes significantly (Teachey
evolved to include multi-agent chemotherapy and and Hunger 2013). Patients with HR B-ALL and
multi-modality approaches. Two approaches all patients with T-ALL require more intense
have greatly impacted outcomes: the intensifica- therapy than patients with SR B-ALL. As patients
tion of therapy based on risk and the introduction with suboptimal MRD response have been allo-
of therapy to target the CNS. cated to intensified therapy in modern protocols,
the outcome gaps have narrowed. Patients with
end-induction MRD treated on a recent COG HR
Risk-Adapted Therapy protocol, AALL0232, had much improved dis-
ease-free survival if they became MRD-negative
The therapy for childhood ALL includes several with additional therapy (Borowitz et al. 2015).
combinations of chemotherapy lasting approxi- Lastly, maintenance therapy is important in
mately two to three and a half years. While varia- ALL to maintain remission and reduce the risk of
tions exist amongst protocols employed by the relapse. This phase of therapy consists of repeated
different cooperative groups, the basic principles cycles of reduced intensity, mostly oral, chemo-
are shared. Therapy is divided into discrete therapy. Daily oral mercaptopurine and weekly
phases, with 6–9 months of intensive chemother- low-dose methotrexate comprise the backbone of
apy followed by 18–30 months of maintenance maintenance chemotherapy, with some groups
therapy (Hunger and Mullighan 2015a). also delivering periodic combined pulses of a
The first phase of therapy, called induction, corticosteroid and vincristine given typically
ranges from 4 to 6 weeks in duration and typi- monthly. The length of therapy varies between
cally consists of a corticosteroid (prednisone or cooperative groups (Stary et al. 2014; Conter
dexamethasone), vincristine, asparaginase, and et al. 2014), and in COG protocols, varies
may contain an anthracycline. Some cooperative between girls and boys, with boys receiving an
groups, such as the COG, employ different induc- additional year of therapy. However, the impor-
tion regimens for B-ALL based on NCI/Rome risk tance of prolonged therapy for boys and the ideal
group, with SR patients receiving only 3 drugs length of maintenance therapy are not known.
(corticosteroid, vincristine, and asparaginase)
and HR patients also receiving an anthracycline.
Other groups use four drugs in all patients. After CNS-Directed Therapy
induction therapy, the vast majority of patients
enter CR, which is absence of clinical signs of With the first introduction of multi-agent chemo-
leukemia in the setting of normal hematopoiesis therapy, most children achieved CR but subse-
(Miller et al. 1983). Post-induction therapy is quently relapsed, and recurrence of disease in the
commonly altered based on early MRD response CNS was common. The recognition of the CNS as
(Borowitz et al. 2008; Coustan-Smith et al. 2000). a leukemia sanctuary site led to the introduction
Subsequent intensive phases of therapy consist of CNS-directed therapy (George et al. 1968).
of additional cytotoxic and lympholytic chemo- Many chemotherapeutic agents do not penetrate
therapeutic agents, including cyclophosphamide, the CNS when given systemically, or only pene-
cytarabine, methotrexate, mercaptopurine, and trate when given in high doses; therefore, the
thioguanine in addition to the four induction response of leukemic blasts in the CNS to
drugs. The combination of drugs used and dose systemic chemotherapy may be negligible, slow,

or incomplete. To overcome this relapse risk, cra- considered high-risk, such as early medullary
nial or craniospinal radiation was added to ther- relapses and all T-ALL relapses (Eapen et al.
apy. The introduction of radiation therapy 2006; Uderzo et al. 1995). The role of HSCT in
dramatically increased long-term survival rates other relapse subsets (late relapse, isolated extra-
but also produced significant long-term toxicity, medullary relapse) and in frontline therapy is less
including deleterious effects on growth and cog- clear; however, some cooperative groups utilize
nitive development (Aur et al. 1971; Krull et al. HSCT in first remission for patients at high risk
2013). In addition to irradiation, the CNS was tar- of relapse (Peters et al. 2015). A potential benefit
geted by administering chemotherapy via the of allogeneic HSCT is induction of a graft-
intrathecal route (injecting chemotherapy into the versus- leukemia (GVL) effect. A recent COG
thecal sac through lumbar puncture). Over time, HSCT clinical trial found a significantly lower
the use of cranial radiation has decreased signifi- risk of subsequent relapse in patients who devel-
cantly with the vast majority of children (80–95%) oped acute graft-versus-host disease (GVHD)
with ALL no longer undergoing irradiation (Vora after allogeneic HSCT, implying GVL played an
et al. 2016). Radiation therapy is more commonly important role in leukemia control (Pulsipher
employed in T-ALL (which has a higher inci- et al. 2014). For chemotherapy-resistant leuke-
dence of CNS disease) and is still used frequently mias, HSCT may improve outcomes through
in B-ALL that presents with CNS disease; how- immune-mediated leukemia cell killing.
ever, some groups have nearly or completely
eliminated cranial radiation with similar out-
comes (Vora et al. 2016; Wilejto et al. 2015; Pui Novel Therapy Approaches
et al. 2009; Veerman et al. 2009). The elimination
of irradiation is often achieved both by the use of Despite advances in therapy for childhood ALL,
CNS-penetrating systemic chemotherapy and by there remains a subset of patients for whom cur-
increasing the number and/or intensity of intrathe- rent treatment approaches are inadequate. For
cal chemotherapy, which is not without neurocog- these children who go on to relapse, there has
nitive effects (Krull et al. 2013; Duffner et al. been very little improvement in outcomes
2014). Nevertheless, the introduction of CNS- (Nguyen et al. 2008; Raetz and Bhatla 2012).
directed therapy into the management of ALL led Two approaches to overcome this obstacle are
to the single largest improvement in overall sur- employed: (1) identification of patients at high
vival for children with ALL (Aur et al. 1971). risk for relapse with consequent augmentation of
therapy (Teachey and Hunger 2013); (2) intro-
duction of novel therapies into relapse regimens.
ematopoietic Stem Cell
H
Transplantation (HSCT)
New Cytotoxic Agents
Approximately 80–85% of children will be cured
with chemotherapy alone; however, for high-risk Most, if not all, of the chemotherapeutic agents
patients who relapse, HSCT is an important com- that currently comprise standard-of-care regi-
ponent of therapy. Many factors influence prog- mens for pediatric ALL were approved by the
nosis after relapse, including immunophenotype, U.S. Food and Drug Administration (FDA)
time to relapse, and site of relapse (bone marrow, 40–60 years ago. Only recently, in the last
extramedullary, or combined) (Raetz and Bhatla 10 years, have new agents been added to the
2012). Relapse during primary therapy suggests armamentarium for pediatric ALL.
resistance to chemotherapy, which is often dem-
onstrated through acquired mutations (Ma et al. Bortezomib
2015). HSCT decreases subsequent relapse risk Bortezomib is a proteasome inhibitor that specifi-
and is therefore recommended for those relapses cally inhibits the 26S proteasome, responsible for

degrading proteins in such key cellular pathways and cyclophosphamide demonstrated an initial
as cell cycle regulation, transcription, and apop- high rate of severe hepatoxicity in 4/8 patients,
tosis (Teicher et al. 1999). It was approved by the prompting amendment of the study to exclude
FDA for refractory mantle cell lymphoma in patients with prior HSCT, viral hepatitis, cirrho-
2006 and multiple myeloma in 2008. sis, and conjugated hyperbilirubinemia (Hijiya
In initial phase 1 clinical trials of bortezomib et al. 2011). Moreover, the incidence of febrile
in pediatric relapsed/refractory ALL, little single- neutropenia and severe infection was high with
agent activity was observed (Horton et al. 2007). this combination (Hijiya et al. 2009).
Due to its mechanism of action, it was suspected Due to its promising efficacy in relapsed pedi-
that bortezomib may sensitize cancer cells to atric ALL, clofarabine was incorporated into the
chemotherapeutic agents (Horton et al. 2006). In current COG phase 3 trial for newly diagnosed
a phase 1/2 study of bortezomib in combination HR B-ALL. However, enrollment onto the
with standard chemotherapeutic agents, activity clofarabine-containing arm was suspended and
was demonstrated in relapsed/refractory pediat- subsequently halted due to prolonged cytopenias
ric ALL, with an overall response rate of 73% and infections. A recent trial of the German
(Messinger et al. 2012). Toxicities include Co-operative Study Group for treatment of ALL
peripheral neuropathy (Richardson et al. 2009) (CoALL) combined clofarabine with asparagi-
and severe lung injury, reported in adults, but not nase for children with high-risk ALL defined by
children, treated with bortezomib (Miyakoshi high MRD at the end of induction, demonstrating
et al. 2006; Chew et al. 2007; Yoshizawa et al. a 61% conversion rate to MRD negativity com-
2014; Akosman 2015). pared to 46% in historical controls (Escherich
Bortezomib is now incorporated into relapse et al. 2013).
reinduction regimens by many pediatric oncolo-
gists and is considered for chemorefractory leu- Nelarabine
kemias. In addition, the current COG phase 3 Nelarabine, a water-soluble prodrug of
trial for newly diagnosed T-ALL is studying bort- the purine nucleoside antimetabolite araG
ezomib in frontline therapy. (9-B-arabinofuranosylguanine), received FDA
accelerated approval for the treatment of relapsed/
Clofarabine refractory T-cell acute lymphoblastic leukemia
The purine nucleoside analog clofarabine was and lymphoblastic lymphoma in 2005. This
the first cytotoxic chemotherapy approved by the approval was based in part on a phase 2 trial con-
FDA for the indication of pediatric ALL in over ducted by the COG showing single-agent activ-
20 years. It received accelerated approval in ity of nelarabine with overall response rates of
2004 for relapsed/refractory pediatric ALL based 55% in first relapse and 27% in second or greater
on a phase 2 study of single agent clofarabine relapse (Berg et al. 2005).
showing a 30% overall response rate in patients A prior phase 1 study of nelarabine in children
refractory to at least two prior regimens (Jeha and adults demonstrated a striking response rate
et al. 2006). in T-ALL, with 54% achieving a complete or par-
Several prior and subsequent studies have tial response (Kurtzberg et al. 2005). Subsequent
demonstrated the efficacy of clofarabine in ALL clinical trials combined nelarabine with standard
(reviewed by Hijiya et al. (2012)). Clofarabine chemotherapy. In a pilot study of nelarabine in
has been studied in combination with cyclo- combination with standard intensive chemother-
phosphamide and etoposide as well as other apy for high-risk T-ALL patients with a slow
chemotherapy regimens, with response rates of early response to therapy, the COG found no
44–58% in relapsed/refractory pediatric ALL increased toxicity with the combination and dem-
(Hijiya et al. 2009, 2011; Locatelli et al. 2009; onstrated similar 5-year EFS rates compared to
Nelken et al. 2016). The phase 2 portion of the patients with a rapid early response (Dunsmore
study combining clofarabine with etoposide et al. 2012).

Significant neurotoxicity has been associated et al. 2009; Clarke et al. 2011; Weston et al. 2013;
with nelarabine. In the initial phase 1 and 2 stud- Roberts et al. 2014). The COG will soon be
ies of nelarabine, the incidence of neurologic incorporating targeted therapies into frontline
events, including peripheral neuropathy, somno- clinical trials via two paths. Patients whose leu-
lence, seizure, ascending paralysis, ataxia, and kemic blasts carry lesions potentially responsive
coma, is high, occurring in 72% of patients on the to ABL kinase inhibition (e.g. fusions involving
phase 1 study (Berg et al. 2005; Kurtzberg et al. ABL1, ABL2, CSF1R, and PDGFRB) will be eli-
2005). However, in subsequent combination tri- gible to receive dasatinib in combination with
als, less neurotoxicity was observed, possibly cytotoxic chemotherapy on the current phase 3
related to the newly diagnosed patient population trial for HR B-ALL, AALL1131 (Hunger and
compared to the heavily pretreated population in Mullighan 2015b). For patients with B-ALL har-
the early studies (Dunsmore et al. 2012; Winter boring lesions potentially responsive to JAK
et al. 2015). kinase inhibition (e.g. lesions in JAK1, JAK2,
Nelarabine was introduced into frontline ther- EPOR, and IL7R), a phase 2 trial of ruxolitinib
apy for T-ALL in the COG randomized phase 3 combined with chemotherapy is in development.
trial, AALL0434. A recent report on the initial Beyond genetic alterations influencing gene
safety phase of that study showed no increase in expression, some leukemias have dysregulation
neurotoxicity on the nelarabine arm compared to of transcription through epigenetic mechanisms.
the control arm (Winter et al. 2015). Efficacy data The epigenome tightly regulates transcription by
from this trial is not yet available. controlling DNA availability to transcriptional
activators and repressors through methylation and
histone formation. Infant ALLs with MLL trans-
Precision Medicine Therapies locations provide one example of hypermethyl-
ation in leukemia (Schafer et al. 2010; Stumpel
As the understanding of the biology underlying et al. 2011). Due to the suspected contribution of
pediatric ALL has expanded, so has the repertoire epigenetic dysregulation to chemotherapy resis-
of therapeutic options (Hunger and Mullighan tance, epigenetic agents are attractive targets
2015b). Next-generation sequencing technolo- (Bhatla et al. 2012). Both histone deacetylase
gies have identified several genetic lesions, inhibitors and demethylating agents are under
thought to either drive leukemogenesis or be investigation in pediatric ALL (Burke et al. 2014).
important for blast survival, in subsets of ALL at
high risk for relapse. Ph+ ALL is one such subset
harboring a driver genetic lesion, the BCR-ABL1 Immunotherapy
translocation leading to constitutive ABL1 kinase
activity. The use of the TKI imatinib in Ph+ ALL The field of immunotherapy for cancer made
established a paradigm for drugs targeting a spe- remarkable strides in several refractory malig-
cific anomaly found in leukemic blasts. nancies and received widespread attention in
Recent genomic studies have identified multi- recent years. This alternative approach is particu-
ple lesions affecting kinases and signaling path- larly attractive for relapsed leukemia or leukemia
ways in a subset of B-ALL termed Ph-like that is refractory to chemotherapy. Decreased
ALL. While some of these lesions are recurring, incidence of relapse is largely responsible for the
many are individually rare. Yet several common improved survival rates for childhood ALL, with
pathways are affected, notably the ABL kinase very little improvement in survival rates for chil-
family and the JAK kinase family, both of which dren who relapse for more than twenty years
can be targeted by TKIs (Roberts et al. 2014). A (Nguyen et al. 2008; Raetz and Bhatla 2012).
few case reports show the benefit of the TKIs These disappointing statistics highlight the need
imatinib and dasatinib in select cases with fusions for alternative therapies with novel mechanisms
resulting in constitutive kinase activation (Deenik of action. Approaches based on the immune

system may overcome resistance mechanisms class BiTE blinatumomab joins an anti-CD19
intrinsic to cancer cells. The three approaches antibody scFv domain with an anti-CD3 scFv
described herein target unique antigens expressed domain, thereby linking CD19-expressing target
on the surface of cancer cells. cells with CD3-expressing T cells (Wolf et al.
2005). Antibody binding engages the T cell cyto-
Antibody Conjugates toxic machinery, leading to target cell lysis.
In the first immunotherapy approach, a monoclo- CD19 is an attractive target for immunotherapies
nal antibody against a specific antigen on malig- due to its near universal expression on B cell
nant cells is created. The monoclonal antibody malignancies, including B-ALL.
can then be conjugated to a toxin or drug, which Blinatumomab has an extremely short half-
is released into the cell upon internalization of life (approximately 2 h). Lack of objective
the antibody, as is the case for the two antibody response with 2- to 4-h intravenous infusion in
conjugates described below. initial studies prompted a change in administra-
Moxetumomab pasudotox (formerly known tion to continuous intravenous infusion in 4-week
as HA22) is an anti-CD22 monoclonal antibody cycles (Nagorsen et al. 2012). The first clinical
conjugated to the Pseudomonas exotoxin trial of blinatumomab to demonstrate efficacy
A. CD22 is an early differentiation antigen was a phase 1 trial in adults with refractory lym-
expressed on the B cell lineage and on 90% of phomas showing a 35% objective response rate
B-ALL blasts. In a phase 1 study of moxetu- (Bargou et al. 2008). Blinatumomab was subse-
momab in pediatric B-ALL and non-Hodgkin quently studied in B-ALL in a phase 2 trial of
lymphoma, objective responses were observed in adults with persistent MRD, with 16/20 (80%)
29% of 17 evaluable patients (Wayne et al. 2011). evaluable patients becoming MRD-negative
Neutralizing antibodies were detected in 14% of within four cycles of treatment (Topp et al.
patients, potentially posing the challenge of resis- 2011). With a median follow-up of 33 months,
tance. The treatment-related toxicity of capillary relapse- free survival (RFS) was 61% (Topp
leak syndrome was dose-limiting in two patients. et al. 2012). Nine patients subsequently received
Inotuzumab ozogamicin is a humanized HSCT, and six remained in remission. Six of
monoclonal antibody against CD22 that has the 11 patients who did not go on to receive
been conjugated to calecheamicin. It has shown allogeneic HSCT remained in remission with
considerable promise in relapsed/refractory a median follow-up of 31 months. A German

B-ALL. A phase 2 study of inotuzumab ozo- phase 2 trial of 36 adults with refractory/relapsed
gamicin in children and adults with relapsed/ ALL showed 69% achieved CR with a median
refractory B-ALL demonstrated an overall RFS of 8.8 months and overall survival (OS) of
response rate of 58% (Kantarjian et al. 2012, 13 months (Zugmaier et al. 2015). Most of the
2013). These results showed remarkable single- long-term survivors received HSCT, but two did
agent activity in this population. Early results of not, receiving additional courses of blinatumamb.
the phase 3 randomized trial of inotuzumab ozo- A larger multi-center phase 2 trial in adults with
gamicin in relapsed/refractory adult B-ALL are relapsed/refractory ALL demonstrated a lower
even higher, with CR rates of 80.7% in the inotu- CR rate of 43% in patients with higher disease
zumab arm compared to 33.3% in the standard- burden at the start of treatment (Topp et al. 2015).
of-care arm (DeAngelo et al. 2015). Toxicities Results of this study led to accelerated FDA
included cytopenias (most commonly thrombo- approval of blinatumomab for relapsed/refrac-
cytopenia) and veno-occlusive disease. tory B-ALL. Finally, initial data from a phase 1/2
dose-escalation trial of blinatumomab in children
Bispecific Antibodies with relapsed/refractory B-ALL showed a CR
This approach links two monoclonal antibodies rate of 39% (Hoffman and Gore 2014).
to form a new class of antibodies termed Notable toxicities associated with blinatu-
Bispecific T-cell engagers (BiTE). The first-in- momab include cytokine release syndrome (CRS)

and neurotoxicity. Significant elevations in cyto- 2013). However, these first reports included small
kine levels related to T cell engagement and pro- numbers of patients. Larger studies have vali-
liferation result in inflammatory symptoms. CRS dated these findings, demonstrating CR rates of
manifests as a prodrome of flu-like symptoms, 70–90%. Importantly, these results have been
including fever, myalgias, headache, anorexia, replicated amongst different groups using dis-
and nausea/vomiting (Maude et al. 2014a). In tinct vectors and CAR designs (Lee et al. 2014;
some patients, these symptoms can progress to a Maude et al. 2014b; Davila et al. 2014). Our
severe systemic inflammatory response, includ- group initially reported a 90% CR rate in 30
ing vascular leak, hypotension, pulmonary patients with relapsed/refractory ALL treated
edema, and coagulopathy (Teachey et al. 2013). with CTL019 on pediatric and adult phase I trials
Reversible neurologic events, including tremor, at the Children’s Hospital of Philadelphia
encephalopathy, aphasia, and seizure, were com- (CHOP) and the University of Pennsylvania
monly seen in patients treated with blinatu- (Penn), respectively (Maude et al. 2014b).
momab (52%), most (39%) were grade 1–2 (Topp CTL019 cells express a CAR composed of anti-
et al. 2015). CD19 scFv, CD3ζ, and 4-1BB domains. In a
Memorial Sloan Kettering Cancer Center
Engineered T Cells (MSKCC) study of 19–28z CAR T cells, Davila
In the third immunotherapy approach, the et al. (2014) reported a similar CR rate of 88% in
patient’s own T cells are reprogrammed to recog- a cohort of 16 adults with relapsed B-ALL. Lastly,
nize and kill cells expressing a particular antigen. Lee et al. (2014) reported a 70% CR rate in an
T cells collected from the patient are engineered intent-to-treat analysis of 20 children and young
to express a chimeric antigen receptor (CAR) adults with ALL treated on the NCI trial. CR
consisting of an extracellular scFv domain rates as high as 90% are unprecedented in this
(derived from a monoclonal antibody) linked to highly refractory population, making these initial
intracellular T cell signaling and costimulatory reports encouraging.
domains. The scFv domain targets an antigen of Engineered T cells have the potential to act as
interest, one expressed on the surface of malig- “a living drug” providing continued protection
nant cells, such that antigen binding redirects the from relapse. The CAR-expressing T cells
T cell to the tumor cell, leading to engagement, a described above are permanently modified;
cytotoxic response, and T cell proliferation. however, these engineered T cells need to per-
Because any cell expressing the antigen targeted sist (the minimum time needed is not known).
by the CAR is killed, an ideal antigen would be Persistence of CAR-modified T cells varies
one that was ubiquitously expressed on malig- across studies and may distinguish CAR designs,
nant cells and unique to malignant cells. While despite similar CR rates. The manufacturing
the ideal antigen may not exist, CD19 comes process and viral vector used for CAR transduc-
close, as its expression is limited to the B cell lin- tion are thought to be important contributors to
eage and, as noted above, it is expressed on most persistence, but the costimulatory domain may
B cell malignancies, including B-ALL. CARs also be an important factor. The CD28 costimu-
directed against CD19 have led the way, demon- latory domain (used in both the NCI and
strating the potential for engineered T cell MSKCC CD19 CARs) is associated with shorter
therapies. persistence, with loss of CAR T cells and recov-
Enthusiasm for the potential of this technol- ery of normal B cells by 1–3 months in both
ogy in B-ALL was spurred by early results of studies (Davila et al. 2014; Lee et al. 2014). We
several ongoing clinical trials of CD19-targeted have observed longer persistence (2 years or
CAR-modified T cells, which showed striking more) with the 4-1BB costimulatory domain.
clinical responses in patients who were no longer The probability of CTL019 persistence in our
responsive to chemotherapy and considered to be ALL cohort at 6 months was 68% (95% CI:
incurable (Brentjens et al. 2013; Grupp et al. 50–92%) (Maude et al. 2014b). B Cell aplasia

provides a surrogate marker of CD19 CAR 2014b). Neurotoxicity ranging from confusion
function as normal CD19-expressing B cells are and delirium to aphasia, global encephalopathy,
also cleared. The longer duration of B cell apla- and seizure has been reported in several CD19
sia (3 years or more) seen with the 4-1BB CAR clinical trials (Davila et al. 2014; Lee et al.
domain suggests continued effector function of 2014; Maude et al. 2014b). In our experience,
CTL019 cells. neurotoxicity resolves without intervention or
Continued optimism stems from the report of apparent long-term sequelae. An on-target off-
durable remissions with CD19-directed CAR- tumor toxicity is B cell aplasia related to deple-
modified T cells. In the initial report describing tion of all cells of the B lineage, which express
the CHOP/Penn cohort of 30 children and adults CD19, and leading to hypogammaglobulinemia
with ALL, sustained remissions of 2–24 months requiring immunoglobulin replacement. Lastly,
were observed in 19 patients (15 with no further although GVHD is a potential concern with acti-
therapy). At a median follow-up of 6 months, vated T cells in patients with a prior history of
EFS was 67% (95% CI: 51–88%) and OS was allogeneic SCT, it has not been reported to date
78% (95% CI: 65–95%) (Maude et al. 2014b). In in these studies (Davila et al. 2014; Lee et al.
an expanded cohort of 53 pediatric patients with 2014; Maude et al. 2014b).
ALL reported at the 2015 American Society of
Hematology Annual Meeting, we observed a CR
rate of 94% and a 6-month RFS of 72% (95% CI: oving Novel Therapies into
M
59–87%) with a median follow-up of 10.6 months Frontline Treatment
(range 1–39 months) (Grupp et al. 2015).
Twenty-nine patients were in continuous remis- As we learn more about the biology of ALL as
sion, with only five of these patients receiving well as the characteristics of these new
subsequent SCT. Short persistence or, more com- approaches, ALL therapy has the potential to
monly, loss of the CD19 epitope (n = 13) led to change significantly. Much of the progress made
relapse in a total of 20 patients. The MSKCC and to improve outcomes for children with ALL
NCI studies reported sustained remissions in the evolved from decreasing the incidence of relapse.
approximately 50% of patients who proceeded to That approach is likely to continue to improve
allogeneic SCT (Davila et al. 2014; Lee et al. outcomes in the future. With ever-increasing
2014). Further studies with expanded cohorts advances in technologies and analyses to not only
and more mature follow-up across CAR designs identify patients at high risk for relapse but also
will be needed to better elucidate differences and discover key features underlying their leukemia,
determine the full potential of engineered T cell it may be possible in the near future to match
therapy. patients with specific therapy schemas best suited
Toxicities of engineered T cells are simi- to their disease. The chemotherapy backbones
lar to those observed with the T cell engaging that brought pediatric ALL outcomes to their cur-
bispecific antibody blinatumomab. CRS, the rent high level will undoubtedly remain an impor-
most notable and serious toxicity, is associ- tant part of therapy, but the addition of new agents
ated with supraphysiologic T cell proliferation targeted against driver genetic lesions or specific
and significant cytokine elevations, as its name leukemogenic mechanisms may improve out-
suggests. Nearly all ALL patients treated with comes further for a subset of patients. Moreover,
highly active CAR-modified T cell therapies the incorporation of approaches with novel
experience some degree of CRS. We and oth- mechanisms, such as immunotherapies, may
ers have reported that severe CRS correlates decrease relapse rates for ALLs that are refrac-
with high disease burden and can be effec- tory to chemotherapy. Pediatric oncology coop-
tively reversed with cytokine blockade by the erative groups are developing approaches to
IL6R inhibitor tocilizumab (Davila et al. 2014; incorporate several of the above novel approaches
Grupp et al. 2013; Lee et al. 2014; Maude et al. into frontline therapy.

Conclusions Aur RJA, Simone J, Hustu HO, Walters T, Borella L, Pratt

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in cancer research when ALL therapy has the A, Bernstein M, Billett A, Kurtzberg J, Reaman G,
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improve the chance of cure when relapse does study of nelarabine (compound 506U78) in children
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Philadelphia chromosome-positive acute lympho-
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Conflicts of Interest Dr. Maude has received consulting
chemosensitivity in childhood B-lymphoblastic leu-
fees from Novartis Pharmaceuticals. Dr. Hunger has
kemia. Blood. 2012;119(22):5201–10. https://doi.
received consulting fees and/or honoraria from Jazz
org/10.1182/blood-2012-01-401687.
Pharmaceuticals, Sigma Tau Pharmaceuticals, and
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Update in Pediatric Oncology:
Section B—Solid Tumors 19
of Childhood
Allison F. O’Neill
The care of pediatric patients with solid tumors continues to improve. The goals of this chapter
is complex given the tissues and organs affected are to focus on the epidemiology, pathophysiol-
by disease, the multidisciplinary nature to clini- ogy, presenting symptoms, work-up, and stan-
cal decision-making, treatment toxicities, and dard treatment for the most common extracranial
the complex medical and psychosocial care solid tumors (focusing predominantly on the
required during and in the aftermath of treat- North American, Children’s Oncology Group
ment. Therapeutic regimens are selected on the approach) while highlighting recent advances in
basis of patient risk-stratification, which for therapy and overall outcomes.
many tumors is tailored to account for disease
histology, extent of spread, and in some cases
molecular profile. Treatment considerations I maging, Biopsy, and Surgical
focus on the primary tumor (i.e. local control) Considerations
as well as metastatic or microscopic circulating
disease (i.e. systemic therapy). Local control can Suspicion of a new solid tumor diagnosis on
consist of surgery, radiotherapy, or a combina- physical exam prompts great anxiety on the
tion of the two. “Neoadjuvant” treatment is the part of the family and patient and a perceived
term given to systemic agents administered prior urgent need for work-up on the part of the treat-
to surgery with the term “adjuvant” assigned to ing physician. However, the work-up for a new
treatment given post-operatively. Over the last diagnosis has migrated, whenever possible, to
decade, goals of therapy have evolved to main- the outpatient setting assuming patient stabil-
tain excellent outcomes for patients with low- ity, familial comfort with outpatient care, and a
risk disease, while reducing overall therapy, reliable primary caregiver. Initial tumor imaging
minimizing toxicity, and improving outcomes with X-ray or ultrasound and attention to labora-
for patients with high-risk disease through treat- tory work are crucial to guide further work-up.
ment intensification. In the era of personalized Pursuit of computed tomography (CT) scans,
medicine and genomic tumor profiling, our magnetic resonance imaging (MRI), or positron
understanding of the molecular drivers of dis- emission tomography (PET) can be deferred
ease as well as targeted approaches to therapy until the patient is further evaluated by a multi-
disciplinary team to assure that the appropriate
considerations (imaging modality and field, ion-
izing radiation dose, use of contrast, and need
A.F. O’Neill, M.D.
Dana-Farber Cancer Institute, Massachusetts, USA for sedation) are met. Biopsy specifics (percu-
e-mail: allison_oneill@dfci.harvard.edu taneous versus open, core versus fine needle,


486 A.F. O’Neill
interventional versus surgical, placement of the located at the bifurcation of the aorta. Tumors
needle track, and procurement of sufficient tis- can metastasize to neighboring lymph nodes,
sue for both diagnosis and genomic studies) are encasing vital structures within the thoracic or
likewise important to consider prior to any proce- abdominal cavities, and spread hematogenously
dure. An experienced oncologic surgeon should to the bone and bone marrow. Neuroblastoma is
be consulted for all upfront or delayed resections rarely familial (1–2% of patients) but when heri-
such that margins, field, and surgical approach table is secondary to a mutation in the anaplas-
are well planned. tic lymphoma kinase (ALK) gene, the PHOX2B
gene (associated with central hypoventilation
syndrome and/or Hirschsprung’s disease), or a
Delivery of Bad News deletion at the 1p36 or 11q14–23 locus (Mosse
et al. 2008, 2004; Satge et al. 2003).
More often than not, initial conversations regard-
ing a potential new diagnosis are performed in
the outpatient setting prior to referral to a sub- Presenting Symptoms
specialty center. An initial introduction to disease
can follow the approach outlined in the literature Presenting symptoms vary substantially depen-
regarding delivery of bad news: (1) acknowl- dent on location and extent of disease. The
edgement of an abnormal finding on exam, labo- most common presenting symptom is that of an
ratory work, or imaging; (2) inability to assign abdominal mass, however smaller, incidentally
the abnormality a name or diagnosis until further discovered adrenal neuroblastomas are often
studies are obtained; (3) anticipation that a diag- not palpable. Symptoms can be caused by mass
nosis will be made and treatments will be avail- effect from the primary tumor and/or metasta-
able; and (4) emphasis on the fact that the family ses. Vital sign changes can include intermittent,
and child played no role, nor had any fault in the low-grade fevers without clear origin, tachypnea
diagnosis (Mack and Grier 2004). While intuitive, or diminished O2 saturations caused by thoracic
this upfront approach will lay invaluable ground- disease or a large abdominal primary causing
work for conversations to follow regarding dis- restrictive lung patterns, tachycardia secondary
ease specifics, treatment plan, and prognosis. to anemia, or hypertension due to tumor cat-
echolamine release or impingement on the renal
vasculature. Physical exam findings can include
Neuroblastoma abdominal distension with a palpable mass,
proptosis or periorbital ecchymoses secondary
Epidemiology, Pathophysiology, to retrobulbar metastases, a Horner’s syndrome
and Genetic Predisposition caused by an apical mass arising from the stel-
late ganglion, or weakness or paralysis second-
Neuroblastoma is the most common extracra- ary to invasion of the tumor into the spinal canal
nial solid tumor affecting approximately 650 (Mahoney et al. 2006). Rarely, bluish discolored
pediatric patients annually in North America skin nodules can be seen but only in a subset of
(Howlader et al. 2012). About a third of cases infants with disease designated as “stage 4S” (see
occur in infancy and 90% of children diagnosed below). Children with periorbital ecchymosis are
are younger than 5 years of age (London et al. occasionally, inadvertently evaluated for non-
2005). The disease can occur in adolescence accidental trauma prior to a diagnosis of neuro-
but is rare and tends to follow a more indolent blastoma (Bohdiewicz et al. 1995).
course. Neuroblastoma arises from cells of neural Rarely, patients can present with a para-
crest origin and can present as a solitary adrenal neoplastic syndrome, presumed immuno-
mass, at a site along the sympathetic chains, or logic, with symptoms that include cerebellar
at the organ of zuckerkandl, a chromaffin body ataxia or opsoclonus/myoclonus (irregular eye

19 Update in Pediatric Oncology: Section B—Solid Tumors of Childhood 487
ovements, cognitive deficits, and psychomotor

m a uniform, prognostic evaluation of tumor tissue
retardation). These symptoms don’t necessarily sampled at diagnosis taking into account the extent
resolve following treatment and are curiously of Schwannian stroma, degree of neuroblastic
associated with neuroblastomas of smaller size maturation, mitoses, and patient age (Shimada
and favorable pathology (Matthay et al. 2005; et al. 1999, 2001; Teshiba et al. 2014). A differ-
Rudnick et al. 2001). Laboratory abnormalities ent approach to classification, the International
can include pancytopenia or anemia secondary Neuroblastoma Risk Group (INRG), focuses
to bone marrow involvement or chronic disease. more on cellular characteristics allowing age
Rarely, patients with rapidly growing tumors and other clinical and molecular characteristics
have an elevated uric acid indicative of tumor to factor into assigned treatment algorithms later
lysis (Milano et al. 2003). As neuroblastoma on (Cohn et al. 2009). The molecular abnormal-
tumors secrete catecholamines, a single-void ity of greatest prognostic value is MYCN copy
urine for elevated catecholamine metabolites number, amplification of which denotes high-risk
(vanillylmandelic acid, VMA, and homovanillic disease (Cohn et al. 2009; Schleiermacher et al.
acid, HVA) can be utilized both as a diagnostic 2012). DNA index, presence of somatic acti-
tool and later for assessment of disease response vating mutations in the ALK gene, expression
to therapy. Additional history may reveal irrita- of neurotrophin receptor kinase B (TrkB), and
bility in excess of baseline, verbalized bony pain, genomic alterations resulting in telomere elonga-
or watery diarrhea secondary to tumoral secretion tion are among additional factors associated with
of vasoactive peptide (Bourdeaut et al. 2009). high-risk disease (Bresler et al. 2014; Maris and
Physicians should have a low threshold of sus- Matthay 1999; Peifer et al. 2015).
picion for further work-up should a child present
with any of the symptoms on this broad spectrum.
Staging
Histology and Molecular Profile Staging for neuroblastoma, as for all solid

tumors, is designed to evaluate sites of known
After preliminary imaging studies are obtained tumor spread.
(per below), percutaneous, core-needle biopsy of As neuroblastoma can invade local structures,
an accessible lesion is pursued to obtain a diag- spread via the lymphatics, and to distant sites via
nosis. In the age of molecular and genomic tumor the blood stream, a comprehensive staging work-
analyses, the need for viable, pre-treatment up is required. Imaging with pan-CT or chest
specimens is of increasing relevance. While stud- CT scan and/or abdominopelvic MRI is required
ies have been performed to estimate the median for evaluation of the chest, abdomen, and pel-
number of needle cores required for a diagnosis of vis. For a subset of infants with small adrenal
soft tissue tumors, the number of cores required masses discovered prenatally, serial ultrasounds
to complete a work-up across solid tumors may be sufficient to follow tumors for regression.
is poorly defined (Acord and Shaikh 2015). Intratumoral calcifications, detected on X-ray or
Neuroblastomas can develop central necrosis CT, are a hallmark of disease but can also be seen
making it difficult to reliably obtain viable tissue. in other diagnoses (Fig. 19.1). Paraspinal tumors
For all of these reasons, some centers have tran- may require more emergent evaluation with spine
sitioned to obtaining tissue via an open approach. MRI to image for spinal cord impingement.
Under the microscope, neuroblastoma tumors are Metaiodobenzylguanidine (MIBG) imaging is
characterized by the presence of small round blue pursued for all patients and consists of injection of
cells, varying in degree of differentiation, upon a a radiopharmaceutical (iodine-123) that localizes
background of nerve fibers, or neuropil. to noradrenergic tissues and illuminates sites of
The International Neuroblastoma Pathology disease. A Curie score is assigned to sites of dis-
Classification (INPC), or Shimada system, allows ease at diagnosis and following therapy to allow a

488 A.F. O’Neill
(stage III); or disseminated disease to distant

lymph nodes, bone, bone marrow, liver, skin, or
other organs except as defined by 4S (stage IV).
Stage 4S disease occurs in infants younger than
12 months who present with a localized primary
tumor and dissemination limited to the skin, liver,
or bone marrow. More recently, the International
Neuroblastoma Risk Group Staging System
(INRGSS) was developed; this system focuses
more specifically on image defined risk factors
(IDRFs) that may preclude a successful surgery
and uses 18 months as a cut-off for 4S disease
(Fig. 19.2) (Pinto et al. 2015). Newer treatment
protocols through the Children’s Oncology Group
(COG) have relied upon the INRGSS approach.
Treatment and Outcomes
Fig. 19.1 Sagittal CT images demonstrating a large left-
Historically, patients with neuroblastoma have
sided retroperitoneal neuroblastoma with internal necrosis
and calcifications. The tumor arises from the left adrenal been risk-stratified taking into account patient
gland and encases the intra-abdominal vasculature age, INPC categorization, ploidy, INSS stag-
ing, and MYCN status. More recent studies have
quantitative measure of avidity and prediction of relied upon the INRG staging system. While
prognosis (Yanik et al. 2013). Patients must take patient risk assignments will continue to evolve,
potassium iodine before and after the injection/ generally, disease falls into one of three catego-
scan to protect thyroid function. Occasionally ries: low, intermediate, or high risk. Patients of
PET/CT scans are pursued for tumors that fail younger age, favorable histology, limited disease,
to illuminate with I-123 (10% of tumors) or that and absence of MYCN tend to fall into a low
require anatomic co-localization as MIBG scans risk category while older age, unfavorable histol-
fail to provide this level of specificity (Sharp ogy and MYCN amplification denote high risk.
et al. 2009). Sampling of the bone marrow from Patients with low-risk disease can be (1) observed,
bilateral iliac crests is also a required evaluation. (2) undergo surgery with subsequent observation,
Staging has historically followed the or (3) receive chemotherapy. Observation with-
International Neuroblastoma Staging System out biopsy has been safely used to treat perinatal
(INSS), which categorizes disease on the basis of small adrenal tumors; on the COG ANBL00P2
surgical resectability (Brodeur et al. 1993, 1988). study 81% of patients demonstrated spontaneous
An over-simplified summary of this staging sys- regression with a 3-year overall survival (OS) of
tem is as follows: localized tumor with gross 100% (Nuchtern et al. 2012). The phenomenon
excision or with microscopic residual (stage I); of tumor regression has also been described for
localized tumor with incomplete gross resection patients with 4S disease, therefore these patients
and ipsilateral nodes negative or localized tumor are often closely observed without treatment.
with or without complete resection and ipsilat- Infant screening programs (assessing for urine
eral nodes positive (stage II); unresectable tumor spot HVA/VMA) have been pursued in the hopes
crossing the midline (defined by the vertebral col- of detecting high risk disease; however, most
umn), localized tumor with contralateral lymph tumors detected fall into this low risk category
node involvement, or a midline tumor with bilat- and will spontaneously regress, thereby ren-
eral extension and infiltration of the lymph nodes dering screening of little benefit (Woods et al.

Fig. 19.2 The Stage Description

International
Neuroblastoma Risk L1 Localized tumor confined to one body
Group Staging System compartment and not involving vital
(INRGSS) with structures as defined by IDRFs*
definition of image
defined risk factors L2 Locoregional tumor with one or more
(IDRFs) IDRFs
M Distant metastases (excluding MS)
MS Metastatic disease in a child <18

months with metastases confined to
skin, liver, and/or marrow
*IDRFs (image defined risk factors): ipsilateral tumor extension within two body
compartments, infiltration of adjacent organs/structures, encasement of major
vessels or brachial plexus, compression of the trachea or central bronchi,
infiltration of the porto-hepatic or hepato-duodenal ligament, infiltration of the
costo-vertebral junction between T9 and T12, tumors crossing the sciatic notch or
invading the renal pedicle, extension of tumor to the base of the skull, intraspinal
tumor extension (>1/3 of spinal canal invaded, leptomeningeal space obliterated,
or spinal cord MRI signal abnormal)
2002; Schilling et al. 2002). A subset of low-risk patients with favorable histology, demonstrating
patients will undergo surgical resection of their a retained 3-year OS of 95% (Baker et al. 2010).
disease and then be observed post-operatively More recently, COG ANBL0531 investigated a
also achieving excellent outcomes (Strother et al. response-based approach to treatment, further
2012). Neuroblastoma remains one of the few tailoring the amount to chemotherapy patients
tumors for which a positive surgical margin may received. While publication remains pending,
remain and does not impact outcome. A small preliminary results have been promising. Patients
subset of low-risk patients, those who are symp- with high-risk disease have an unfortunately poor
tomatic, have unfavorable histology, or have unre- prognosis. Treatment is intensive requiring induc-
sectable progressive disease after surgery, will tion chemotherapy (cyclophosphamide, topo-
receive chemotherapy. Infants with 4S disease tecan, cisplatin, etoposide, cyclophosphamide,
can present with a fulminant course (rapid dis- doxorubicin, and vincristine), surgery, radia-
ease growth and organ dysfunction) also requir- tion, tandem autologous stem cell transplants,
ing chemotherapy. Agents utilized are typically and immune therapy with an anti-GD2 antibody
extrapolated from regimens used to treat interme- and concomitant isoretinoin, the latter of which
diate-risk disease and include carboplatin, cyclo- encourages maturation of residual neuroblastoma
phosphamide, doxorubicin, and etoposide. Even cells to ganglioneuroma. Addition of immune
with the need for chemotherapy, these patients therapy was the most recent therapeutic change
achieve excellent outcomes (Strother et al. 2012). to result in an improvement in 5-year EFS from
For patients with intermediate-risk disease 46% to 66% (Yu et al. 2010). Therapeutic MIBG,
chemotherapy is often given prior to resection. A utilizing a slightly different radioisotype than that
select group of infants with intermediate disease for the diagnostic scans (I-131), has been studied
have been observed following upfront resection, in pilot protocols for patients with upfront high-
but more often than not, these children receive risk disease or poor disease response to therapy;
neoadjuvant treatment (De Bernardi et al. 2009). long-term efficacy has not yet been determined.
COG protocol A3961 investigated outcomes Radiation is occasionally used in emergent sit-
following a reduction in chemotherapy, for uations such as severe respiratory compromise or

490 A.F. O’Neill
spinal cord impingement. As neuroblastoma is an an increased risk for tumor formation and can
exquisitely chemotherapy-sensitive tumor, time have imaging characteristics difficult to differ-
to onset of action of chemotherapy compared with entiate from malignancy (Perlman et al. 2006).
radiotherapy is similar therefore chemotherapy Nephrogenic rests are found in 1% of pediatric
is preferentially pursued when possible. Rapid autopsies, approximately a third of unilateral
referral to a tertiary care center for work-up and Wilms tumor cases, nearly all bilateral cases, and
treatment initiation is therefore prudent. Targeted in patients with heritable causes of Wilms tumor
therapies, i.e. ALK inhibitors for patients with (Beckwith 1993).
exonic mutations, can be considered but have not Renal tumors arise within the kidney, can rup-
been extensively studied given that the fraction of ture through the renal capsule or extend through
patients harboring this mutation is small (Bresler the renal vasculature, spread to regional or con-
et al. 2014). A complete response to therapy by tralateral lymph nodes, or hematogenously to the
INRG criteria includes: no evidence of tumor on lungs. Approximately 10% of Wilms tumors arise
imaging studies, resolved MIBG uptake and res- in the context of a congenital anomaly (hemihy-
olution of urine HVA and VMA elevations. pertrophy or gigantism, urinary tract abnormali-
ties, phenotypic abnormalities including aniridia)
or germline mutations in the WT1 (i.e. WAGR
Kidney Tumors syndrome, Denys-Drash and Fraiser syndrome)
or WT2 genes (Beckwith-Wiedemann) (Narod
Epidemiology, Pathophysiology, et al. 1997; Scott et al. 2006). Wilms tumor has
and Genetic Predisposition also been described in association with germ-
line TP53 mutations, i.e. in individuals with Li
Wilms tumor is the most common pediatric renal Fraumeni Syndrome. Familial Wilms tumors
tumor with approximately 650 cases diagnosed occur rarely and have been reported in associa-
annually in the United States, typically affecting tion with FWT1 or 2 mutations, or inactivating
children less than 5 years of age, and account- CTR9 mutations (Ruteshouser and Huff 2004;
ing for approximately 7% of all childhood Hanks et al. 2014). Additional mutations result-
cancers (Howlader et al. 2012). Renal cell caring in impaired expression of tumor-suppressing
cinoma (RCC), the second most common renal miRNAs have been reported including those of
tumor, is extremely rare and typically affects the DICER1 gene (Palculict et al. 2016).
pediatric patients aged 15–19 years. Apart from
these two tumor types, the differential for renal
tumors is broad and includes: rhabdoid tumors, Presenting Symptoms
clear cell sarcoma, Ewing sarcoma of the kidney,
desmoplastic small round blue cell tumor, renal Children with a primary renal tumor often pres-
synovial sarcoma, anaplastic sarcoma, and con- ent with an acute increase in abdominal size with
genital mesoblastic nephroma (to name a few). or without parental reports of a palpable mass.
This portion of the chapter will focus on the two Nearly half of all children describe vague symp-
most common diagnoses: i.e. Wilms tumor and toms of abdominal pain and may endorse nausea
RCC. While renal tumors typically arise from and vomiting. Gross hematuria occurs in about
one kidney, Wilms tumor can affect one or both 18% of Wilms tumor patients, occasionally con-
kidneys (the latter more common in the context current with incidental trauma making the his-
of a cancer predisposition syndrome) (Porteus tory more difficult to interpret (Green 1985).
et al. 2000; Huff 1998). Nephrogenic rests of Anorexia, fatigue and weight loss can also occur.
the kidney are a benign neoplasm, caused by While many renal tumors can metastasize to the
clustered, retained embryonic kidney precursor lung, respiratory symptoms at presentation are
cells; nephroblastomatosis refers to the presence rare. Vital sign changes typically include hyper-
of diffuse or multifocal rests. These rests denote tension caused by renal vascular involvement

and activation of the renin-angiotensin system. the presence of three distinct tissues reminiscent
Low grade fevers without clear origin can also be of normal kidney development: blastemal, epi-
reported. Laboratory abnormalities can include thelial (tubular), and stromal. Not all tumors
hypercalcemia (more frequently seen with rhab- are triphasic and monophasic patterns may pre-
doid tumors or congenital mesoblastic nephroma) dominate. Anaplastic histology accounts for
and microscopic hematuria on urinalysis about 10% of all Wilms tumor cases and is an
(approximately 25% of patients). Approximately important predictor of survival given an associ-
1–8% of patients presenting with Wilms tumor ated poor response to chemotherapy. Anaplastic
have acquired von Willebrands disease but are Wilms tends to occur more frequently in older
typically asymptomatic (Callaghan et al. 2013). patients or those with bilateral disease (Popov
Children should be carefully evaluated for signs et al. 2011; Hamilton et al. 2011). Focal anaplasia
of associated cancer syndromes, i.e. aniridia, does not carry the same poor prognosis as diffuse
developmental delay, urinary tract abnormali- anaplasia. Germline TP53 mutations have been
ties, or overgrowth. Children with known cancer strongly associated with anaplastic Wilms tumors
predisposition syndromes or hemihyperplasia (Bardeesy et al. 1994). Gains in chromosome 1q
are typically screened for Wilms tumor with are the single most powerful predictor of poor out-
an abdominal ultrasound every 3 months until come across all Wilms tumor histologies (Gratias
6–8 years of age. et al. 2016). Loss of heterozygozity of both 16q
and 1p are also felt to confer a poor overall sur-
vival (Grundy et al. 2005). Confirmation of reten-
Histology and Molecular Profile tion of INI1, immunohistochemical loss of which
is associated with rhabdoid tumors, is important
While biopsy of most pediatric solid tumors is for ruling out a diagnosis of rhabdoid tumor as it
required for diagnosis, molecular profiling, and carries a worse outcome.
risk stratification, hesitation is warranted before
biopsy of a renal lesion. Needling of the renal
capsule in a patient with Wilms tumor is felt to Staging
cause tumor rupture with spillage and upstaging
of disease. For this reason, clinicians must rely Preliminary tumor imaging with abdominal X-ray
upon imaging characteristics working closely or abdominal ultrasound with dopplers can be
with an oncologic radiologist and an onco- informative. Ultimately, chest, abdomen, and pel-
logic surgeon or urologist to determine ease of vis CT with contrast serves to more definitively
upfront tumor resection (as resection of the pri- characterize sites of disease as well as vascular
mary tumor remains a consideration even in the spread. A characteristic “claw sign,” formed by
context of metastases to allow for pre-treatment the rim of residual renal tissue cupping the pri-
evaluation of histology). Biopsy of the mass may mary tumor, is often seen (Fig. 19.3). Abdominal
be required if the primary tumor is not amenable CT can fall short with regards to interpretation
to upfront resection or if radiographic character- of lymph node involvement or characterization
istics are inconsistent with Wilms tumor. of nephrogenic rests. Abdominal MRI can often
Wilms tumors are felt to arise from the clonal better help to differentiate rests from malignant
expansion of a nephrogenic rest. Mutations in tumor (Servaes et al. 2015). Staging of renal
many somatic genes can contribute to this malig- tumors follows a surgical approach which, in
nant transformation including WT1, CTNNB1, oversimplified terms, is as follows: intact, com-
WTX or TP53 (Ruteshouser et al. 2008). Under pletely resected, non-ruptured primary without
the microscope, Wilms tumors are also small, lymph node involvement (stage I); non-ruptured
round, blue cell tumors that are separated into but with regional extension and penetration of
one of two histopathologic categories: favorable the capsule, or involvement of the renal sinus
or anaplastic. Favorable histology demonstrates or vessels if resected en-bloc (stage II); lymph

492 A.F. O’Neill
of 98% (Shamberger et al. 2010). Patients with

stage I disease falling outside of these param-
eters typically receive two chemotherapeutic
agents (vincristine and actinomycin, termed
EE4A) ± radiotherapy depending on whether
anaplastic features are present. Outcomes for
those with favorable histology reach 98% with
the presence of anaplasia conferring a slightly
worse prognosis, ranging from 79% to 89%
(Shamberger et al. 2010). Patients with stage II
disease likewise receive EE4A following tumor
resection however, the presence of focal anapla-
sia earns addition of doxorubicin (DD4A) and
radiotherapy while diffuse anaplasia receives
an even more aggressive regimen (Dome et al.
2006). The focus of the most recent COG trial
studied addition of doxorubicin to patients with
stage I or II disease and favorable histology but
loss of 16q and 1p; incorporation of doxorubicin
for these patients has now become standard.
Fig. 19.3 Sagittal CT images demonstrating a left-sided Patients with stage III disease and favorable
renal tumor obliterating much of the original kidney. An histology and/or focal anaplasia receive DD4A
inferior rim of residual kidney can be visualized and is and flank radiotherapy while those with diffuse
radiographically referred to as a “claw sign.” (arrow) anaplasia are again treated with a more intense
regimen. Typically radiotherapy is limited to
node involvement in the abdomen or pelvis, local the involved flank unless diffuse rupture is sus-
infiltration into vital structures, or tumor rupture pected in which case whole abdominal radio-
either spontaneous or secondary to biopsy (stage therapy is pursued. Outcomes for patients with
III); hematogenous metastatic disease or lymph stage III favorable histology are upwards of 94%
node spread outside the abdomen (stage IV); or while those with diffuse anaplasia fall as low as
bilateral disease (stage V) (Perlman 2005). 50% (Dome et al. 2006). Patients with stage IV
favorable histology disease have, until recently,
received DD4A, with flank and lung radiotherapy
Treatment and Outcomes (Dome et al. 2006; Grundy et al. 2012). The most
recent COG trial (AREN0533) studied addition
The global cure rate for Wilms tumors remains of cyclophosphamide and etoposide to DD4A
excellent with receipt of combination chemo- (termed Regimen M) for patients with favorable
therapy, surgery, and occasionally inclusion of histology and a slow lung nodule response. Early
radiotherapy. Favorable prognosis is linked to results to this trial demonstrated an excellent
histopathologic features (favorable vs. anaplastic 3-year OS of 92%. There is no standard approach
histology), stage, molecular characteristics, and for patients with stage V Wilms tumor; at present
patient age. While chemotherapy plays an impor- treatment is focused on the use of pre-operative
tant role in the treatment of Wilms tumor, surgi- chemotherapy, renal-sparing surgery when pos-
cal removal of disease is crucial for cure. Patients sible, and renal transplantation if required once
less than 24 months of age diagnosed with a stage an extended remission is documented (Breslow
I Wilms tumor of favorable histology weighing et al. 2005). Patients are often treated without
less than 550 g can be observed without addi- undergoing an upfront biopsy; if no response is
tional therapy. These patients can achieve an OS achieved within 12 weeks of treatment initiation,

biopsy is warranted for histologic evaluation and typically demonstrate an advanced stage at
(Hamilton et al. 2011). presentation. They can metastasize to the lung
and brain. Molecularly, they demonstrate loss
of function of the SMARCB1 gene leading to
Other Renal Tumors the abnormal function of the SWI/SNF chroma-
tin remodeling complex which is important for
Renal cell carcinoma (RCC), while the second gene transcription (Eaton et al. 2011). Germline
most common renal tumor in pediatric patients, mutations in SMARCB1 have also been detected
remains rare affecting only four in one million in one-third of cases but are typically de novo;
adolescent children annually. A small subset of these patients are noted to have a worse prognosis
RCCs is familial, associated with an inherited (Biegel et al. 1999). Tumor immunohistochem-
chromosomal translocation involving chromo- istry demonstrates INI1 loss. Stage I and II dis-
some 3 (Wang and Perkins 1984). Others cases ease has been reported to have an OS of 42%.
have been described in associated with von Advanced stage disease remains incurable. EZH2
Hippel-Lindau disease and tuberous sclerosis inhibitors are currently under study given that
(Bruder et al. 2004; Pea et al. 1998). A rare sub- inactivation of SMARCB1 leads to oncogenic
set of RCC, renal medullary carcinoma, has been dependency on EZH2. Clear cell sarcoma arises
seen in association with sickle cell hemoglo- from a unilateral kidney and has the propensity to
binopathy trait (Swartz et al. 2002). RCCs have spread to bone, brain, or soft tissue. Doxorubicin-
also been reported as a consequence of therapy containing chemotherapy, radiotherapy and sur-
in patients previously treated for other malignan- gery are a mainstay of treatment. While patients
cies. Translocation-positive RCCs, involving the with early stage disease fare well (85–95%), out-
TFE3 gene, are a distinct entity seen more com- comes are poor for those with stage IV disease
monly in children (Geller et al. 2015). Children (45%) (Siebel et al. 2006).
with RCC often present with an abdominal mass,
pain, or hematuria. Prognosis is very strongly
linked to stage and lymph node involvement, as Sarcomas
surgical resection with radical nephrectomy is
necessary for cure. Survival rates of ~90% have Bone Tumors
been quoted for stage I–II disease but unfortu-
nately <15% of children with metastatic disease Epidemiology, Pathophysiology,
are cured (Indolfi et al. 2003). Interestingly, and Genetic Predisposition
children with local lymph node involvement but Osteosarcoma and Ewing sarcoma are the two
absence of distant metastases fair better than most common bone tumors affecting pediatric
adults (~75% OS) (Geller and Dome 2004). patients, with approximately 450 cases of osteo-
There are no standard therapies for patients with sarcoma and 120 cases of Ewing sarcoma diag-
unresectable disease. Immune therapies such nosed each year (Howlader et al. 2012). While
as interferon-alpha and interleukin-2 may have both diseases tend to occur in adolescents a
some efficacy and case reports have demonstrated fraction can occur in children <12 years of age.
response to tyrosine kinase inhibitors in pediatric Osteosarcoma tends to originate from the long
translocation-positive disease however global bones surrounding the knee (distal femur, proxi-
outcomes remain poor. ALK mutations should be mal tibia/fibula) but can likewise arise from the
explored in translocation-positive patients given proximal humerus, pelvis, or rarely, the soft tis-
the option for targeted therapy. sues. Ewing sarcoma tumors tend to arise from
Rhabdoid tumors and clear cell sarcomas rep- the diaphyses of the flat bones; these tumors
resent the two most commonly diagnosed renal can more commonly affect the rib (termed an
tumors following RCC. Rhabdoid tumors often Askin tumor of the chest), mid-femur, or pelvis.
occur in very young children (<12 months of age) Ewing sarcomas can likewise arise from the soft

494 A.F. O’Neill
tissues with the trunk being the most common resected during local control surgery. It has been
site; subcutaneous Ewing sarcomas are rare but postulated that failure to resect the needle tract
have an excellent prognosis (Di Giannatale et al. portends a higher risk for recurrence (Andreou
2015). Both tumors have a propensity to metasta- et al. 2011). Histologically, osteosarcoma tumors
size to the lungs or to other bones. Osteosarcoma are unique; tumor cell formation of osteoid
has been described in association with familial is visualized in the specimen. Osteosarcoma
TP53 or Rb gene mutations (the latter of which tumors are separated into one of two subtypes:
confers a risk for ocular retinoblastoma in early central (or medullary) and surface (or peripheral)
childhood but osteosarcoma later in life particu- tumors. Central tumors include conventional
larly following radiotherapy) (Ognjanovic et al. central osteosarcomas (the most common patho-
2012; Wong et al. 1997). Other heritable con- logic subtype), as well as intraosseous low-grade
ditions associated with osteosarcoma include osteosarcomas, telangiectatic tumors, and small-
Bloom syndrome, Pagets disease, and Rothmund- cell osteosarcomas. Surface tumors include par-
Thomson syndrome (German 1997; Grimer et al. osteal low-grade tumors as well as periosteal
2003; Wang et al. 2003). Ewing sarcoma has not low- to intermediate- and surface high grade
been associated with any genetic predisposition tumors. Osteosarcomas are characterized molec-
syndromes. ularly by an exceptionally high number of struc-
tural variants and chromosomal instability (Chen
Presenting Symptoms et al. 2014). Somatic mutations in the TP53 gene
Patients diagnosed with osteosarcoma or Ewing are present in most cases.
sarcoma typically note pain at the site of the Ewing sarcoma tumors are histologically
tumor often paired with a temporally related small, round, and blue (Fig. 19.4) and char-
injury. Pathologic fracture at the tumor site is acterized by diffuse membranous staining for
more common with osteosarcoma and may cor- CD99, a transmembrane protein (Kovar et al.
relate with a worse prognosis (Sun et al. 2015). 1990). A translocation involving the EWSR1
Eventual visualization of a mass at the primary gene and a TET family member (i.e. FLI1 or
site, unless the primary is pelvic, is common. ERG) is reported in 85% of cases (Sankar et al.
Children with Ewing sarcoma may have recur- 2013). Alternative translocations have also been
rent, low-grade fevers, anorexia, or weight loss; reported (i.e. CIC:DUX4); tumors harboring
systemic symptoms are typically lacking in chil- these chromosomal abnormalities while felt to be
dren with osteosarcoma (Bacci et al. 2000a). Vital in the Ewing sarcoma family at present, may be
sign abnormalities may include elevated blood re-categorized going forth as they tend to carry
pressures secondary to pain at the primary tumor a worse prognosis (Smith et al. 2015). Somatic
or sites of bony metastases. While bone tumors mutations in STAG2 and TP53 in classic Ewing
can metastasize to the lung, respiratory symp- tumors have been associated with poor outcomes
toms at presentation are rare. Physical exam find- (Tirode et al. 2014; Crompton et al. 2014).
ings include limitations to range of motion of the
involved limb or joint and/or a palpable extremity Staging
mass. Laboratory abnormalities are non-specific The recommended staging approach for both
however elevated LDH levels have been impli- osteosarcoma and Ewing sarcoma is similar
cated with poor prognosis for patients with both given the pattern of spread for both diseases.
osteo- and Ewing sarcomas (Bacci et al. 2000a; X-rays of the primary site may demonstrate one
Ferrari et al. 2001). of two abnormalities in the periosteum at the
bony cortex: (1) a starburst formation (tenting
istology and Molecular Profile
H of the periosteum caused by calcification and
Percutaneous core-needle biopsy should be pur- bone formation) denoting osteosarcoma or (2)
sued following X-ray and MRI of the primary site onion skinning (lifting of the periosteum) denot-
(see below). Needle tract placement should be ing Ewing sarcoma (Fig. 19.5). An MRI of the
cautiously planned in a region anticipated to be primary site can best delineate the degree of soft

Fig. 19.4 Under the microscope, Ewing sarcoma tumors, importance of obtaining additional immunohistochemical
like many other childhood malignancies, are small round and molecular studies to make the diagnosis. This figure is
and blue in appearance. The similarity between tumors on courtesy of Antonio R. Perez-Atayde, M.D., Ph.D.
hematoxylin-eosin (H&E) staining underscores the
a b
Fig. 19.5 Radiographs demonstrating characteristic periosteal reactions in patients diagnosed with (a) osteosarcoma
(sunburst) and (b) Ewing sarcoma (onion skinning)

496 A.F. O’Neill
tissue, joint, and bony involvement and can help Patients with lung metastases must undergo tho-
with local control planning. For osteosarcoma, racotomies for removal of disease that does not
the bone above and below the primary tumor resolve with chemotherapy. The EURAMOS-1
should be imaged to rule out skip metastases (European and American Sarcoma Study Group)
(Kager et al. 2006). A chest CT is warranted for trial investigated the addition of ifosfamide and
evaluation of lung metastases. More recently, use etoposide to the standard MAP backbone for
of PET scan in Ewing sarcoma has gained favor patients with poor tumoral necrosis; addition of
both as a means of evaluating the primary site these agents did not impact outcome (Marina
of disease as well as assessing for bony involve- et al. 2016). Low-grade osteosarcomas can be
ment (Newman et al. 2013). Osteosarcoma, treated with wide resection alone (Grimer et al.
while PET avid, still more traditionally relies 2005). Nearly 80% of patients with extremity
upon the use of bone scan to evaluate for bony osteosarcoma can be treated with limb-sparing
spread (Byun et al. 2013). Staging of Ewing procedures to avoid amputation (Bacci et al.
sarcoma traditionally involves assessment for 2000b).
marrow involvement with bilateral bone marrow Pre-treatment factors dictating outcome in
aspirates and biopsies. However, patients with patients with Ewing sarcoma also include tumor
single-site disease are highly unlikely to have site, size/volume, and the presence of metasta-
isolated marrow spread therefore a shift from ses (Cash et al. 2016; Rodriguez-Galindo et al.
this paradigm may occur. (Kopp et al. 2015). 2007). Given that Ewing sarcoma tumors are
Staging of bony tumors departs from the more exquisitely sensitive to chemotherapy, treatment
traditional surgical or imaging based approaches response is likewise an important prognostic fac-
utilized for other tumors. Prognostically, high- tor (Paulussen et al. 2001; Wunder et al. 1998).
grade osteosarcomas and Ewing sarcoma tumors Treatment hinges upon systemic chemotherapy
fall into one of two categories: metastatic or and surgery and/or radiotherapy for local control
non-metastatic. (the latter for positive margins, an unresectable
tumor, or lung metastases) (Donaldson 2004; Liu
Treatment and Outcomes et al. 2011). Unlike for osteosarcoma, outcomes
Pre-treatment factors dictating outcome in are equivalent for patients receiving surgery
patients with osteosarcoma include primary versus radiotherapy for local control of the pri-
tumor site, size, and the presence of metastatic mary tumor; surgery is prioritized when possible
disease as all of these factors impact the ability to avoid the late effects associated with radio-
to perform a complete resection (Donati et al. therapy (DuBois et al. 2015). Results from the
2004; Pakos et al. 2009; Harris et al. 1998). As COG AEWS0031 trial delivering interval com-
osteosarcoma tumors are not very radiosensitive, pressed chemotherapy every 2 weeks, alternating
complete surgical resection is crucial for cure. between vincristine, doxorubicin, and cyclophos-
Axial skeletal tumors and those of large size phamide and ifosfamide, etoposide demonstrated
carry a poor prognosis; patients with bilateral an improvement in event-free survival to 73% at
pulmonary metastases, unresectable skip metas- 5 years (Womer et al. 2012). A recent pilot study
tases, and bony metastases fare worse (<20% (COG AEWS1031) incorporating cyclophos-
OS). High grade osteosarcoma of either cen- phamide and topotecan, agents efficacious in
tral or surface etiology requires systemic che- the relapsed setting, to upfront use demonstrated
motherapy and surgical resection. Patients with tolerability when incorporated with interval com-
single-site, surgically resectable disease can pressed therapy (Mascarenhas et al. 2016). There
achieve a 65% OS. Standard of care chemother- have been no recent improvements in overall sur-
apy consists of cisplatin, doxorubicin, and high- vival for patient with metastatic disease (<30%).
dose methotrexate (MAP); 90% necrosis of the An ongoing COG trial (COG AEWS 1221) is
primary tumor after induction cycles of chemo- investigating the use of an anti-IGFR (insulin-
therapy has been linked to a lower rate of recur- like growth factor receptor) antibody combined
rence (Kim et al. 2007; Anninga et al. 2011). with conventional chemotherapy. High dose che-

motherapy with hematopoietic stem cell rescue individual under 40 years of age should prompt
has been studied for patients with high risk of concern for a hereditary cause, most notably Li
relapse and has demonstrated little proven benefit Fraumeni Syndrome (Li and Fraumeni 1969;
(Meyers et al. 2001). Diller et al. 1995) Anaplasia in RMS cases has
Local control options have advanced dramati- also been linked to germline TP53 mutation car-
cally over the last few decades; while amputation riage (Hettmer et al. 2014). Large birth weight and
for extremity tumors was a previous standard, gestational size have been linked to an increased
limb-sparing procedures with use of metal pros- incidence of embryonal RMS (Ognjanovic et al.
theses and/or bony allografts are increasingly 2010). While other, hereditary cancer syndromes
pursued. Internal or external hemipelvectomies have been implicated, they are paired to rare sub-
with reconstruction remain promising for the sets of non-RMS tumors and will not be further
treatment of pelvic primaries. Rotationplasty, a explored in this chapter.
technique best suited for patients with a distal
femur primaries (typically osteosarcoma) requir- Presenting Symptoms
ing an above-the-knee amputation, remains an Given the range of tissues from which these
approach requiring specialized skill but allow- tumors can arise, symptoms are largely depen-
ing for excellent post-surgical functionality (Han dent upon the site of the primary tumor, degree
et al. 2016). of local invasion to adjacent structures, and
metastases. Dependent upon histology, patients
may present with a slow, indolently growing
Soft Tissue Sarcomas lesion (synovial sarcoma) or a rapidly enlarging
mass. Pain at the sites of metastases may also be
Epidemiology, Pathophysiology, reported. Vital sign changes can include hyper-
and Genetic Predisposition tension secondary to pain, tachycardia secondary
Soft tissue sarcomas fall into one of two catego- to anemia (of chronic disease or due to bone mar-
ries on the basis of histology: rhabdomyosarcoma row involvement), or weight loss. Physical exam
(RMS) and non-rhabdomyosarcoma (non-RMS). findings include palpation of the primary mass,
These tumors are of mesenchymal origin: i.e. which is often firm and immobile. Patients with
striated muscle (rhabdomyosarcoma), smooth the botryoid variant of RMS may have a tumor
muscle, connective, nerve, or vascular tissue and mimicking a “cluster of grapes” protruding from
account for approximately 7% of all childhood a body orifice such as the vagina, bladder, or
malignancies (Pappo and Pratt 1997; Gurney nasopharynx.
et al. 1995). Soft tissue sarcomas can arise in
any age group with certain histologies preferen- istology and Molecular Profile
H
tially affecting different age ranges. For example, Percutaneous core-needle biopsy should be
alveolar RMS is more commonly seen in adoles- pursued from the primary tumor site or a meta-
cents while embryonal RMS is more typically static site if more readily amenable to needle
seen in younger children with a peak incidence in access. RMS can be divided into three histo-
the 0–4 year age range (Ognjanovic et al. 2009). logic categories: embryonal (which accounts for
Non-RMS tumors more typically affect adoles- approximately 60–70% of cases), alveolar, and
cents and adults. RMS tumors most commonly pleomorphic or anaplastic. Embryonal tumors
involve the head and neck region, genitourinary typically involve the head, neck or GU track but
tract, and extremities while non-RMS tumors can occur at any site (Parham and Ellison 2006).
typically arise from the trunk and extremities Alveolar RMS account for approximately 20% of
(Crist et al. 1995; Maurer et al. 1993; Dillon et al. RMS tumors and have a propensity to arise from
1992). Both tumors can spread to regional or dis- the extremities, trunk and perineum (Parham and
tant lymph nodes, or hematogenously to lung and Ellison 2006). Pleomorphic RMS is rarely seen
bone. RMS tumors have the capability to spread in pediatric patients. Molecularly, approximately
to bone marrow. A diagnosis of sarcoma in any a third of embryonal RMS tumors demonstrate a

498 A.F. O’Neill
Ras pathway mutation (Chen et al. 2013). These nostic and therapeutic significance of regional
tumors can also contain anaplasia, more com- lymph node spread (Kayton et al. 2008; Alcorn
monly seen in children with TP53 mutations et al. 2013; Andreou et al. 2013).
(Hettmer et al. 2014). 70–80% of alveolar RMS RMS follows a complex staging algorithm
cases harbor a translocation between the FOXO1 (stage I through IV) determined by the tumor’s
gene and the PAX3 or PAX7 genes (Barr et al. primary site, size, and the presence or absence of
2006). regional lymph nodes or distant metastases. The
Non-RMS tumors include a wide range of tumor’s primary site is deemed either favorable
histologies including: alveolar soft part sar- or non-favorable. Oversimplified, stage I tumors
coma, clear cell sarcoma, dermatofibrosarcoma are of favorable site without distant spread, stage
protuberans, desmoid fibromatosis, epitheliod II or III tumors are of unfavorable site (and of
sarcoma, infantile fibrosarcoma, inflammatory variable size and lymph node involvement) and
myofibroblastic tumors, malignant peripheral stage IV tumors are metastatic. Tumors are like-
nerve sheath tumors, and synovial sarcomas (to wise grouped by their degree of resectability:
name only a few). Each has a unique histologic completely resected with clear margins (group
appearance, some have unique imaging charac- I), resected with microscopic margins and/or
teristics, and many have a characteristic chromo- with involved but resected lymph nodes (group
somal translocation. Tumor grade is based upon II), gross residual disease (group III), and distant
cellularity, cellular pleomorphism, mitotic activ- metastases (group IV). The stage and group of
ity, necrosis, and invasion (Parham et al. 1995). each tumor is subsequently coupled with histology
(embryonal or alveolar) to determine the patient’s
Staging risk status (Fig. 19.6). Non-RMS tumors are risk-
Imaging of RMS and non-RMS tumors relies stratified by tumor grade, the presence or absence
upon the use of MRI both for delineation of the of metastases, tumor size, and surgical margins.
soft tissues as well as for radiation planning given
that patients who require radiotherapy for an Treatment and Outcomes
unresectable primary receive doses based upon Prognostic factors for RMS include age at
diagnostic tumor volumes (Wolden et al. 1999). diagnosis, tumor size, and site of primary dis-
Chest CT should likewise be obtained to evalu- ease. Patients >9 years or <1 year, with tumors
ate for lung metastases. For patients with a para- >5 cm, or alveolar histology have a worse prog-
testicular primary, thin-cut abdominopelvic CT nosis (Crist et al. 1995; Malempati et al. 2011;
images should be obtained to evaluate the size Ferrari et al. 2010; Meza et al. 2006). Treatment
and shape of retroperitoneal nodes and a retro- for RMS tumors typically involves receipt of
peritoneal lymph node dissection should be pur- chemotherapy (with the regimen dependent
sued for patients >10 years of age (Wiener et al. upon risk status) and local control by means of
2001). PET scan is now routinely used to help surgery, radiotherapy or a combination of the
verify sides of nodal involvement as well as for two. Use of radiotherapy is reserved for alveo-
the detection of bony metastases (Federico et al. lar tumors (even if completely resected), resid-
2013; Grant et al. 2010). Patients with a diagno- ual disease after tumor resection, inoperable
sis of RMS must also undergo bilateral bone mar- tumors, metastases, or the presence of involved
row aspirates and biopsies. For patients with a lymph nodes. Tumors are resected at diagnosis
parameningeal RMS tumor, brain/spine MRI and if possible; this approach is pursued only if the
lumbar puncture are likewise warranted. Sentinel tumor can be removed without disfigurement or
node biopsy is recommended at diagnosis for all functional compromise. Low risk patients (25%
patients with RMS and for a handful of patients of patients) are those with embryonal tumors in
with non-RMS (dictated by histology: epitheliod, favorable sites that have been grossly resected,
synovial, clear cell for example) given the prog- embryonal tumors of the orbit, or localized


a Site Classification Sites

Favorable Orbit, head and neck (non-
meningeal), genitourinary (non-
bladder, non-prostate), biliary
tract/liver
Unfavorable Parameningeal, bladder/prostate,
extremity, trunk and retroperitoneum
(non-biliary tract/liver), other
b
Risk Histology Stage Sites Group
Low Embryonal 1 Favorable I, II, III (orbital)
2, 3 Unfavorable I, II
Intermediate Embryonal 2, 3 Unfavorable III
Alveolar 1, 2, 3 I, II, III
High Embryonal or Alveolar 4 IV
Fig. 19.6 Rhabdomyosarcoma follows a complex stag- vs. unfavorable sites of disease. Table (b) delineates the
ing algorithm contingent upon site of disease, histology, risk stratification schema used to select an appropriate
and surgical resectability. Table (a) delineates favorable chemotherapeutic regimen
embryonal tumors in an unfavorable site that treatment regimen for high-risk patients with the
have been grossly resected. Low risk patients goal to diminish toxicity and maintain quality of
can achieve survival rates greater than 90% when life (Weigel et al. 2016).
treated with vincristine and actinomycin (VA), Treatment of non-RMS patients is dichoto-
vincristine, actinomycin, and cyclophosphamide mized depending on the presence or absence
(VAC), or shorter-duration VAC with transition of metastatic disease and is modeled after
to VA ± radiation if tumors are incompletely the approach laid forth in a recent COG trial
excised (Raney et al. 2011; Walterhouse et al. (ARST0332) with use of ifosfamide and doxo-
2014). Intermediate risk group patients (50% rubicin for all risk categories (Spunt et al. 2014).
of patients) are those with embryonal RMS of Low risk patients are those with grossly resected,
unfavorable sites with gross residual disease or non-metastatic disease of either (1) low histologic
non-metastatic alveolar RMS. The most recent grade and any tumor size or (2) high histologic
COG trial ARST0531 found no improvement in grade but small tumor size (<5 cm). Patients with
outcome (3-year OS ~85%) for patients treated low-grade histology can be observed status-post
with VAC alternating with vincristine and irino- resection even if microscopic positive margins
tecan (VAC/VI) but fewer toxicities, therefore remain. Patients with high-grade histology and
this regimen has been adopted as standard and microscopic margins receive adjuvant radio-
will serve as the backbone in the next clinical therapy. Intermediate risk patients have either
trial (Crist et al. 2001). For high-risk patients, grossly resected, high-grade histology, and
those with metastatic disease of either histology, tumors >5 cm, or unresectable high-grade tumors
outcomes remain quite poor at less than 50% for which delayed resection is planned. Those
(Breneman et al. 2003). Treatment intensification with grossly resected disease receive adjuvant
(inclusion of doxorubicin, irinotecan, ifosfamide, chemo- and radiation therapy while those with
and etoposide) has failed to improve outcomes, a planned resection receive neoadjuvant chemo-
only delaying relapse, therefore VAC/VI has and radiation therapy. Finally, high risk patients
been adopted in many institutions as a standard are those with metastatic d isease: (1) of low grade

500 A.F. O’Neill
histology, completely resected (observation), Presenting Symptoms

(2) of low or high grade histology and grossly As germ cell tumors typically arise from the
resected (adjuvant chemotherapy and radiother- midline, patients with a mediastinal tumor can
apy) or (3) that remains unresectable (neoadju- present with a persistent cough, difficulties lying
vant treatment). Patients meeting guidelines for flat, or other non-specific respiratory symp-
observation can achieve 99% OS, those receiving toms. Others can present with abdominopelvic
adjuvant radiotherapy 100% OS, those receiv- distension, pain, and a palpable abdominal or
ing adjuvant chemoradiotherapy 81%, and those testicular mass. Vital sign changes may include
requiring neoadjuvant treatment 66% OS (Spunt tachypnea, altered O2 saturations, or hyperten-
et al. 2014). Patients with unresectable, meta- sion secondary to pain. Yolk sac tumors produce
static non-RMS tumors have a poor outcome. alfa-
fetoprotein (AFP) while germinomas and
choriocarcinomas produce beta-human chorionic
gonadotropin (beta-hCG). Most pediatric malig-
Rare Tumors nant germ cell tumors have a component of yolk
sac tumor thereby causing an elevation in AFP.
Germ Cell Tumors Fetal teratomas, while technically benign, can
be diagnosed in utero and result in hydrops fata-
Epidemiology, Pathophysiology, lis or a difficult delivery (Heerema-McKenney
and Genetic Predisposition et al. 2005). Clinicians must be cognizant that in
Germ cell tumors (GCTs) arise from primor- a child <3 years of age, baseline AFP levels are
dial germ cells that fail to migrate to the gonads elevated due to residual circulating AFP synthe-
during embryonic development (Dehner 1983). sized by the yolk sac and fetal liver. This can pose
As a result, the vast majority grow in close a challenge for interpreting elevated AFP levels
approximation to the midline (mediastinum, at diagnosis or when following decline of levels
retroperitoneum, coccyx). Germ cell tumors fall during treatment (Blohm et al. 1998).
into two categories on the basis of their loca-
tion: gonadal and extragonadal. More globally, istology and Molecular Profile
H
these tumors can be mature (benign), immature, Percutaneous, core-needle biopsy is pursued
or malignant. Tumors can be further subdivided to sample tumors of the mediastinum or abdo-
into histologic categories: germinomas (dysger- men/pelvis unless the lesion is readily amenable
minoma of the ovary or seminoma of the tes- to upfront resection. If the mass is testicular
tis) or nongerminomas (teratoma—mature or or ovarian, care must be taken when planning
immature, yolk sac or endodermal sinus tumors, the surgical approach. Radial orchiectomy as
choriocarcinoma, gonadoblastoma, embyronal opposed to a transscrotal biopsy is preferred to
carcinoma, or mixed tumors). GCTs account avoid scrotal contamination while ovarian tumor
for approximately 3% of cancers in children mobilization, peritoneal washes, and lymph node
less than 15 years of age with teratomas more sampling are crucial both to avoid spillage and to
frequently occurring in the fetal or neonatal age complete the staging work-up. Biopsy of a mass
group (Kaatsch et al. 2015). Extracranial GCTs might miss immature elements but histology
account for approximately 14% of cancers in coupled with serum tumor markers can help com-
adolescents aged 15–19 years. DICER1 muta- plete the diagnostic picture. Mature teratomas
tions have been described in association with a typically occur in the ovary and at extragonadal
small subset of germinomas (juvenile granulosa locations while immature teratomas more fre-
cell tumors) (Schultz et al. 2011). Patients with quently occur in young children at extragonadal
Klinefelter or Turner syndrome are at increased sites and in the ovaries of peri-pubertal females
risk for GCTs as are children with cryptorchi- (Gobel et al. 1998; Heifetz et al. 1998). Malignant
dism (Dexeus et al. 1988; Tanaka et al. 1994; GCTs contain frank malignant tissues with a frac-
Johnson et al. 2009). GCTs have a propensity to tion of mature or immature teratoma also present.
spread to the liver, bone, brain, and lung. Testicular GCTs in early childhood can be either

teratomas or malignant pure yolk sac. Testicular Treatment and Outcomes

tumors in adolescents can be of either pure or Prognosis for pediatric GCTs typically depends
mixed histology. Ovarian GCTs include benign upon histology, patient age, disease stage, and
teratomas, immature teratomas, dysgerminomas, primary disease site (Frazier et al. 2015). Patients
yolk sac tumors or mixed tumors. Extragonadal with non-sacrococcygeal mature teratomas and
tumors in young children are often present at birth stage I immature teratomas, as well as mature
or during early childhood and are typically benign and immature sacrococcygeal teratomas can be
(Malogolowkin et al. 1990). However, malignant observed following surgery with a >95% OS
GCTs most frequently occur in the mediastinum (Gobel et al. 1998; Marina et al. 1999). Resection
in older children and adolescents. Age greater of a sacrococcygeal mass requires removal of
than 11 years and advanced stage of disease have the coccyx in an effort to minimize the risk of
been demonstrated to be poor prognostic factors tumor recurrence (Gobel et al. 1998). Higher
(Marina et al. 2006; Bokemeyer et al. 2002). stage immature teratomas do not respond well to
chemotherapy and typically portend a poor prog-
Staging nosis (Norris et al. 1976). The half-life of AFP
The work-up of a patient with known or pre- is approximately 7 days; when post-operative
sumed malignant GCT includes MRI of the observation is perused, values are serially fol-
abdomen ± spine dependent upon the site of lowed to assure return-to-normal.
tumor origin, chest CT, and either radionuclide Patients with completely resected gonadal
bone scan or PET scan to assess for bony dis- tumors (stage I) can be closely observed fol-
ease or to further delineate sites of soft tissue lowing resection with excellent survival rates
involvement. A brain MRI might also be con- approaching 100% (Rescorla et al. 2015; Dark
sidered to rule out intracranial disease. Disease et al. 1997). The treatment of higher stage
staging is highly dependent upon histologic sub- malignant gonadal GCTs and all extragonadal
type. The Children’s Oncology Group stages GCTs typically requires surgical resection of
non-germinomatous testicular GCTs as follows: disease, when possible, and administration of
limited to the testis (stage I), transscrotal orchiec- platinum- based chemotherapy (cisplatin, eto-
tomy with tumor spillage or microscopic disease poside and bleomycin termed PEB) to achieve
in the scrotum or high in the spermatic cord with an OS >90% (Rogers et al. 2004; Cushing
failure of tumor markers to normalize post-oper- et al. 2004). Treatment of higher stage testicu-
atively (stage II), gross residual disease or retro- lar disease in adolescents (>15 years) typically
peritoneal lymph node involvement (stage III), follows an adult treatment approach involv-
and distant metastases (stage IV). Retroperitoneal ing RPLND, risk stratification on the basis of
lymph node dissection is not required in males histology, tumor markers, measure of serum
<15 years of age but is routinely pursued in older LDH, and cisplatin-based chemotherapy with
adolescents and adults (de Wit and Fizazi 2006). weekly bleomycin (termed BEP) (Williams
The COG ovarian GCT staging is similar: local- et al. 1987). The combination of carboplatin,
ized disease that is completely resected with no etoposide, and bleomycin, as a means by which
evidence of capsular rupture and negative peri- to limit platinum exposure and lessen ototoxic-
toneal cytology (stage I), microscopic residual, ity, has been studied in the UK; outcomes using
capsular invasion, or microscopic lymph node this regimen were comparable to cisplatin-
involvement (stage II), gross residual disease based therapies but a head-to-head trial has not
including cytologic evidence of tumor cells in yet been performed (Mann et al. 2000). The
ascites (stage III), and disseminated disease successful treatment of extragonadal disease is
(stage IV). Extragonadal, extracranial GCTs fol- highly dependent upon patient age and disease
low a surgical algorithm similar to that for other location. Patients with stage I or II disease can
solid tumors distinguishing completely resected achieve a 90% OS while those with stage III or
disease from that with microscopic, gross mar- IV disease can achieve an 80% OS. As noted,
gins, or metastatic disease. patients >12 years of age with mediastinal

502 A.F. O’Neill
d isease have a worse outcome with less than may demonstrate irritability in excess of baseline.
60% OS (Bokemeyer et al. 2002). Similar to malignant GCTs, HB and up to two-
thirds of HCCs secrete AFP. Clinicians must
again be cognizant that in a child <3 years of age,
Liver Tumors baseline AFP levels are elevated due to residual
circulating AFP synthesized by the yolk sac and
Epidemiology, Pathophysiology, fetal liver. This can pose a challenge for interpret-
and Genetic Predisposition ing elevated AFP levels at diagnosis or when fol-
Liver tumors comprise approximately 1% of all lowing decline of levels during treatment (Blohm
pediatric malignancies (Meyers 2007; Czauderna et al. 1998). A small subset of HB tumors likewise
et al. 2001). Hepatoblastoma (HB) accounts for secrete hCG leading to precocious puberty (Eren
greater than two-thirds of all tumors while hepa- et al. 2009). Additional laboratory abnormalities
tocellular carcinoma (HCC) is the second most include thrombocytosis, given that HB has been
common. Other primary pediatric liver malignan- associated with higher levels of thrombopoeitin
cies include undifferentiated sarcoma, rhabdoid (Komura et al. 1998).
tumors, and angiosarcoma but these diagnoses are
exceedingly rare. HB is traditionally diagnosed istology and Molecular Profile
H
in children less than 3 years of age while HCC is Percutaneous core-needle biopsy is again recom-
more typically diagnosed in adolescence. Liver mended when making the diagnosis of HB and
tumors can directly extend through the portal or HCC. Biopsy of “normal” liver tissue is useful to
hepatic vasculature or advance locally to regional obtain concurrent with tumor biopsy to aid with
lymph nodes. Distant metastases most frequently evaluation of liver dysfunction or an underlying
occur in the lung but rarely can affect the bone predisposition for HCC. Tumors can demonstrate
or brain. Very-low-birth weight premature infants a range of histologies: HB tumors can be epithe-
are at substantially higher risk of developing hep- lial (including pure fetal with or without mitoses,
atoblastoma than those of average birth weight mixed embryonal/fetal, macrotrabecular, and
(Ikeda et al. 1998). Inheritance of an APC gene small cell undifferentiated) or mixed epithelial
mutation (familial adenomatous polyposis) has and mesenchymal (with teratoid or non-teratoid
been linked to a higher risk of developing hepa- features) (Lopez-Terrada et al. 2014). Small cell
toblastoma, particularly multifocal disease, as is undifferentiated (SCU) features, with the pres-
a diagnosis of Beckwidth- Weidemann (Gupta ence of rhabdoid elements (with immunohisto-
et al. 2013; Maas et al. 2016). Hepatocellular car- chemical INI-1 loss), are associated with a low
cinoma has been linked to Hepatitis B or C infec- AFP and portend a worse prognosis (Meyers
tion, the former less common since institution et al. 2009; Trobaugh-Lotrario et al. 2009). HB
of widespread vaccination programs, and other tumors are characterized by abnormalities in
more rare hereditary syndromes predisposing to the WNT pathway with the majority of tumors
underlying liver dysfunction (e.g., glycogen stor- demonstrating CTNNB1 activation mutations
age disease, biliary atresia, alpha-1-antitrypsin or deletions (Eichenmuller et al. 2014). Tumors
deficiency, etc.) (Tajiri et al. 2011; Bhadri et al. with mixed HB and HCC histologies have also
2005; Labrune et al. 1997). been described in late childhood and early ado-
lescence and are termed transitional cell tumors
Presenting Symptoms or HCC not otherwise specified (HCC NOS)
Pediatric patients with HB or HCC typically (Lopez-Terrada et al. 2014). These tumors are
present with an enlarged abdomen and a palpable variably chemotherapy responsive and por-
abdominal mass. Vital sign changes may include tend a poor prognosis. HCC tumors are of two
tachypnea secondary to restrictive lung indices or specific histologies: classic and fi brolamellar.
hypertension secondary to pain. Younger children Classic HCC can arise de novo or in the c ontext

of underlying liver dysfunction secondary to liver tumor trial (AHEP0731) sought to adopt
infection or hereditary metabolic syndromes. PRETEXT staging in addition to surgical stag-
These tumors are characterized by chromosomal ing. The staging system for HCC in pediatric
instability, TP53, and TERT mutations (Sumazin patients is not as well defined but generally fol-
et al. 2016). Fibrolamellar HCC, conversely, lows a surgical staging approach.
arises in the context of a healthy liver and is not
associated with an elevated AFP. These tumors reatment, Outcomes, and Surveillance
T
have recently been found to uniformly harbor a Prognosis is clearly linked to surgical resectabil-
DNAJB1: PRKACA chimeric fusion transcript ity, histology, PRETEXT/stage, vascular involve-
(Honeyman et al. 2014). ment, and serum AFP levels although recent
retrospective data suggests that age may like-
Staging wise play a role (Fuchs et al. 2002; Czauderna
Liver ultrasound can be obtained as first-pass et al. 2016). Poor prognosis has been linked to
imaging for a new liver tumor. A more focused an upfront unresectable tumor, metastatic dis-
evaluation of the liver parenchyma is sub- ease, a low AFP (<100 ng/mL), and small cell
sequently required and best achieved by the undifferentiated features. Cisplatin is a staple
use of MRI with Eovist contrast agent, which chemotherapeutic for the treatment of HB with
allows delineation of disease, differentiation addition of doxorubicin for higher risk cases.
between benign and malignant entities, and an Surgical resection of the primary tumor is cru-
evaluation for multifocality (Meyers et al. 2012; cial for cure. Patients with completely resection
Asayama et al. 2016). Chest CT is required (stage I), pure fetal histology with <2 mitoses
for evaluation of pulmonary metastases. Liver per 10 high powered fields can be observed post-
tumors are staged by one of two methods: the operatively with excellent outcomes approach-
COG Evans surgical staging approach or the ing 100% (Malogolowkin et al. 2011). Those
European imaging-based PRETEXT method. with stage I or II upfront resected disease of
COG surgical staging, greatly oversimplified, other histologies (excluding small cell undiffer-
relies upon the ability to resect a tumor at diag- entiated) have, on COG protocols, traditionally
nosis: completely resectable (stage I), resectable received adjuvant chemotherapy consisting of
with positive microscopic margins (stage II), cisplatin, 5-FU, and vincristine (C5V). An arm
unresectable—i.e. attempts would leave macro- of the current COG AHEP0731 trial focused on
scopic disease behind (stage III), and metastatic a reduction in the number of cycles administered
(stage IV). PRETEXT staging relies upon the post-operatively with the goal to maintain excel-
anatomic and radiographic division of the liver lent survival rates of ~90%; results to this arm of
into four quadrants. Tumor involvement of one the trial remain pending (Douglass et al. 1993;
quadrant (PRETEXT I), two adjoining quad- Ortega et al. 2000). COG AHEP0731 also studied
rants (PRETEXT II), three adjoining or two non- the addition of doxorubicin to C5V (i.e. C5VD)
adjoining quadrants (PRETEXT III) or all four for patients with unresectable stage III disease
quadrants (PRETEXT IV) is established at diag- and low stage SCU disease. While survival for
nosis and demonstrated to be prognostic (Brown this cohort previously approximated 70–80%, the
et al. 2000; Maibach et al. 2012; Roebuck et al. preliminary 3-year OS for patients on protocol
2007; Aronson et al. 2005). Suffixes are likewise has been reported at 92% (publication pending).
applied to the PRETEXT algorithm to further The increasing use of liver transplantation in this
describe tumor extent: portal venous involve- patient population has likewise contributed to
ment (P), vena cava or hepatic venous involve- improved survival rates however the long-term
ment (V), extrahepatic disease (E), multifocality outcome of children undergoing liver transplan-
(F), rupture (R), lymph node involvement (N) tation remains under study (Malek et al. 2010;
or metastases (M). The most recent COG Tiao et al. 2005).

504 A.F. O’Neill
Patients with metastatic disease are often chemoembolization (TACE), while utilized rou-
prescribed a doxorubicin-containing regimen tinely in adult patients as a bridge to resection
(C5VD) given that their outcomes remain quite or liver transplantation, remains under study for
poor. COG AHEP0731 studied the addition of both the pediatric HB and HCC populations.
vincristine and irinotecan (VI) to C5VD. Results
demonstrated a 62% 3-year OS, improved from
the historically reported outcomes of 20–50% Other Tumors
for this cohort (Katzenstein et al. 2017). Our
European colleagues have focused their study on Retinoblastoma
eliminating doxorubicin from patients perceived Retinoblastoma is a tumor arising from the retina
to be at lower risk (PRETEXT I-III) while esca- commonly affecting children less than 3 years
lating therapy intensity for those with metastatic of age. It is frequently detected by families and
disease (Perilongo et al. 2009). A recent pilot for outpatient practitioners and can be successfully
patients with metastatic disease receiving dose- treated if diagnosed early. Families often report
dense cisplatin (i.e. weekly), doxorubicin, and the absence of a red reflex or a “white” appearing
carboplatin achieved a 79% 3-year OS (Zsiros pupil (leukocoria) in photographs with outpatient
et al. 2013). Controversy still remains regard- practitioners identifying the same phenomenon
ing the appropriate treatment approach for lung on exam. Eye tumors are “grouped” according to
metastases and whether metastatectomy is war- size, degree of retinal and vitreous involvement,
ranted to improve overall survival (O’Neill et al. as well as location and proximity to the foveola
2017). For patients undergoing liver transplan- and optic disc (Shields et al. 2006). Metastatic
tation, metastatectomy is typically pursued to disease to the intracranial space or distantly to the
render patients free of extrahepatic disease. The bone marrow is possible although rare in devel-
upcoming Pediatric Hepatic tumor International oped countries. Exams under anesthesia are cru-
Therapeutic Trial (PHITT) will be the first inter- cial for grouping, as is the use of MRI to define
national collaborative trial aimed at determining disease extent and evaluate for intracranial spread.
the optimal treatment approach for patients with For higher risk patients (i.e. those with extraocu-
localized and metastatic disease (both for HB lar disease or more aggressive histology), lumbar
and HCC), while allowing an opportunity for the puncture and bilateral bone marrow aspirates are
study of biology and toxicity. pursued. Children with retinoblastoma should
The treatment of hepatocellular carcinoma be tested for a germline Rb mutation as carriage
remains challenging; while 50% of patients dictates risk for “bilateral” disease involving the
respond to upfront chemotherapy, only a small contralateral eye, “trilateral” disease involving
fraction become resectable. Current treatment the pineal gland, disease at a young age, multiple
regimens employ use of cipslatin and doxoru- tumors, and secondary cancers (Abramson et al.
bicin with or without sorafenib given data in 1998). Use of intra-arterial and intravitreous che-
adults that sorafenib single-agent therapy is life- motherapy has been adopted as a means by which
prolonging (Schmid et al. 2012; Llovet et al. to preserve vision and avoid enucleation and sys-
2008). Immunotherapy (PD-1 inhibition) has temic chemotherapy whenever possible (Gobin
shown promise in adult HCC but further study is et al. 2011).
warranted (El-Khoueiry et al. 2015). Liver trans-
plantation is utilized conservatively for patients Adrenocortical Carcinoma
with disease confined to the liver (Patel et al. Adrenocortical carcinoma is a rare but aggres-
2012). While patients with upfront surgically sive cancer arising from the adrenal gland and
resectable disease can achieve a greater than 80% affecting adolescents and adults. As these tumors
OS, those with metastatic disease have a dismal can secrete cortisol, aldosterone, testosterone or
prognosis of <15% OS (Katzenstein et al. 2002; estrogen, findings on exam may include cushin-
Czauderna et al. 2002). The role for transarterial goid features and hirsutism (cortisol), high blood

pressure (cortisol and aldosterone) acne (testos- work to be done in the treatment of pediatric
terone) or irregular menstrual periods in females solid tumor malignancies.
(testosterone, estrogen). Single site, surgically
resectable disease carries an excellent progno-
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Update in Pediatric Psychiatry
20
Sabina Abidi
Introduction of subsyndromal symptoms that have yet to con-

vert to meeting full criteria for diagnosis. This
Roughly 30–50% of severe and persistent psychi- offers an opportune and exciting time to not only
atric illnesses have their onset in childhood and assist in managing symptoms with which youth
adolescence (Girolamo et al. 2012). Psychiatric and family present, but also offer indicated pre-
disorders are now revealed as one of the major vention to reduce the risk for conversion to more
contributors to the burden of disease in young severe and chronic psychiatric outcomes in adult-
people age 10–24 years and are now projected to hood. A clinical staging framework of illness,
be one of the five most common cause of morbid- often used in general medicine, proposes that ill-
ity, mortality and disability in young people ness symptoms exist on a continuum of severity
(Gore et al. 2011). The overall prevalence of any with normal variants of experience on one end
psychiatric disorder with severe impairment and ranging to severe illness with associated morbid-
distress in adolescents is roughly 22% with most ity and mortality on the other. The early interven-
in fact meeting criteria for more than one disor- tion model purports that the emergence of early
der (Kessler et al. 2005). Psychiatric disorders signs of mental concern may represent an oppor-
that are specific to onset in childhood interfere tunity to not only treat the current episode or pre-
with navigation of developmental milestones for sentation but also recognize that early states may
the child and oftentimes significantly disrupt represent modifiable risk factors to progression
family dynamics and function leading to deterio- to later and more serious stages of illness. This
ration of protective factors. The childhood and concept is relatively new in child and adolescent
adolescent age is a critical period of active synap- psychiatry and offers a more optimistic outlook,
tic pruning and maturation of brain circuitry and supported by research on the potential for early
function and thus is significant not only in terms intervention and treatment of psychiatric disor-
of the potential impact psychiatric symptoms can ders (McGorry et al. 2007a, b).
have on current functioning but also on the risk of Identifying a psychiatric diagnosis in children
future impairment. Youth often present help and particularly the adolescent not only requires
seeking to mental health services with functional the awareness of active brain development and
impairment and distress secondary to a mixture acknowledgment that the impact of and symp-
toms themselves are fluid and subject to change
over time but also accurate knowledge of the
S. Abidi, M.D., F.R.C.P.C. diagnostic criteria that must be met in full with-
Department of Psychiatry, Dalhousie University,
Halifax, NS, B3K 6R8 Canada out which a diagnosis cannot be made. The recent
e-mail: Sabina.Abidi@iwk.nshealth.ca fifth edition of the Diagnostic and Statistics


514 S. Abidi
Manual of Mental Disorders (DSMV) appropri- tifying and initiating evidence-based treatment
ately emphasizes the dimensional perspective or recommendations.
continuum of symptom presentation and clini- Interviewing and assessing for child/adoles-
cians should familiarize themselves with this (or cent psychiatric illness requires a vulnerability
the most widely accepted diagnostic guide rele- and honest curiosity on the part of the clinician.
vant to their population) to aid in clarifying diag- One must have a sharp awareness of the develop-
noses (American Psychiatric Association 2013). mental, emotional, intellectual and social stage of
The dimensional perspective outlined in the the child or youth at the time as these impact the
DSMV differs from previous editions that had a significance of the presenting symptom and its
more categorical approach which risks classify- implication regarding illness identification. For
ing pathologic normal variants of behavior and example, a 5 year old child presenting with hal-
lowers the detection of atypical presentations that lucinations may be a developmentally normal
do not fit specific criteria as noted above. The variant phenotype as compared to a 16 year old
DSMV adopts a more developmentally oriented youth, where the symptom may be a marker of
approach conceptualizing all psychiatric disor- illness. Further, hallucinations in a 16 year old
ders in a lifespan perspective and is organized as with the intellectual and emotional capacity of an
such. The new edition of the DSM equally 8 year old might carry a different significance.
emphasizes the need to consider other possible Moreover, cultural, spiritual and family beliefs
aetiologies of symptom presentation such as and behaviors must all be factored in when
medical, medication-related, stress- induced or attempting to clarify the significance of symp-
related, substance use, potential risk syndromes tomatology. Symptoms must always be appreci-
and comorbidities before making a diagnosis. ated in the context within which they occur and in
Furthermore, essential to meeting diagnostic cri- conjunction with collateral observations from
teria is a noted change in function or impairment family or primary carers or other sources with
in navigating developmental milestones that per- whom the patient spends time. The clinician must
sists and is directly associated with the symptoms be curious and humble in the pursuit of possible
presentation (Table 20.1). Due to the fluidity by illness presentations recognizing that more often
which psychiatric symptoms can present in chil- than not, the thoughtful and comprehensive
dren and youth oftentimes directly influenced by assessment and gathering of collateral will guide
both developmental stressors and environmental accurate conclusions and the most appropriate
triggers, meeting full diagnostic criteria accord- treatment recommendations to pursue. Adopting
ing to the DSMV is generally regarded as the heightened sensitivity and awareness of possible
threshold for making reliable and accurate psy- illness presentations within the context of the
chiatric diagnoses, the first step to towards iden- family and remaining mindful of risk for poten-
tial worsening as the child ages is crucial to fos-
Table 20.1 Points to consider when attempting to distin- tering stage-specific intervention decisions to
guish signs and symptoms of illness from normal variants maximize positive outcome.
of behavior
Is the symptom persistent
Is the symptom a significant change from baseline hanges in the DSMV for Child
C
Is the symptom inappropriate to the context and Adolescent Psychiatric
(developmental/emotional/cognitive age) in which it Disorders
occurs
Does the symptom cause social, academic,
interpersonal and functional impairment The new edition of the DSM has reorganized its
Does the symptom present in more than one setting or structure to better reflect the experiences of
with more than one person symptoms of illness in children and youth. The
Is there any other identifiable etiology or cause for the manual has adopted a lifespan approach to men-
symptom/change tal disorders reflected in the organisation of

20 Update in Pediatric Psychiatry 515
Table 20.2 The new organisation of the DSM V is conceptualization encompassing the three previ-
sequenced with the developmental lifespan in mind recog- ous diagnoses from the DSMIV edition (perva-
nizing that vulnerabilities to illness can occur at any stage
sive developmental disorder not otherwise
Neurodevelopmental disorder specified, autistic disorder and Asperger’s syn-
Schizophrenia spectrum and other psychotic disorders drome) as one single condition with symptom
Bipolar and related disorders presentation that is thought to exist on a contin-
Depressive disorders
uum of differing levels of severity.
Anxiety disorders
Changes in age of onset of impairment for
Obsessive-compulsive and related disorders
ADHD (from prior to age 7 to age 12) and lower
Trauma- and stressor-related disorders
diagnostic threshold reflects an attempt to
Dissociative disorders
decrease false negatives and capture a wider
Somatic symptom disorders
range of children impaired by the illness.
Feeding and eating disorders
The previously termed mental retardation
Elimination disorders
(MR) has been abandoned for the newer term
Sleep-wake disorders
intellectual disability (ID) due to a history of
Sexual dysfunctions
pejorative connotations with the MR label.
Gender dysphoria
Disruptive, impulse control and conduct disorders
Emphasis is placed on the requirement for more
Substance use and addictive disorders
comprehensive patient assessment and measures
Neurocognitive disorders of adaptive functioning along with IQ to meet
Personality disorders diagnostic criteria.
Paraphilic disorders
Neurodevelopmental disorders typically diagnosed in
childhood are first, followed by those with onset in ado- Disruptive, Impulse-Control
lescence and finally later life and Conduct Disorders
disorders of childhood towards the beginning, The criteria for oppositional defiant disorder
those that tend to have onset in adolescence in the (ODD) and conduct disorder (CD) have not
mid-section and those that present later in life changed substantially in the DSMV. However,
towards the end (Table 20.2) (American requirement of increased duration, consistency
Psychiatric Association 2013). In the effort to and frequency of symptom criteria now exists to
enhance early identification of illness- related account for the fact that many behaviors associ-
symptoms and improve diagnostic accuracy the ated with ODD in fact occur quite commonly in
DSMV has integrated new disorders as well and developing children and adolescents who do not
some changes. Below are outlined a few of the have nor develop psychiatric illness. For exam-
recent changes that influence child and adoles- ple, for children under the age of 5, the behavior
cent psychiatric care: must now be identified on most days for a period
of at least 6 months consecutively and consis-
tently. Symptoms should also be pervasive across
Neurodevelopmental Disorders settings, as an indicator of severity.
Diagnoses including attention deficit hyperactiv-

ity disorder (ADHD), autism spectrum disorder rauma and Stressor-Related
T
(ASD), learning disorders, intellectual disability Disorders
(ID) and motor and communication disorders
fall under the new neurodevelopmental disorders This is a new category outlining disorders that
category emphasizing a delay or deviation in have as their core exposure to a traumatic or
brain development that influences symptoms stressful event as an etiological factor leading to
presentation. The ASD diagnosis is a now a new expression of the illness. Included are reactive

516 S. Abidi
attachment disorder, disinhibited social engage- voidant/Restrictive Food Intake

A
ment disorder, posttraumatic stress disorder Disorder (ARFID)
(PTSD), acute stress disorder and adjustment dis-
orders. While the diagnostic criteria for PTSD is Pica, rumination disorder and the new diagnosis
relatively unchanged for adolescents and adults, ARFID are now listed in the new Feeding and
DSMV now recognizes that preschool children Eating disorders chapter. ARFID is a new diag-
(under age 6) are exposed to traumatic events and nosis attempting to capture children and adoles-
may manifest the symptoms of PTSD differently. cents who suffer significant weight loss secondary
The guide fosters enhanced awareness and recog- to substantial restriction and experience conse-
nition of symptoms by outlining a specific sub- quent physiological and psychological distress
type for this age group with criteria more in but are distinct in that they lack body image pre-
keeping with their developmental stage and cog- occupation, drive for weight loss or thinness or
nitive level. fear of weight gain typically associated with
Another recent change is the conceptualiza- anorexia or bulimia nervosa.
tion of disinhibited social engagement disor-
der which shares with reactive attachment
disorder the requirement for neglect (absence Research Criteria
of adequate caregiving in childhood) as a
causal factor, but the two differ in terms of life Section III of the DSMV outlines conditions that
course, response to intervention and manifes- are of clinical concern warranting further
tation and are considered separate conditions research and delineation. Pertinent to child and
as a result. adolescent psychiatry is the recognition of non-
suicidal self-injury (NSSI)—self harm without
the intention of suicide- and internet gaming dis-
Depressive Disorders order as conditions of significant relevance to the
population warranting further review. The atten-
Disruptive mood dysregulation disorder uated psychosis syndrome (APS) is a new con-
(DMDD) is a new diagnosis in the DSMV sideration underscoring the neurodevelopmental
developed to more accurately represent children etiology of psychotic disorders highlighting the
and adolescents who present with hyperarousal clinical at-risk (earliest) stage of illness onset
and severe, chronic non- episodic irritability that with further research may be reliably identi-
with frequent temper outbursts. These children fiable and a focus of intervention and possibly
were often misidentified as having bipolar dis- prevention.
order, or the early stages of it, despite lack of Clinicians should familiarize themselves with
traditional manic symptoms. Evidence from the changes in the DSMV as they pertain to child/
longitudinal studies suggests that these children adolescent psychiatry. The following outlines
and youth in fact tend to develop other psychiat- some of the more common and impairing pediat-
ric conditions such as major depressive disorder ric psychiatric disorders that oftentimes first
or anxiety disorder and not bipolar disorder. present for care within a primary health care set-
Family history data supports this finding further ting. Emphasis in this chapter is on those that are
contradicting the previous assumption that lifespan diagnoses, the course of which follow a
severe and chronic irritability in children repre- continuum of phenotypic severity, namely
sents an alternative presentation or risk for bipo- ADHD, depression and bipolar disorder, anxiety
lar disorder (see below for further discussion of disorders and psychotic spectrum disorders.
DMDD). Updates in regards to diagnosis and treatment are

reviewed as are any pertinent points of clinical cognitive measures of attention, distractibility
concern that have arisen in the last decade in and impulsivity if indicated, are the main tools
child/adolescent psychiatry. used for diagnosing ADHD. Interviews must be
obtained from the patient combined with collat-
eral from multiple sources including parents,
ttention Deficit Hyperactivity
A teachers and other caregivers. Interviewing any
Disorder (ADHD) one of these sources without the other is not a
reliable means to ensuring symptoms are present
Prevalence in more than one setting and not due to another
cause, e.g. medical, stress related, substance-
ADHD is one of the most prevalent psychiatric dis- induced. Oftentimes obtaining a psychoeduca-
orders in children under age 18 affecting about tion or cognitive assessment if possible can assist
3–4% of youth (Polanczyk et al. 2015). It is a neu- in clarifying learning disabilities or deficits in
rodevelopmental disorder that has its onset in child- cognitive function that could contribute or
hood and is characterized by at least 6 months of a explain symptoms. Further, a comprehensive
persistent pattern of developmentally inappropriate psychiatric assessment is important in identifying
impairing inattention and/or hyperactivity and other potential causes for symptoms that might
impulsivity that result in functional impairment in mimic ADHD such as anxiety, OCD, depression
multiple settings. A range of 50% and 80% of chil- or psychosis. ADHD carries significant comor-
dren have continued symptoms of ADHD into ado- bidity with other illnesses namely autism spec-
lescence; in about 40%, symptoms continue into trum disorder, communication and specific
adulthood (Polanczyk et al. 2015; Bussing et al. learning or motor disorders, intellectual disabil-
2010). Criteria as outlined in the DSMV include ity, tic disorders, OCD and anxiety disorders
specifiers that capture how symptoms can manifest making clarification of diagnosis difficult. Some
in older adolescents and adults recognizing the children also have a temperamental phenotype
marked heterogeneity in presentations and that phe- marked by aggressiveness, irritability and mood
notypes are not necessarily stable over time. lability. Recognition and intervention is impera-
tive as untreated ADHD can lead to compounded
negative outcomes in several life domains (Jensen
Diagnosis and Steinhausen 2015; Taylor et al. 1996).
ADHD shows marked heterogeneity at clinical,

etiological and pathophysiological levels making Treatment
diagnosis based on a pattern of phenotype diffi-
cult. Furthermore, the clinical interview in con- Parent skills training, behavioral therapy, school
junction with objective standardized scales1 and adjustments and academic and school environ-
ment accommodations are first line of treatment
Standardized scales and screening tools for symptoms of
1
(multisystemic therapy) particularly for chil-
ADHD are not required for diagnosis. Use however can dren under the age of 6 (except for very severe
assist clinicians in supporting a clinical diagnosis and
monitoring efficacy of psychological and pharmacologi-
complex cases where consultation with pediat-
cal interventions. Scales such as the Child Behavior ric psychiatry colleagues and suggestions for
Checklist–Attention Problem (CBCL-AP) scale, the pharmacotherapy might be warranted) but
Conners Rating Scale–Revised (CRS-R) and the SNAP highly encouraged for young people of all ages
[Swanson, Nolan and Pelham Teacher and Parent Rating
Scale], and BASC [Behavior Assessment Scale for
in combination with medicine if warranted
Children can be useful (Chang et al. 2016). (Thapar 2016).

518 S. Abidi
There is strong empirical support for the use of and weight loss, emotional lability and irritability
psychostimulants (methylphenidate, dexmethyl- (particularly in younger children or those with
phenidate, mixed amphetamine salts, dextroam- developmental delay). For some, a rebound lability
phetamine, and lisdexamfetamine) as first line and escalation of ADHD symptoms can be seen
treatment for symptoms of ADHD. The combina- with wearing off of the medication that might war-
tion of medicine with behavioral therapy can pro- rant consideration of an alternate trial (Thapar 2016;
vide benefit with comorbid and associated Giles and Martini 2016). Considering strategies to
symptoms as well as level of functioning (The MTA manage side effects in the face of positive response
Cooperative Group 1999). All p sychostimulants are to psychostimulants are important. Involving dieti-
either methylphenidate or amphetamine derivatives cian colleagues to assist with managing intake and
which among other things, enhance neurotransmis- diet and monitoring growth and recommending
sion of dopamine. There is growing evidence for the good sleep hygiene techniques to manage insomnia
use of non-stimulant formulations as augments or assists in managing not only side effects but also
second line with slightly decreased efficacy. Of the symptoms of illness that worsen with lack of nutri-
non-stimulant medications, atomoxetine is a selection and sleep. Elevations in heart rate and blood
tive norepinephrine reuptake inhibitor; Clonidine pressure have also been associated with stimulant
and Guanfacine are selective alpha-adrenoceptor use. There is however as yet no evidence of
agonists (Thapar 2016; Hirota et al. 2014). increased risk for cardiac complication even in
Generally, the response rate to psychostimu- those with family history of cardiac disease second-
lants for symptoms of ADHD is 60-70% with ary to psychostimulants (Correll et al. 2011).
equivalent efficacy between the methylphenidate Despite this, good clinical practice dictates inquiry
and amphetamine-based medications. At least about family history of cardiac disease, congenital
30% experience adverse effects and roughly 15% cardiac conditions and complications to identify at-
require a switch to an alternate medication as a risk children. Routine ECGs are not indicated how-
result of side effects (Thapar 2016; Faraone ever clinical indication may warrant consultation
2009). There is no reliable patient profile that with cardiology colleagues prior to initiation of psy-
helps identify preferential response to one formu- chostimulant medication. Non stimulant medica-
lation or another thus selection among options is tions differ in terms of side effects with less
based on practical issues such as cost, dosing fre- pronounced effects on sleep and appetite and reports
quency and availability. There is no clear thera- of gastrointestinal distress, sedation and mood
peutic dose window for stimulants; it is important changes. As per other medications that affect sero-
to start at a low dose and titrate upwards every 1–3 tonin metabolism, atomoxetine carries a boxed
weeks targeted to symptoms and tolerance of side warning regarding a small risk of suicidal thinking
effects. If one class of psychostimulant is ineffec- that warrants psychoeducation and attention for the
tive, a trial of the alternate class is reasonable. For clinician, patient and family. Due to the effect of the
those with intolerant side effects a switch to a alpha-agonists on cardiovascular system, monitor-
non-stimulant formulation or adjunctive use with ing of blood pressure and heart rate, particular if in
lower stimulant doses is indicated. The effect combination with psychostimulants reflects good
sizes for guanfacine and clonidine as monother- practice. For optimal outcome a combination of
apy are smaller. However use of these in combina- medication, psychoeducation and support plus
tion with stimulants for those who are suboptimally behavioral management for the child along with
treated with (or can only tolerate lower doses of) parenting skills training2 for the family is key.
stimulants can be effective (Thapar 2016; Faraone
2009; Giles and Martini 2016). Clinicians need to
be mindful however of the potential for increased The Incredible Years (Kessler et al. 2012) is one example
2
side effects with polypharmacy. of a multicomponent parenting skills program. IY empha-

sizes opportunities for active involvement, reinforcement
All stimulant formulations have similar adverse
of positive behavior and setting clear limits all of which
effect profiles, the most common among which have proven successful in treating disruptive behaviors
include delayed onset of sleep, appetite suppression associated with ADHD in the family system.

Clinical Point within the first year, however depression in

childhood and adolescence is often the first epi-
The diagnosis of ADHD, as per all psychiatric sode of the illness that continues into adulthood
disorders often is based on reported symptoms with high rates of recurrence: follow-up studies
alone; there are no biological tests. There is cur- report 50–70% within 5 years without effective
rently no evidence for increased population rates intervention (March et al. 2004). Twenty-five
of ADHD despite societal opinion, yet the pre- percent of adolescents report subthreshold
scription rate of pharmacological intervention for symptoms of depressive disorder that signifi-
ADHD across high income countries has cantly impact emotional, social and academic
increased in recent years (Giles and Martini functioning; at the same time the subsyndromal
2016). Despite having clear-cut diagnostic crite- presentation carries increased risk for later
ria, there is risk of over diagnosis (and underdiag- development of the full blown disorder (Klein
nosis) and inappropriate use of pharmacological et al. 2009). Moreover, those who meet diagnos-
intervention. Certainly this risk underscores the tic criteria carry increased rate of comorbidities,
need for diligent and rigorous as well as patient substance misuse and physical health problems.
expert assessment. In adolescents, suicide is often a consequence of
Of concern in terms of side effects is growth depression and is the second leading cause of
retardation secondary to psychostimulant and death for youth age 12–17 in North America.
secondary appetite suppression. Monitoring of The prevalence for depression is lower in
growth parameters is essential during treatment younger children as compared to adolescents
and if needed potential use of drug holidays to but rises sharply around age 12; by age 18 the
offset risk for impaired growth rates may be lifetime prevalence of a major depressive disor-
warranted. Psychostimulants are drugs of abuse der reaches 20%; higher in girls (about 17%)
certainly and prescribing clinicians need be than boys (about 7%) (Klein et al. 2009;
wary of this particularly in youth and families at Avenevoli et al. 2015).
risk. In such cases use of non-stimulant formu-
lations may be preferable; there is no evidence
that use of stimulants for ADHD predisposes Diagnosis
children/youth to addiction or concurrent
disorders. There are clear genetic underpinnings to depres-
ADHD presentations for care are rarely sim- sion which shows increasing heritability from
ple; more often than not are complex with comor- childhood to adolescence; the biological corre-
bidities and complicating factors. Consultation lates are increasingly being uncovered. Diagnosis
with colleagues in pediatric psychiatry is often is often complicated due to the clinical heteroge-
warranted and welcomed to best clarify course of neity with which symptoms of depression can
action that will optimize outcomes for the youth occur in children and youth, with multiple inter-
and family. nal and external risk factors contributing to the
presentation, the weight or clinical significance
of which is individual and difficult to predict.
Depression Studies show that those with stronger familial
risk may be inherently more sensitive to psycho-
Prevalence social risk factors or adversity contributing to
risk for manifestation of symptoms via the gene-
Depression has been identified as one of the environment interplay (Thapar et al. 2012).
leading causes of global disability by the World Symptoms that might herald the onset of depres-
Health Organization (WHO) (Gore et al. 2011; sion are outlined in Table 20.3 and are important
World Health Organization 2009). Early identi- to consider when screening. Standardized, reli-
fication and treatment in youth predicts a remis- able screening tools for depression in children
sion in 60–90% (Dunn and Goodyer 2006) and youth are widely available and useful in

520 S. Abidi
Table 20.3 Symptoms that might warrant screening for The most common differential diagnosis in
depression in youth children and youth is that the presentation of
What it might look mood change is a developmentally normal
Symptom like response to an adverse childhood experience,
Irritability/depressed mood Short temper, new trauma or grief. Most youth will experience sad-
negativistic attitude,
difficult interactions ness and have varying degrees of irritability and
with peers, new impaired vegetative symptoms in response to
onset substance use stressors. Of concern however is the fact that
Poor concentration and Poor performance at many youth who meet criteria for depression are
attention school, decline in missed. Major depressive disorder (MDD) is dis-
grades
tinguished by the intensity of the presenting
Loss of interest Withdrawal from
previously enjoyed symptoms, the duration, and presence with other
activities and peers, symptoms according to DSMV criteria along
family with a consistent and persistent level of impair-
Anhedonia/loss of energy Withdrawal, ment of functioning that outweighs that expected
isolation, frequent
in response to the stressor. Furthermore, symp-
absences
toms of depression can occur without identifiable
Insomnia//hypersomnia Restlessness or
fatigue environmental stressor.
Guilt, low self-esteem, Crying, sadness, Comorbidity is the norm for adolescents
cognitive distortions avoidance with depression the risk for which increases
Loss of appetite/increased Change in with severity of symptoms. Comorbidity com-
appetite appearance, body plicates identification and treatment and impairs
habitus
long term outcomes. Two-thirds have at least
Psychomotor retardation Unable to perform
assigned tasks
one comorbid psychiatric disorder and in
Thoughts of suicide Isolation, 10–15%, two or more. Anxiety, ODD and sub-
avoidance, crying, stance use disorders are particularly common;
self harm almost 20% of adolescents with depression also
meet diagnostic criteria for generalized anxiety
identifying those at risk3. Screening must be disorder (Thapar et al. 2012; Angold and
complimented by a thorough clinical assessment Costello 1993).
of the child or youth clarifying symptom presen-
tation. The clinician should be aware of atypical
symptoms of depression in the younger popula- Suicide
tion and subclinical presentations recognizing
that the symptoms are heterogeneous and fluid Suicidal thoughts can be a manifestation of the
depending on the age and stage of the child. depressed mood secondary to negative cognitive
Assessment must also include including incorpo- distortions that can occur. The risk for youth sui-
rating collateral information from caregivers and cide is difficult to predict and despite societal
of particular importance, screening for risk for opinion, the overall prevalence has not signifi-
suicide. cantly increased in recent years. Suicide is
uncommon in childhood but certainly the fre-
quency of attempts increases post puberty into
There are several screening tools available to assist in
3
identifying risk for depression in children and adoles- adolescence particularly among females.
cents. All have particular age groups and populations as Roughly 16% of students between the ages of 14
targets and are well reviewed in the literature. Of import is and 18 years have considered suicide; 7.8% have
utilization of the same tool in a repeated fashion that is attempted in one study (Centred for Disease
clinically relevant and generalizable to the population and
other respective clinicians and caregivers (National Control and Prevention 2012). While attempts
Collaborating Centre for Mental Health (UK)2005). are twice as frequent in females, more males have

died by suicide than females (9.4/100,000 vs. Treatment

2.7/100,000). Data reveals that victims of suicide
had often visited primary care or mental health Psychotherapy for depression aims to assist the
care prior to the fatal attempt (Dilillo et al. 2015) youth in connecting their consequent mood to
emphasizing the need for screening for suicide their life experiences and thoughts. Building
risk at each office visit. Screening tools asking resilience by strengthening awareness of this
about factors that might confer increased risk for relationship and strategies or skills to modify per-
suicide in this population are available and useful ceptions about experiences can be preventative.
(Shain 2007). Cognitive behavioral therapy (CBT) and inter-
Both acute and chronic factors contribute and personal therapy (IPT) are the most widely stud-
can be fluid in terms of their relevance over time ied for treatment of depression in youth and
and as the child ages. Chronic factors include a adults (Thapar et al. 2012; Weisz et al. 2006). For
family history of suicide, past suicide attempts, younger children and youth with less severe and
chronic medical illness, and low socioeconomic more chronic mood symptoms, psychotherapy
status, among others. Acute factors include (CBT) can be very effective treatment.
recent suicidal attempt, current ideation and Combination treatment of antidepressant medi-
plan, access to lethal means, current substance cation and evidence based psychotherapy proves
use, significant psychosocial stressors, and psy- to have some added treatment benefit as com-
chotic symptoms among others. It is imperative pared to placebo alone for the moderate-severely
to screen for suicide risk with all pediatric and ill population and those who are treatment-
adolescent patients and be reassured that asking resistant or do not respond to psychotherapy
about suicide and associated safety planning is alone (March et al. 2004; Thapar et al. 2012;
protective (Table 20.4) (Dilillo et al. 2015). March and Vitiello 2009). Further though, one
study found that for those where therapy was not
Table 20.4 Examples of factors associated with feasible, even a switch from one SSRI to another
increased/reduced suicide risk can yield improvement in symptoms (March and
Factors associated with increased Vitiello 2009; Brent et al. 2008).
suicide risk Protective factors Antidepressants in the form of selective sero-
Psychiatric illness (more than Access to mental tonin uptake inhibitors (SSRI) have the most doc-
60% meet criteria for health care umented evidence of efficacy for treatment of
depression)
depression in this population (Giles and Martini
Previous suicide attempt Positive stable
(20–30% will attempt again in support 2016), but in truth the evidence is still sparse.
the ensuing 2–4 years) connections There are very few studies supporting utilization
School of other classes of medicines such as tricyclic
Family antidepressants or mood stabilizers in the treat-
Peers
ment of child/adolescent depression. In most tri-
Family dynamics/familiarity Lack of access to
with suicide (stress, loss, means and als, the response rate for SSRIs as antidepressants
member committed suicide) substances is about 60% in this population. There is limited
Substance abuse (alcohol Resilience—coping evidence suggesting a stronger efficacy for one
intoxication significantly strategies, ability to SSRI over another for depression. Thus, the
increases current risk) overcome adversity choice of SSRI is determined by side effect pro-
History of trauma, neglect, Help-seeking
file, previous experience with medicine, pharma-
abuse (sexual/physical)
codynamics of the medication and relative risk
Gender dysphoria
Bullying (both bullies and
profile. Recommendations include starting at a
victims) low dose and tapering weekly to target symptoms
Safety of home environment and tolerability as effective dose is not related to
(access to means, safety weight. An adequate trial of an SSRI is 4–6 weeks
planning, supportive caregivers) at a therapeutic dose with consideration of a

522 S. Abidi
switch to an alternate SSRI after a failed trial. 2007). It is important to note also the risk of
Once effective treatment is established it is rec- increased suicide-related thoughts associated
ommended medication be continued for 12 with initiation of psychotherapy (without medi-
months before considering a discontinuation trial. cation) for depression is 25% in some studies
There is some evidence supporting a longer term (March and Vitiello 2009). There is a clear pos-
treatment benefit of combination psychotherapy, itive benefit to risk ratio of treating depression
allowing for more successful medication discon- in youth with medication as required, particu-
tinuation after 12 months (March et al. 2004). larly if in combination with psychotherapy.
Nonetheless, educating and monitoring youth
and families of the risk and the studies available
Safety is good clinical practice. It does appear that the
risk for suicide related events is largely con-
Most side effects in youth treated with SSRIs are fined to trials on youth with depression (the risk
transient and generally well tolerated. Common is diminished for those taking SSRIS for anxi-
side effects include gastrointestinal side effects ety, e.g. in OCD the number needed to harm
such as nausea and dyspepsia as well as head- (NNH) is 200) (Giles and Martini 2016; Correll
aches, increased appetite and fatigue. Less fre- et al. 2011); nonetheless, educating youth and
quent experiences include irritability, agitation, families with anxiety or other illnesses for
restlessness, insomnia, weight loss and affect which SSRIs are being prescribed about the
instability. Rare but more troublesome side potential risk is recommended.
effects include sexual dysfunction, temperature
dysregulation, bruxism and more severe GI dis- ong Term Effects of SSRIs and Youth
L
tress. Rarely, SSRIs can induce a manic or hypo- There are no studies completed assessing the
manic switch in youth with familial risk for potential long-term adverse effects of antide-
bipolar disorder type I (Giles and Martini 2016; pressant use in youth with mood or anxiety dis-
Strawn et al. 2015). orders. It is important to discuss this lack of data
with the youth and family and risk must be
weighed against the potential risk of untreated
Clinical Point illness on brain development. Following a period
of stability (usually at least 12 months in remis-
SRIs and Suicide Related Events
S sion) consideration of a slow taper with physi-
In 2004, the FDA reviewed results of a metal cian advice and eventual discontinuation if
analysis of 24 clinical trials of nine different tolerated is warranted.
antidepressants in about 4000 pediatric patients.
The cumulative risk for suicide-related thinking on-suicidal Self-Injury (NSSI)
N
(thoughts of suicide, increased agitated Non suicidal self-injury (NSSI) has been pro-
thoughts related to hopelessness, worsening posed as a possible separate diagnostic entity in
intent to self-harm) collected as spontaneous section III of the DSMV (American Psychiatric
adverse events was 4% versus 2% with placebo Association 2013). Consensus agreement on def-
(Hetrick et al. 2007). Further analysis of the initions, however have not been agreed upon
data revealed no completed suicides in this pop- regarding self- harming behaviors. Research
ulation. Furthermore following a consequent often uses the terms NSSI which refers to harm-
nation-wide decrease in prescribing practice of ful behaviors without suicidal intent (cutting,
SSRIs for depression in youth, there was identi- burning, etc.) and self-directed harmful b ehaviors
fied an increased risk of death by suicide in (SDH) which have suicidal intent (overdose,
untreated youth with depression as compared to hanging) interchangeably. NSSI is not uncom-
those treated with antidepressants (March and mon among adolescents, with lifetime prevalence
Vitiello 2009; Hetrick et al. 2007; Bridge et al. rates of 4% and 7% for adolescent community

samples, increasing dramatically to roughly 50% et al. 2012; Beesdo et al. 2010). Despite the
for child and adolescent psychiatric samples prevalence, most youth with anxiety disorders
(Muehlenkamp et al. 2012; Swannell et al. 2014). go unrecognized. There is considerable hetero-
The prevalence decreases sharply into adulthood, geneity in the onset of the specific anxiety disor-
possibly reflecting that this is a behavior specific ders with separation anxiety and social anxiety
to youth. Despite perception that NSSI lacks sui- presenting commonly in early childhood while
cidal intent, the behavior has been described as generalized anxiety disorder (GAD), panic dis-
strong risk factor for suicidality in adolescence order, and obsessive compulsive disorder (OCD)
(Andover et al. 2012), the association between mostly emerging in adolescence. Oftentimes the
which is still unclear. Research is focused on symptoms of specific anxiety disorders co-
identifying possible predictors of risk associated occur; accumulating data suggests a pediatric
with NSSI. Depressive symptomatology and anxiety disorder “triad” of separation anxiety,
associated distress, past NSSI or SDH, female generalized anxiety and social anxiety reflecting
gender and exposure to adversity for example similar trajectories, neurophysiology and
may carry increased safety risk (Kessler et al. response to treatment in these disorders (Kendall
2012). Clinicians should be aware of past history et al. 2010; McGuiness and Durand 2016).
and current factors with which youth present in Identifying anxiety disorder as a psychiatric ill-
association with NSSI. Asking about intent for ness early is important as these can interfere
harm and reasons for behavior is of import in with optimal growth and development and pre-
accurately determining the clinical relevance of dict worsening or development of other anxiety
NSSI in the moment and potential risk for future disorders among other illnesses (ADHD, ODD,
SDH in relation to this. and depression) in adolescence and adulthood.
Further, anxiety disorders carry high rates of
comorbid illnesses such as substance use disor-
Anxiety ders and mood disorders and also risk for
suicide.
Prevalence
Childhood and adolescence is a key period for Diagnosis

the development of symptoms of anxiety that
can range from transient, self-limited symptoms As with other psychiatric illnesses, the role of
to full-blown anxiety disorders. Anxiety is not the caregivers and other support persons in other
typically pathological and is adaptive and pro- settings e.g. teachers, as integral informants dur-
tective in most cases. Anxiety becomes mal- ing the assessment for anxiety disorders particu-
adaptive however when subclinical symptoms larly in children is key. Oftentimes, the anxiety
begin to worsen, persist and interfere with func- disorders, particularly the “triad”, but also sepa-
tioning and certainly when symptoms present in ration anxiety and specific phobias are associ-
situations that typically would not be anxiety- ated with avoidance (of anxiety) behaviors such
provoking. Difficulty arises in distinguishing as school refusal and selective mutism. Selective
between normal worries and fears of childhood mutism appears in childhood, sometimes by the
and adolescence or specific to emotional and age of 4 and may be a variant of or predictive of
developmental stages, and those which cause development of social anxiety disorder in later
significant distress impacting academic, social years (McGuiness and Durand 2016).
and emotional function. Anxiety disorders in Good clinical practice recommends screen-
childhood and adolescence as a group constitute ing for anxiety symptoms and carefully assess-
the most prevalent mental disorder affecting ing for potential comorbid psychiatric and
roughly 15–20% of youth with a threefold general medical conditions that can mimic anx-
female preponderance in adolescence (Kessler iety. Distinguishing normal anxious responses

524 S. Abidi
in childhood and adolescence from pathologi- Treatment

cal responses is key as is identifying other
potential internal or external factors or determi- Cognitive behavioral therapy is highly regarded
nants that might have contributed to or assist in as first line treatment with strong evidence base
understanding the anxious response and symp- for anxiety disorders in this population. Mild
tomatology. Screening instruments are avail- severity of symptoms respond very well to
able and widely used to identify and monitor CBT. CBT is most successful in this population if
anxiety disorders in children and youth4 and combined with a behavioral component of intro-
should be used in conjunction with a compre- ducing graded exposure to the anxiety-provoking
hensive assessment interview with the young stimulus or thoughts. Furthermore, development
person and family (March et al. 1997; Birmaher of coping skills and relaxation strategies to assist
et al. 1999). children in exposure to anxiety provoking stimuli
Trauma in childhood and adolescence is a is key. Finally, psychoeducation for both the child
prevalent cause of development of anxiety dis- but also the parent/caregiver is also helpful for
orders in children and adolescents. The life- younger children particularly. Education
time prevalence of posttraumatic stress enhances caregivers’ awareness of their own
disorder (PTSD) is about 9.2% in the general behaviors and anxious responses that might
population; may children and youth likely enable avoidance behaviors in their children.
experience subthreshold symptoms of PTSD Parenting style is determined as one of the most
that carry significant risk for impairment if important environmental factors contributing to
unrecognized (McGuiness and Durand 2016). anxiety disorder development in children and
As noted above the DSMV now recognizes youth. More specifically, overly critical over pro-
that preschool children, in the face of trauma tective approaches have been associated with
may manifest the symptoms of PTSD and have pathological anxiety in children and can be a
specified criteria to foster reliable identifica- focus of intervention. For example assisting par-
tion of this presentation. ents to be aware and learn to regulate their own
Anxiety heritability is estimated as high as emotional response to their child’s fear can
50% which when combined with environmental enhance a child’s ability to cope in anxiety-
factors which might include parenting styles provoking situations. Strong empirical evidence
(modeling), exposure to traumatic events leading supports CBT plus parent education and training
to a fear response and chronic risk factors (famil- in this way as first line intervention for anxiety
ial risk) plays a role in the genesis of the disor- disorders in this population (Giles and Martini
ders. The temperament of the child reflected in 2016; McGuiness and Durand 2016; Walkup
early childhood behavior may further predict et al. 2008).
anxiety disorder development. Anxiety disorders Moderate to severe symptoms of anxiety that
often co-occur as noted in children and youth but are more impairing and do not respond to psy-
may also morph in terms of phenotype over time chotherapy alone have been shown to respond
depending on the developmental and emotional very well to combination pharmacotherapy and
age of the person (Kessler et al. 2012; Beesdo psychotherapy. Strong evidence based data dem-
et al. 2010; Kendall et al. 2010; McGuiness and onstrates up to 80% improvement in symptom-
Durand 2016). atology (World Health Organization 2009;
McGuiness and Durand 2016; Rynn et al. 2015)
with combination therapy in this population.
The Multidimensional Anxiety Scale for Children
4 Anxiety disorders with comorbid psychiatric
(MASC), and the Screen for Child Anxiety and Related conditions and certainly those that are treatment
Emotional Disorders (SCARED) are examples of tools
resistant benefit from both a psychotherapeutic
designed to monitor anxiety symptoms in youth with good
psychometric properties (March et al. 1997; Birmaher and pharmacological approach to treatment by
et al. 1999). virtue of severity of symptoms.

SSRIs are commonly used both on and off- DSMV it is listed in its own chapter under OCD
label in treatment of anxiety disorders in children and related disorders and has added specifiers
and youth with good clinical practice emphasiz- qualifying varying levels of insight into the con-
ing their use first line. Multiple medications from tent of the thoughts and behaviors reflecting the
the SSRI class have good evidence for efficacy in continuum of severity of the illness and heteroge-
treating anxiety disorders including obsessive neity of presentation depending on age and devel-
compulsive disorder (OCD) as compared to pla- opmental stage.
cebo (Pediatric OCD Treatment Study (POTS) OCD is prevalent (1–2%) in the younger popu-
Team 2004). Fluoxetine and Sertraline have good lation but oftentimes goes undetected especially
evidence base for use in treating anxiety and often in children. OCD is highly heritable with a risk of
choice is dictated by adverse effects and history 12% in first degree relatives with a more severe
(Correll et al. 2011; Rynn et al. 2015; Pediatric manifestation of the symptoms in those with
OCD Treatment Study (POTS) Team 2004). familial risk (McGuiness and Durand 2016). CBT
Benzodiazepines have not been shown to be with the exposure-response prevention (ERP)
efficacious in the treatment of anxiety disorders component is first line treatment for mild-moder-
in youth as single agents. Case reports do exist ate symptoms of OCD. Antidepressant medica-
demonstrating benefit of short-term benzodiaze- tion (SSRIs) is recommended as adjunctive
pine for extreme anxiety symptoms particularly treatment to CBT for moderate to severe cases.
during progression of or a switch among SSRI The evidence for combination therapy as opposed
options. Clinicians need be mindful of added to monotherapy is strong for other anxiety disor-
adverse effects and potential for dependence in ders as well as OCD with relatively low numbers
using this class of medication. Evidence for the needed to treat (NNT) at 3 and 6 respectively
use of atypical antipsychotics or buspirone (often (Correll et al. 2011; Strawn et al. 2015; Pediatric
used to treat anxiety in adults) in treating anxiety OCD Treatment Study (POTS) Team 2004).
in the child/youth population is lacking (Giles Moreover, for those who were initially treated
and Martini 2016; Correll et al. 2011; Strawn with SSRIs in one study with only partial response,
et al. 2015). augmentation with OCD-specific (exposure
Trauma-focused CBT is the mainstay of treat- based) brief (12 weeks) CBT provided a superior
ment for PTSD in children and youth. Data is treatment response as compared to medication
unfortunately lacking in terms of effective phar- alone or medication plus nonspecific CBT strate-
macological management of symptoms of child- gies (Giles and Martini 2016; Correll et al. 2011;
hood/adolescent PTSD. SSRIs have been McGuiness and Durand 2016).
identified in case reports as acceptable options
for augmentation of psychotherapy but there is
less evidence for this as compared to other anxi- Bipolar Disorder
ety disorders potentially due to lack of studies in
the younger population. This is in sharp contrast Prevalence
to research in the adult population that strongly
supports use of SSRIs for PTSD (McGuiness and The prevalence of bipolar disorder is difficult to
Durand 2016). ascertain in the pediatric population due to a het-
erogeneous clinical presentation in youth (includ-
ing unipolar mania, mania with depression, brief
Clinical Point hypomanias, and chronic mood lability). Overall
the prevalence of bipolar spectrum disorders
bsessive Compulsive Disorder (OCD)
O (bipolar I, II, cyclothymic disorder) across ages is
OCD is an illness marked by intrusive thoughts about 1.7–2.5% with about two thirds
and compulsive behaviors that previously fell experiencing their first mood episode before age
within the category of anxiety disorders. In the 18 (Cosgrove et al. 2013). For this update, focus

526 S. Abidi
is primarily on bipolar I disorder. There has been and are at increased risk for comorbid disorders.
a marked increase in diagnosis of bipolar I disor- However, if recognized early and with appropri-
der in North America, particularly in the US in ate treatment the trajectory of BD may be signifi-
recent years, reasons for which are unclear. It is cantly improved. The illness is marked by
surmised that this is secondary to an increasing extreme episodic mood states, depression and at
problem of over diagnosis in this area of the least one episode of mania (Cosgrove et al. 2013;
world (as increase prevalence has not been Van Meter et al. 2016). DSMV criteria requires
observed internationally). Certainly under diag- the mood states, to persist for up to 14 days for
nosing bipolar disorder can lead to prognostic depression and 5 for mania with the onset of the
consequences, worsening frequency and severity episodes being a marked change in presentation
of the mood episodes and consequent prolonged from baseline. For example, pathological ele-
impairment. Over diagnosis may be due to clini- vated or euphoric mood, persistent insomnia
cian misidentification of symptom overlap of without need for sleep and disinhibition with
bipolar disorder with symptoms of disruptive hyper sexuality are specific to the manic phase of
behavior disorders such as ADHD, conduct dis- bipolar disorder. Furthermore, symptoms such as
order and oppositional defiant disorder. grandiosity and elation must be inappropriate to
Disruptive mood dysregulation disorder (DMDD) the context and unprovoked. Irritability as a
is a new DSMV diagnosis developed in response symptom of bipolar disorder is difficult to clarify
to this very issue and in hopes to decrease the risk and confirm. Irritability is a manifestation of
of misidentification and false positives and con- many other psychiatric illnesses in youth includ-
sequent exposure to adverse effects of pharmaco- ing depression, anxiety, ADHD, CD and
therapy such as antipsychotics and mood OCD. Irritability in association with bipolar dis-
stabilizers (Leibenluft 2011) (see below and order must be episodic, connected to the mood
Table 20.5). state and again a change from baseline (in
between extreme mood states). Moreover, irrita-
bility alone even if episodic does not meet the
Diagnosis threshold for diagnosis. It is generally accepted
that symptoms heralding onset of bipolar I disor-
Bipolar I disorder (BD) is a serious and persistent der exist on a continuum or dimensional scale
psychiatric disorder. Early onset BD is associated however as yet recognition of risk for or signs of
with a more severe presentation and neurocogni- new onset bipolar disorder in youth can be diffi-
tive deficits relative to peers. Youth with BD may cult (Cosgrove et al. 2013; Singh et al. 2014).
be less likely to develop adequate social skills,
Table 20.5 Distinguishing DMDD from bipolar I disorder

Features associated with DMDD Features associated with BD I
Must present between age 6–18. Symptoms must have Rare in childhood, onset peaks in early 20s–30s with
onset by age 10; cannot be diagnosed outside of this age early onset cases in adolescence
range for the first time
Prevalence between 2% and 5% in childhood; decreases Prevalence stable about about 1% in young adulthood;
to 0.8–1.1% in older youth rare in childhood
Symptoms must be present for 1 year; no period greater Episodic, must meet criteria for manic episodes, are
than 3 months symptoms free unprovoked
Chronic, unremitting irritability with or without severe Episodes of mania ± depression, may have baseline
explosive outburst (3/week) normal mood without irritability
No psychosis May have symptoms of psychosis in the extremes of
mood
Usually associated with development of a unipolar mood Presentation associated with the development of
disorder chronic bipolar mood disorder

Depression is often the first symptom of pedi- Johnson syndrome. Divalporex is associated with
atric Bipolar disorder with 20% of youth with polycystic ovarian syndrome with associated
MDD experiencing manic episodes by adult- symptomology. Carbamazepine is at higher risk for
hood. Risk factors for developing bipolar disor- drug-drug interactions by virtue of induction of the
der identified in the younger population include: hepatic CP450 isoenzyme system. Diligence and
family history, acute onset of major depressive awareness of and monitoring strategies for poten-
disorder, psychotic features with severe depres- tial adverse events and risk associated with these
sion and psychomotor retardation. Further atypi- medications in children and youth is essential.
cal depressive features such as hypersomnia, Lithium adverse effects commonly can
hyperphagia, low energy and antidepressant include weight gain, acne, psoriasis, polydipsia,
mood destabilization or inefficacy may also pre- polyuria, and sedation, gastrointestinal distress
dict later conversion to bipolar disorder. It with nausea, pain and diarrhea. Hypothyroidism,
appears that youth with MDD that later develop ataxic gait and tremor and nephrogenic diabetes
bipolar depression are more severe in initial pre- insipidus are rarer. Baseline investigations of
sentation of low mood, more anhedonic, have an renal function, thyroid indices, electrolytes and
earlier age of onset and lower functioning than complete blood count are recommended with
youth with unipolar depressive disorder routine monitoring (Giles and Martini 2016;
(Cosgrove et al. 2013; Van Meter et al. 2016; Cosgrove et al. 2013).
Singh et al. 2014; Chang 2009).
Clinical Point
Treatment
DMDD encompasses children age 6–18 with
Lithium and a select few of the atypical antipsy- mood dysregulation that is reflected in a presenta-
chotics are approved as first line treatment in the tion of persistent, irritable and angry mood with
pediatric population for acute mania and bipolar recurrent temper outbursts that occur before the
I disorder maintenance treatment. Treatment of age of 10. Evidence from longitudinal studies sug-
and utilization of other mood stabilizers in this gests that these children and youth tend to develop
population is both on and off-label; involvement other psychiatric conditions such as major depres-
of colleagues in child psychiatry can be useful. sive disorder or anxiety disorder and not bipolar I
Lithium has been proven to be efficacious in disorder. Family history data supports this finding
treatment of bipolar I disorder in children and further contradicting the previous assumption that
youth with symptoms of acute mania. There is severe and chronic irritability in children/adoles-
growing evidence for efficacy of Lamotrigine in cents represents an alternative presentation or risk
treating the depressive phase of pediatric bipolar for bipolar disorder (Leibenluft 2011; Van Meter
disorder as monotherapy and in combination. et al. 2016; Tang and Pinsky 2015). Further longi-
Data however on other mood stabilizers includ- tudinal studies are underway to better understand
ing atypical antipsychotics, Oxcarbazepine, the underpinnings of this disorder.
Gabapentin and Topiramate are limited (Giles
and Martini 2016; Cosgrove et al. 2013).
chizophrenia and Other Psychotic
S
Spectrum Disorders
Safety
Prevalence
All mood stabilizers carry adverse effects and
potential for chronic medical complications. For The WHO has ranked psychosis as third among the
example, Lamotrigine is associated with a rare risk most disabling conditions in youth worldwide
of fatal cutaneous reactions such as Stevens (Gore et al. 2011). The prevalence of schizophrenia

528 S. Abidi
and other psychotic spectrum disorders is between prodromal stage of the illness marked by attenu-
1–1.5% with about 18–30% of cases with onset ated symptoms that cause distress and impair-
before the age of 18, particularly in males. The ment yet do not reach psychotic disorder
average age of onset in males is between 17–21 threshold. The prodrome is a retrospective diag-
years. Rarely, schizophrenia presents in childhood nosis as symptoms overlap with other psychiatric
in 1.6–1.9 per 100,000 children under age 12 illnesses and presentations at this age; however
(Gillberg 2001; Thomsen 1996). At this age, it is work is actively ongoing to elicit diagnostic tools
difficult to clarify the diagnosis and by virtue of the to help identify youth in this phase and initiate
heterogeneous presentation, is often misidentified indicated prevention as warranted (Yung et al.
as autistic spectrum disorder. Childhood onset 2008). At this time diagnostic criteria must be
schizophrenia carries a more severe prognosis with met before initiating treatment with antipsychotic
most experience treatment refractory symptoms medication.
and longstanding impairment. Early onset psy-
chotic disorders (onset between ages 12–18) are
associated with impairments in social, emotional Treatment
and occupational function by virtue of the cluster
of functions affected by the illness symptoms. Schizophrenia and psychotic spectrum disor-
Schizophrenia follows a variable course with one- ders are severe and persistent neurodevelop-
third to forty percent of cases achieving functional mental illnesses. Collaboration with pediatric
recovery (Clemmensen et al. 2012). Recent psychiatry colleagues regarding symptoms
advances in the field of early intervention for psy- management is helpful. Antipsychotic medica-
chosis and the development of multidisciplinary tions are the mainstay of pharmacological treat-
specialized early psychosis programs however has ment of the symptoms of psychosis. Older
fostered early identification of those both a risk for antipsychotics or first generation (FGA) which
psychosis and in the earliest phase of identifiable act via direct blockade at the dopamine receptor
symptoms of the disorder. A more optimistic (such as Chlorpromazine or Haloperidol) while
approach to recovery is attainable in youth whose approved for treatment in adolescents with psy-
illness is identified and treated early. chosis have generally been replaced with sec-
ond generation antipsychotics (SGA) due to
concern regarding movement disorder effects
Diagnosis such as extrapyramidal side effects (EPSE), par-
kinsonism and dystonia. The SGAs block D2
The term ‘psychosis’ refers to the group of psy- receptors as well but primarily via reciprocal
chotic disorders characterized by hallucinations block of serotonin receptors and lower receptor
or delusions and experiences that alter percep- occupancy. Studies show no efficacy difference
tion, thoughts, emotionality and behavior all of between FGAs and SGAs in treating the symp-
which can markedly impair the trajectory of toms of psychosis (with the exception of
social, emotional and physical health of a young Clozapine) yet in the last two decades, the SGAs
person. Psychosis includes schizophrenia but are more widely prescribed when available.
also schizoaffective disorder, schizophreniform Clozapine is an SGA that has demonstrated
disorder and delusional disorder. In the DSMV, superior efficacy for children and adolescents
criteria used to diagnose schizophrenia are rela- with schizophrenia. Clozapine however cannot
tively the same as in adults bearing in mind youth be prescribed without evidence of two failed tri-
with schizophrenia often have a more severe als of antipsychotics and requires specific moni-
form of illness symptoms, more cytogenetic toring due to its propensity, albeit rare for
abnormalities and potentially more neurodevel- potentially life threatening side effects of agran-
opmental abnormalities (Clemmensen et al. ulocytosis and leukopenia (Schimmelmann
2012). Recent work in the field has identified a et al. 2013; Pisano et al. 2016).

Family support and psychoeducation has PTSD) can present with perceptual abnormalities
demonstrated efficacy in reducing relapse rates in children and youth often congruent in content
and rehospitalisation in adolescents with schizo- to the context of the primary illness. In these
phrenia. Individual cognitive behavioral therapy cases, the experiences usually present only in the
has limited evidence however psychosocial reha- face of triggers related to the primary disorder.
bilitation interventions with peer support modali- OCD is an illness that in youth can manifest as
ties can be helpful particularly in the first episode the perception of auditory hallucinations.
of psychosis (Yung et al. 2008). Sometimes the OCD thoughts are described as
“voices” by youth who comprehend the experi-
ence as external to the self. Further, some youth
Clinical Point lack insight into the etiology of their OCD
thoughts and compulsions and in turn qualify for
sychotic Experiences and Other DSMV
P the specifier of OCD “with poor/delusional
Disorders insight”, new in the DSMV. Children with ASD
It is important to recognize that symptom can often also present with psychotic experiences
domains for psychosis can differ depending on that are inherent to the illness itself and not pre-
age and stage of development, and can poten- dictive of increased risk for a psychotic disorder.
tially be a manifestation of multiple diagnostic Youth with depression oftentimes will report
categories. Most children and who report psy- auditory hallucinations that mimic their negative
chotic symptoms do not have schizophrenia or cognitive distortions. It is extremely important to
another psychotic disorder. Children and youth’s distinguish the etiology of the psychotic experi-
interpretation of internal and external percep- ence as the longer term implications and approach
tual experiences can be influenced greatly by to treatment are significantly different. Treatment
factors such as intellect and emotional maturity modalities for example for anxiety or depression
in the face of exposure to developmental stress- (CBT for instance) can target the psychotic expe-
ors, environmental triggers, cultural dynamics riences as a cognitive distortion and support the
and family belief systems. The perception of a youth in reframing the experience in the context
psychotic experience can be a normal variant for of the primary illness. Further, if warranted anti-
very young children and indeed in isolation is depressants (SSRIs) can prove helpful. The het-
relatively common and clinically benign in ado- erogeneous presentation of psychotic experiences
lescents, occurring in 15–20% in some studies as a manifestation of other psychiatric illnesses
(Lachman 2014; Scott et al. 2006). Furthermore, (Yung et al. 2008; Lachman 2014) in youth
the perception of a psychotic experience may be underscores the value of conducting a thorough
the manifestation of other medical or psychiat- comprehensive assessment in order to identify
ric etiologies such as primary mood or anxiety the other clinical correlates of psychotic experi-
disorders. Simultaneously, clinicians need be ences and avoid misattributing their presence to a
aware that many adults with schizophrenia primary psychotic disorder or worse, treating the
report the initial onset of symptoms prior to the child inappropriately as a result.
age 18 before diagnostic criteria were met
(Schimmelmann et al. 2013), making the inter-
pretation of the clinical significance of the psy- Clinical Point 2
chotic experience in childhood and adolescence
complex. typical Antipsychotics: Issue
A
The lifetime prevalence of a psychotic experi- for Consideration
ence that does not go on to develop into a psy- Overall, literature on the use of antipsychotics in
chotic disorder in 10–20% (Scott et al. 2006). children and youth is limited with the best evi-
Severe depression or anxiety (often social anxi- dence for use of these medications for schizo-
ety disorder, generalized anxiety disorder and phrenia and bipolar I disorder (Pisano et al. 2016).

530 S. Abidi
Despite this, in the last decade there has been a in pediatric patients with ASD, lower intellectual
significant increase in the prescription of SGAs function and in fewer studies children with
for more than the symptoms of psychotic or ADHD and conduct disorder. Of particular
bipolar disorder in pediatric and adolescent import is the finding that Risperidone plus parent
patients. SGAs are often prescribed for irritabil- training leads to a greater reduction of maladap-
ity and aggression in autism spectrum disorder tive behaviors than medication alone in these
or intellectual disability, Tourettes’ disorder, populations and often lead to requirement of
mood disorder, conduct disorder and eating dis- lower doses of Risperidone. Furthermore, the
orders. Unfortunately polypharmacy with more treatment effects are limited to aggression; the
than one SGA is also common despite lack of core deficits of the primary disorder are not
evidence supporting this practice (Olfson et al. affected by these medicines (Giles and Martini
2015). Several recent studies have raised signifi- 2016; Pisano et al. 2016). Long term benefit of
cant concerns regarding the adverse effects of antipsychotic use in these children is not substan-
SGAs and the potential risk for iatrogenic sec- tiated and thus regular re-evaluation of prescrib-
ondary metabolic syndrome (weight gain/obe- ing practice with ongoing attention towards
sity, hypercholesterolemia, hypertriglyceridemia, evidence for use is crucial.
hyperlipidemia, hyperinsulinism and hyperten-
sion). These potential adverse effects are more Adverse Effect Profile of SGAs
frequent in children and youth and also include
hyperprolactinemia, cardiovascular effects such Weight Gain and Obesity
as prolonged QTc intervals, and neuromotor The risk for weight gain with use of SGAs is
adverse effects (dystonias, EPSEs, parkinsonism remarkable—highest for Olanzapine and
and akathisia) (Giles and Martini 2016; Clozapine followed by Risperidone, Quetiapine,
Schimmelmann et al. 2013; Pisano et al. 2016). Aripiprazole and Ziprasidone. The risk for
Recommendations for monitoring of SGAs were weight gain is higher in the younger population
put forth by both the Canadian Alliance for and is not always dose dependent. For those
Monitoring Effectiveness and Safety of more vulnerable to adverse effects of medica-
Antipsychotics in Children (CAMESA) and the tion such as children with ASD, the weight
American Academy of Child and Adolescent increase can be significant, with drug-naïve
Psychiatry (AACAP) (Pringsheim et al. 2001; patients presenting with the highest risk in some
American Academy of Child and Adolescent studies. Of note, in one study examining the
Psychiatry 2011) strongly supporting preventa- effects of maintenance vs discontinuation of
tive baseline and periodic measures of indices Risperidone in children, neither those who dis-
related to risk of morbidity and mortality associ- continued Risperidone nor those who switched
ated with prescription of SGA (Fig. 20.1). to another SGA lost their body fat mass incurred
Despite this, national monitoring programs do secondary to Risperidone, indicating that the
not exist and many prescribers of SGAs do not metabolic risks associated with SGAs may be
adhere to recommendations. Consequently the chronic in some (Giles and Martini 2016; Pisano
adverse events from SGA use lead to many pedi- et al. 2016; Calarge et al. 2014; Prinsheim et al.
atric emergency room visits and negative 2011).
outcomes.
Diabetes
ntipsychotics and Aggressive
A The rapid weight gain secondary to SGAs is
Behavior sometimes paralleled by an increased risk for
Randomized control trials do demonstrate posi- diabetes mellitus type 2 (DM2). Moreover
tive results (with small to moderate effect sizes) research identifies that SGAs are associated with
from risperidone and aripiprazole compared to insulin dysregulation independent of weight gain.
placebo in decreasing irritability and aggression Youth with type 1 diabetes prescribed SGAs were

Monitoring Safety of Second Generation Antipsychotics (SGA) in Children
Patient Name: Gender: DOB (YYYY/MM/DD):
SGA Medication: olanzapine (Zyprexa) Target Symptoms (e.g. tics, rage, psychosis):
Parameter Pre-Treatment Baseline 1 Month 2 Month 3 Month 6 Month 9 Month 12 Month
General Information:
Assessment Date (YYYY/MM/DD):
Patient Age at Assessment:
Daily Dose of olanzapine: mg mg mg mg mg mg mg
Physical Examination Maneuvers:
Height (cm)
1 Round to nearest 5, 10, 25,

Height percentile 50, 75, 90, or 95 %ile
Weight (kg)
Round to nearest 5, 10, 25,
Weight percentile1 50, 75, 90, or 95 %ile
BMI (kg/m2)1 #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0!

Use CDC calculator to
BMI percentile1 calculate value1
Waist Circumference (at level of umbilicus) (cm)

>90, or round to nearest 10,
Waist Circumference percentile2 25, 50, 75, or 90 %ile
Systolic Blood Pressure (mm Hg)
Provide range (<50, 50-90,
Systolic Blood Pressure percentile3 90-95, 95-99, or ≥99)
Diastolic Blood Pressure (mm Hg)
Provide range (<50, 50-90,
Diastolic Blood Pressure percentile3 90-95, 95-99, or ≥99)
Neurological Examination:
Neurological Exam completed?4
Neurological Exam Normal or Abnormal?
Laboratory Evaluations:
Test Normal Values
≤ 6.1 mmol/L 5 5 5 5
Fasting Plasma Glucose5
6 6 6 6
Fasting Insulin6 ≤ 100 pmol/L
7
< 5.2 mmol/L 7
Fasting Total Cholesterol
7
Fasting LDL-C7 < 3.35 mmol/L
7
≥ 1.05 mmol/L 7
Fasting HDL-C
7
Fasting Triglycerides7 < 1.5 mmol/L
8
AST8
8
ALT8
10 10
Prolactin9, 10
Amylase11 11 11 11 11 11 11 11
Other (e.g. A1C, OGTT, etc.); Please List
Physician Initials:
Fig. 20.1 Example of monitoring protocol suggested by from http://camesaguideline.org/information-for-doctors

Canadian Alliance for Monitoring Effectiveness and (accessed 29 June 2016)
Safety of Antipsychotics in Children (CAMESA) obtained
found to have poorer glycemic control and higher however long term data is lacking (Lachman
HbA1c levels than placebo (Pisano et al. 2016; 2014; Prinsheim et al. 2011).
Lachman 2014; Prinsheim et al. 2011).
Movement Disorders
Dyslipidemia The risk for extrapyramidal symptoms (EPSE:
Increased triglyceride and cholesterol levels can chronic or acute dystonia, parkinsonism, tar-
occur early in the course of treatment of children dive dyskinesia and akathisia) is lower with
and youth with SGAs and may precede or be SGA use as compared to FGA use but not
independent of weight gain as well as secondary absent. Children and adolescents, particularly
to obesity. Aripiprazole and Ziprasidone seem to those who are drug naïve, are more vulnerable
cause less dyslipidemias than the other SGAs to EPSEs. There is a higher risk for movement

532 S. Abidi
disorders with risperidone, aripiprazole (akathi- and cannabis. The lifetime prevalence of sub-
sia), and olanzapine as compared to placebo; stance abuse and dependence in adolescents
whereas quetiapine and clozapine seem to be rages from 3.3% in 15 year olds to almost 10% in
more neutral. Other factors such as younger age, 17–19 year olds. More than 60% of older adoles-
comorbid substance misuse, polypharmacy, pre- cents with SUD had another psychiatric disorder.
vious history of EPSEs can further contribute to Substance use is rare in childhood and increases
risk (Lachman 2014; Prinsheim et al. 2011). significant after age 12 (Centred for Disease
Other adverse effects of SGAs as noted can Control and Prevention 2012; Schulden et al.
include hyperprolactinemia, cardiovascular 2009).
adverse effects, and neuroleptic malignant syn- SUD impacts all facets of a child’s life interfer-
drome (NMS), a potentially fatal adverse reac- ing with all spheres of development. Substance
tion marked by elevated CPK, muscle rigidity, use can worsen the prognosis for many comorbid
hyperthermia, autonomic dysfunction, confusion psychiatric illnesses, some by potentially reduc-
and leukocytosis (Lachman 2014). ing the effectiveness of medicines, leading to poor
The potential for serious adverse events with prognosis. Comorbidity is the rule rather than the
antipsychotic use emphasizes the need for diag- exception with SUD (Jackson et al. 2000).
nostic diligence and evidence for efficacy of anti-
psychotic use in children and youth. If SGAs are
needed, utilization of monitoring strategies and Diagnosis
standardized scales to monitor for involuntary
movements5 is useful (Guy 1976). A thorough The continuum of substances use ranges from
review of medications, history of substance use, non-users, to experimental or casual users to
medical history and history of adverse effects to those with substance use disorders. The diagnosis
medications, especially antipsychotics is is primarily made via clinical interview as well as
required. Consultation with child/adolescent psy- signs of toxidromes on physical exam in
chiatry colleagues when considering prescription moderate-severe cases. The DSMV divides the
of antipsychotics can be helpful. Regardless, pre- disorders into SUD (which includes combined
scription of antipsychotics should not be chronic criteria for substance abuse and dependence—
unless indicated by the presentation. previously separated in DSMIV) and substance
induced disorders including both intoxication
and withdrawal syndromes specific to the
ubstance Related Disorders
S substance.
in Children and Adolescents Risk for SUD is dependent on the develop-
mental stages of the child or adolescent, e.g. peer
Prevalence pressure during may be more a powerful factor in
adolescence than childhood. Community factors
Substance Use Disorders (SUD) is one of the such as drug availability and societal tolerance
most common mental health disorders with a for drug use are also significant. Certainly stress-
lifetime prevalence of 35% with more than 30% ors in the child’s life such as school transitions
of SUD onset in adolescence. About 50% of 12th are risk factors as is exposure to caregivers who
graders in the US have used at least one illicit abuses drugs and ineffective parenting styles.
substance in their lifetime with the most com- Other factors such as history of trauma, neglect
monly reported substances being alcohol, tobacco and abuse, low self-esteem, aggression or comor-
bid externalizing disorders (ODD, CD) may also
play a role (Jackson et al. 2000; Collins et al.
The Abnormal Involuntary Movement Scale (AIMS)
5
2016; Stone et al. 2012).
(Guy 1976) is, among others, a useful tool to monitor for
neuromotor adverse effects secondary to antipsychotic All children over age 9 should be screened for
use. substance use (younger patients for any accidental

use) at every health visit. Tools such as the There is currently no evidence supporting the use
CRAFFT screen are widely used with good reli- of medicinal marijuana or pharmaceutical canna-
ability and psychometric properties (Knight et al. binoids for psychiatric symptoms in pediatric
2002). For more severe cases consultation with populations and yet it is often prescribed.
child/adolescent psychiatry colleagues may be Marijuana has been identified to have potential
helpful to help evaluate for addiction or depen- negative consequences with both short and long
dence, comorbid psychiatric disorders and sug- term use in adolescents. Learning difficulties sec-
gestions for treatment. ondary to impaired motivation, decreased con-
centration and attention span have been reported.
Further, impairment in judgment, reaction time,
Treatment and motor control have been documented poten-
tially negatively affecting function such as driv-
Treatment methodologies and timing for same in ing, sports, and daily activities. There is strong
adolescents depends on the severity and circum- evidence demonstrating the potential negative
stance of the use. Mild or casual use may benefit effect of cannabinoid exposure to the developing
from brief intervention—support, advice, educa- brain increasing predisposition risk for psychiat-
tion, counseling and monitoring. Further, the stage ric illness or sequela such as psychosis. Moreover
at which the adolescent is regarding readiness to the younger the exposure to marijuana the
change patterns of use is key to determining treat- increased likelihood drug addiction might
ment steps. Developing a therapeutic alliance with develop in adulthood (MacDonald and Pappas
the youth is crucial in determining these factors. 2016; Committee on Substance Abuse,
Several modes of psychotherapy have been evalu- Committee on Adolescence 2015). The American
ated with some evidence for success such as moti- Academy of Pediatrics (AAP) strongly opposes
vational interviewing, CBT, IPT, group therapy to marijuana use in the pediatric and adolescent
motivate and support youth on their path to recov- population 0–21 years (Committee on Substance
ery, help build social skills, enhance distress toler- Abuse, Committee on Adolescence 2015).
ance and reach a point of desire towards harm
reduction and possibly abstinence.
For more severe cases, a youth may consider Clinical Point 2
detoxification, involving physician assistance to
help stabilize the youth from the withdrawal annabis and Psychosis
C
effects of the substances. During detox and In the last decade a substantial amount of
potentially after the youth may benefit from research has demonstrated a strong association
medicines to assist with the detox process and/or between increased risk for psychotic disorders,
facilitate motivation and reduction of cravings/ particularly schizophrenia and exposure to can-
dependence in the attempt to reduce use (Collins nabinoids in those with a familial risk for schizo-
et al. 2016). A multidisciplinary approach fol- phrenia. Adolescents with regular cannabis use
lowing the youth and family throughout the double the risk for reporting psychotic symp-
treatment process promotes optimum treatment toms or being diagnosed with schizophrenia in
success. adulthood. Cannabis use has been shown to
increase morbidity (compared with other drugs
and alcohol) and confer a poorer prognosis on
Clinical Point those with schizophrenia contributing to altered
psychosocial function, cognitive impairment,
Marijuana is the most commonly used drug poor response to medication and nonadherence
among North American adolescents (American and increased rates of rehospitalisation
Academy of Pediatrics, Committee on Substances (Committee on Substance Abuse, Committee on
Abust and Committee on Adolescence 2015). Adolescence 2015; Fergusson et al. 2003;

534 S. Abidi
Radhakrishnan et al. 2014). For youth with a Andover MS, Morris BW, Wren A, Bruzzese ME. The co-
family history of schizophrenia or other psy- occurrence of non-suicidal self-injury and attempted
suicide among adolescents: distinguishing risk factors
chotic outcomes, counseling against cannabis and psychosocial correlates. Child Adolesc Psychiatr
use is essential referring to the specific risk and Ment Health. 2012;6:11.
not just reduction of harm in general. Angold A, Costello EJ. Depressive comorbidity in children
and adolescents: empirical, theoretical, and method-
ological issues. Am J Psychiatry. 1993;150:1779–91.
Conclusion Avenevoli S, Swendson J, He J, et al. Major depression
Most psychiatric illnesses that present in in the national comorbidity survey–adolescent supple-
childhood and adolescence are neurodevelopment: prevalence, correlates, and treatment. J Am
Acad Child Adolesc Psychiatry. 2015;54:37–44.e2.
mental in nature, the symptoms of which exist
Beesdo K, Pine DS, Lieb R, Wittchen H-U. Incidence and
on a continuum of severity and impact on risk patterns of anxiety and depressive disorders and
functioning. The manifestation of phenotypes categorization of generalized anxiety disorder. Arch
may be contingent on exposure to risks factors Gen Psychiatry. 2010;67(1):47–57.
Birmaher B, Brent DA, Chiappetta L, Bridge J, Monga S,
related to illness that influence a child’s vul-
Baugher M. Psychometric properties of the screen for
nerability to illness development. The child- child anxiety related emotional disorders (SCARED):
hood and adolescent period is an exciting time a replication study. J Am Acad Child Adolesc
for clinicians working in the field in terms of Psychiatry. 1999;38(10):1230–6.
Brent D, Emslie G, Clarke G, et al. Switching to another
the potential for earliest identification of psy-
SSRI or to venlafaxine with or without cognitive
chiatric illness and implementation of stage- behavioral therapy for adolescents with SSRI-resistant
specific interventions that may simultaneously depression: the TORDIA randomized control trial.
reduce risk for poor outcomes. Familiarizing JAMA. 2008;299:901–13.
Bridge JA, Yengar S, Salary CB, et al. Clinical response and
oneself with the most up to date information
risk for reported suicidal ideation and suicide attempts
and concepts in this rapidly developing field is in pediatric antidepressant treatment: a meta-analysis of
essential. Clinicians need to adopt a curious randomized controlled trials. JAMA. 2007;63:332–9.
and transparent approach with youth and fam- Bussing R, Mason DM, Bell L, et al. Adolescent out-
comes of childhood attention-deficit/hyperactivity
ilies presenting for care. Engaging the youth,
disorder in a diverse community sample. J Am Acad
their families as well as expert colleagues in Child Adolesc Psychiatry. 2010;49:595–605.
child/adolescent psychiatry and utilizing all Calarge CA, Nicol G, Schlechte JA, Burns
available information including the most cur- TL. Cardiometabolic outcomes in children and ado-
lescents following discontinuation of long term ris-
rent evidence to collaboratively make reliable
peridone treatment. J Child Adoelsc Psychopharmacol.
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mately help to foster optimum outcome for Centred for Disease Control and Prevention. Youth risk
patients. behavior surveillance – United States. MMWR.
2012;61:11–2.
Chang KD. Diagnosing bipolar disorder in children and
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Update in Pediatric Rheumatology
21
Roberta A. Berard and Ronald M. Laxer
Introduction syndrome and advances in the most common

autoinflammatory diseases (periodic fever syn-
Pediatric Rheumatology is a rapidly evolving dromes) will be discussed and reviewed.
field. There have been many exciting advances in
the recognition, diagnosis and management of
autoimmune and autoinflammatory conditions Musculoskeletal Assessment Tool:
over recent years. In addition, pediatric musculo- The pGALs—Pediatric Gait, Arms,
skeletal complaints are very common in children Legs, and Spine (Foster et al. 2006)
presenting to general practitioners, pediatricians
and orthopedic surgeons which mandates a good Musculoskeletal problems are common present-
foundation of knowledge in the common inflam- ing complaints of children and youth to health
matory and non-inflammatory conditions by age care practitioners. This may include clinicians
group for timely, appropriate and evidence-based working in family practice, emergency medicine,
assessments. This chapter will focus on an update orthopedics, pediatrics or adult rheumatology in
in a few key areas in Pediatric Rheumatology. addition to nurse practitioners delivering primary
Advances in the assessment of the pediatric mus- care. A Canadian study published in 2012 exam-
culoskeletal (MSK) complaints for the general ined the annual prevalence of healthcare contacts
practitioner, the diagnosis and management of for MSK complaints using administrative data.
juvenile idiopathic arthritis (JIA), non-inflamma- One in eight children in Ontario make physician
tory MSK causes of pain, macrophage activation visits in a year for MSK complaints (122.1 per
1000 children). The majority of visits are for
injury and related conditions (63.2 per 1000),
R.A. Berard (*) arthritis (27.7 per 1000), bone and spinal condi-
Division of Rheumatology, Department of tions (14.2 per 1000) and congenital anomalies (3
Paediatrics, Children’s Hospital, London per 1000). The majority of children presented to
Health Sciences Centre, Western University, primary care physicians (74.4%), orthopedic sur-
800 Commissioners Road East, London,
N6A5W9 Ontario, ON, Canada geons (22.3%) and pediatricians (10.1%) (Gunz
e-mail: roberta.berard@lhsc.on.ca et al. 2012).
R.M. Laxer, M.D.C.M., F.R.C.P.C The majority of MSK disorders in children are
Division of Rheumatology, The Hospital for benign, self-limited and often trauma-related,
Sick Children, Department of Paediatrics and clearly not always requiring a subspecialist refer-
Medicine, University of Toronto, 555 University
ral. MSK symptoms can also be the presenting
Avenue, Toronto, M5G 1X8 Ontario, ON, Canada
e-mail: ronald.laxer@sickkids.ca features of Juvenile Idiopathic Arthritis (JIA),


538 R.A. Berard and R.M. Laxer
but also of more life-threatening conditions like part of the presenting complaint (Goff et al.
malignancy, infection, vasculitis and non- 2012).
accidental injury. Inflammatory arthritis can also The pGALS (Fig. 21.1) is an evidence-based
be seen in association with other chronic diseases approach to basic pediatric MSK assessment and
in pediatrics such as inflammatory bowel disease is aimed at the non-specialist in pediatric MSK
(IBD), psoriasis, and immune deficiency. medicine to be able to discern normal from
Several studies have highlighted the lack of abnormal. The components of the pGALS are
confidence that doctors have in their pediatric essentially the same as the adult GALS (Doherty
MSK clinical skills and knowledge (Myers et al. et al. 1992) with a few additional maneuvers as
2004; Jandial et al. 2009). Given the prevalence original testing of the GALS in the pediatric
of MSK complaints, clinicians require skills to patients missed significant abnormalities in the
effectively triage patients and when appropriate foot and ankles, wrists and temporomandibular
to refer to a subspecialist. In many conditions, joints. The pGALS has excellent sensitivity (97–
including JIA, there is a reported delay in referral 100%) to detect abnormalities, it is quick to do
to specialist care. It is likely that the delay in (taking an average of 2 min), and incorporates
access to care has an adverse impact on long- simple maneuvers that are used in clinical prac-
term clinical outcomes (Foster et al. 2010). There tice (Foster et al. 2006). The pGALS was vali-
have been considerable efforts to raise awareness dated in school-aged children but can be
of JIA, including educational strategies such as successfully performed in younger ambulatory
the pGALS and e-resources as outlined below. children. However, the examiner must take an
A detailed MSK physical examination should opportunistic approach given the cooperation
include growth parameters and vital signs. The level and attention span of the child.
presence of fever should alert the clinician to There should be a low threshold to perform
more severe conditions requiring urgent treat- the pGALs in the context of a patient with MSK
ment (e.g. septic arthritis). On general examina- complaints. It is particularly relevant in the fol-
tion, clues to the underlying diagnosis include lowing clinical scenarios: unwell child with
rash (psoriasis, viral exanthema, autoimmune), pyrexia, child with a limp, delay or regression of
iritis (IBD or enthesitis-related arthritis), and motor milestones, child with chronic disease
hepatosplenomegaly/lymphadenopathy sugges- with known association with MSK presentations
tive of malignancy. The MSK examination should (such as inflammatory bowel disease), and the
include a review of all joints and examination of “clumsy” child in the absence of neurological
gait but with a focus on the affected joints. Joint disease (Foster and Jandial 2013). The pGALS
abnormalities can be subtle and therefore looking should also be performed when the history is sug-
for asymmetrical changes can often be helpful gestive of inflammatory disease, such as joint
(except in symmetric disease). Additionally, swelling or stiffness, particularly morning or
regional muscle wasting indicates chronicity of post-inactivity (e.g. long car rides), and/or altered
the problem. In contrast to adults where the function (e.g. play, handwriting skills, and regres-
majority of diagnoses can be made by history, in sion of milestones).
pediatric patients, the history is often provided by The pGALs was developed to identify inflam-
an observer and may be vague with non-specific matory disease but has been shown to be effec-
complaints. It is certainly not uncommon to find tive in identifying other joint problems (e.g.
joint involvement that has not been mentioned as orthopedic problems involving the hip, scoliosis,
Fig. 21.1 (a–c) The pGALS musculoskeletal screen Hands on 15: Arthritis Research Campaign; 2008. P. 4–6.
(From Foster HE, Jandial S. pGALS—a screening exami- Copyright © Arthritis Research Campaign; with
nation of the musculoskeletal system in in school-aged permission)
children. Reports on the Rheumatic Diseases (Series 5),

21 Update in Pediatric Rheumatology 539
a
The pGALS musculoskeletal screen
Screening questions
• Do you (or does your child) have any pain or stiffness in your (their) joints, muscles or back?
• Do you (or does your child) have any difficulty getting yourself (him/herself) dressed without any help?
• Do you (or does your child) have any problem going up and down stairs?
FIGURE SCREENING MANOEUVRES WHAT IS BEING ASSESSED?

(Note the manoeuvres in bold are
additional to those in adult GALS2)
Observe the child standing • Posture and habitus

(from front, back and sides) • Skin rashes – e.g. psoriasis
• Deformity – e.g. leg length
inequality, leg alignment
(valgus, varus at the knee
or ankle), scoliosis, joint
swelling, muscle wasting,
flat feet
Observe the child walking • Ankles, subtalar, midtarsal

and and small joints of feet
‘Walk on your heels’ and and toes
‘Walk on your tiptoes’
• Foot posture (note if
presence of normal
longitudinal arches of
feet when on tiptoes)
‘Hold your hands out • Forward flexion of

straight in front of you’ shoulders
• Elbow extension
• Wrist extension
• Extension of small joints
of fingers
‘Turn your hands over and • Wrist supination

make a fist’ • Elbow supination
• Flexion of small joints
of fingers
‘Pinch your index finger • Manual dexterity

and thumb together’ • Coordination of small
joints of index finger and
thumb and functional
key grip

b FIGURE SCREENING MANOEUVRES WHAT IS BEING ASSESSED?
‘Touch the tips of your • Manual dexterity

fingers’ • Coordination of small
joints of fingers and
thumbs
Squeeze the metacarpo- • Metacarpophalangeal

phalangeal joints for joints
tenderness
‘Put your hands together • Extension of small joints

palm to palm’ and of fingers
‘Put your hands together
• Wrist extension
back to back’
• Elbow flexion
‘Reach up, “touch the sky”’ • Elbow extension

and • Wrist extension
‘Look at the ceiling’
• Shoulder abduction
• Neck extension
‘Put your hands behind your • Shoulder abduction

neck’ • External rotation of
shoulders
• Elbow flexion

c FIGURE SCREENING MANOEUVRES WHAT IS BEING ASSESSED?
‘Try and touch your shoulder • Cervical spine lateral

with your ear’ flexion
‘Open wide and put three • Temporomandibular joints

(child’s own) fingers in your (and check for deviation of
mouth’ jaw movement)
Feel for effusion at the • Knee effusion (small

knee (patella tap, or effusion may be missed
cross-fluctuation) by patella tap alone)
Active movement of knees • Knee flexion

(flexion and extension) and • Knee extension
feel for crepitus
Passive movement of hip • Hip flexion and internal

(knee flexed to 90º, and rotation
internal rotation of hip)
‘Bend forwards and touch • Forward flexion of

your toes?’ thoraco-lumbar spine
(and check for scoliosis)
Fig. 21.1 (continued)

Table 21.1 Normal variants in gait patterns and leg referrals to specialist care as needed. Details of
alignment
teaching and performing the pGALS are available
1. Habitual toe walking is common in young children on the following free educational resource: (http://
up to 3 years www.arthritisresearchuk.org/health-profession-
2. Intoeing can be due to:
als-and-students/video-resources/pgals.aspx).
• Persistent femoral anteversion (characterized by
child walking with patellae and feet pointing The same working group has also developed an
inwards and is common between ages of 3–8 years) online evidence based interactive learning tool
• Internal tibial torsion (characterized by child and information resource for education in pediat-
walking with patella facing forward and toes
ric musculoskeletal medicine (Smith et al. 2016).
pointing inwards and is common from onset of
walking to 3 years) Pediatric Musculoskeletal Matters (www.pmmon-
• Metatarsus adductus (characterized by a flexible line.org). This learning tool was designed to target
“C shaped” lateral border of the foot and most medical students and primary care doctors, how-
resolve by 6 years).
ever the content is certainly relevant to pediatri-
3. Bow legs (genu varus) are common from birth to
cians and other clinicians involved in the care of
early toddler, often with out-toeing (maximal at
approximately 1 year of age), and most resolve by pediatric patients. The site is an excellent resource
18 months with learning modules, a guide to the investiga-
4. Knock knees (genu valgus) are common and are tions and management of common MSK com-
often associated with in-toeing (maximal at plaints, case based teaching and problem list by
approximately 4 years of age) and most resolve by
age of 7 years
anatomic sites.
5. Flat feet—most children have a flexible foot with
normal arch on tiptoeing and resolve by 6 years
6. Crooked toes—most resolve with weight bearing pdate on Juvenile Idiopathic
U
Normal variants: indications for referral Arthritis
• Persistent changes (beyond the expected age
ranges) Juvenile idiopathic arthritis (JIA) is the most
• Progressive/asymmetrical changes
• Short stature or dysmorphic features common rheumatic disease in children, affecting
• Painful changes with functional limitations about 1 in 1000 children worldwide (Hayward
• Regression or delayed motor milestones and Wallace 2009). JIA is an umbrella term
• Abnormal joint examination elsewhere describing a group of arthritides of unknown eti-
• Suggestion of neurological disease/developmental
delay ology lasting more than 6 weeks with onset in
Data from Foster, H. E. & Jandial, S. pGALS – paediatric
children younger than 16 years of age (Petty et al.
Gait Arms Legs and Spine: a simple examination of the 2004). There are seven categories of JIA
musculoskeletal system. Pediatric Rheumatology Online (Table 21.2). An accurate diagnosis of JIA
Journal 11, 44, 2013
Table 21.2 Juvenile idiopathic arthritis categories
and hypermobility). The key to an appropriate Category Key features
interpretation of the pGALS is knowledge of Systemic arthritis Fever, rash, serositis,
normal movements of joints in different age adenopathy,
groups, variability in gait, leg alignment, and hepatosplenomegaly
Oligoarthritis 4 or fewer joints
normal motor milestones (Table 21.1). These
Polyarthritis, RF- 5 or more joints, RF-
normal variants are a common cause of parental
Polyarthritis, RF+ 5 or more joints, RF+
concern and often can be addressed with expla-
Psoriatic arthritis Psoriasis, nail pits, dactylitis,
nation and reassurance. family history of psoriasis
The pGALS is an essential clinical skill to be Enthesitis-related Enthesitis, acute uveitis,
acquired at a minimum, by all medical students as arthritis sacroiliitis, HLA-B27
part of undergraduate training and incorporated in Undifferentiated Fit into one or more criteria
the training of other clinicians (such as nurse or satisfy criteria for none
practitioners) to facilitate assessments and timely RF rheumatoid factor

depends on the history and physical examination. of their abilities. Physical activity is encouraged
The presence of a positive anti-nuclear antibody and is safe and important for children with JIA.
(ANA) or rheumatoid factor (RF) is neither nec- Nonsteroidal anti-inflammatory drugs
essary nor sufficient to make a diagnosis of JIA. (NSAIDs) are used frequently, in particular for
(Malleson et al. 2010) Early referral is essential the treatment of oligoarthritis patients and as an
to reduce morbidity in terms of effect on normal adjunct for pain and stiffness in polyarthritis
growth and development, pain and quality of life. patients. The most common side effects are nau-
As well, it is clear that earlier treatment can sea and/or vomiting. Naproxen and indomethacin
improve outcomes in terms of time to and rate of are available in liquid form for younger children
achieving remission (Albers et al. 2009; who cannot swallow pills. Use of NSAIDs is
Broughton and Armon 2012). appropriate before review with a pediatric rheu-
In years past, it has been a common misbelief matologist. Corticosteroid use is limited to bridg-
that children with arthritis outgrow the disease in ing therapy while DMARDs reach their
the adolescent years. Multiple long-term out- therapeutic effect. Corticosteroids are particu-
come studies published early in this century larly helpful in polyarthritis and systemic JIA;
report relatively poor outcomes even for the however, they do not induce remission and given
“mildest” cases (i.e. those with oligoarthritis). A the potential side effects, exposure should be lim-
Canadian multicenter retrospective cohort study ited. Particular attention to bone health and cal-
reported that at age 16, there was only a 50% per- cium and vitamin D supplementation should be
cent probability of remission (defined here as paid for any patient on prolonged oral corticoste-
2 years off medications and no disease activity). roid use. Intra-articular corticosteroid injections
At the time of the study, those patients >16 years can induce inactive disease when used as a mono-
of age had a high probability of active disease therapy or in conjunction with methotrexate.
(62–94% depending on category) in their thirties Triamcinolone hexacetonide is the preferred
and forties (Oen 2002). compound.
Over the last 15 years, tremendous advances The main synthetic DMARD used is metho-
have occurred in the treatment of JIA primarily trexate either by subcutaneous injection or orally
with the use of biologic therapies. More recent once weekly. The most common side effects are
data from a Canadian longitudinal outcomes nausea and vomiting for which anti-emetics are
study (Research on Arthritis in Canadian Children often used with variable effect. Other side effects
Emphasizing Outcomes: ReACCh-Out) suggests include fatigue, mouth ulcers and potentially liver
better outcomes in terms of rate and time to toxicity or bone marrow suppression. Monitoring
achieving remission in the short term (2 year data blood work including liver enzymes and a com-
reported); however, collection of longer-term plete blood count should be performed every
data is ongoing. 3 months (more frequently when the medication
As in other chronic illnesses of childhood, the is initiated). Folic acid is given with methotrexate
treatment of JIA must include a multidisciplinary and is thought to assist with gastrointestinal side
team approach. In all cases, the goal of treatment effects such as ulcers, nausea and transaminitis.
is complete remission and normal physical and Leflunomide and sulfasalazine are also used with
social/emotional development. Particularly with similar (no fatigue or mouth ulcers) side-effect
newer medications available, this end point is profiles. None of these medications are safe for
achievable for the majority of patients. Physical use in pregnancy.
and occupational therapy are essential in the The biologic DMARDs include the tumour
management of JIA. These therapies improve necrosis factor (TNF) inhibitors (etanercept, adali-
range of motion and mobility thereby ideally pre- mumab, infliximab), interleukin (IL) inhibitors
venting permanent disability. The therapists can (IL-1Ra-Anakinra, IL-1β-canakinumab, and IL-6-
also provide exercise guidelines to encourage tocilizumab), T-cell co-stimulatory modulator
children to be physically active within the limits (abatacept), and B-cell inhibitor (rituximab). In

Canada, generally speaking these medications are the side effects, cost, time to onset, length of
used in 15–20% of patients in a JIA cohort. Given therapy, and monitoring needed for each therapy
the potential adverse effects and cost associated to facilitate the conversation.
with these medications, the decision to pursue Uveitis associated with JIA is an important
these treatments must be carefully considered. cause of morbidity for patients with JIA. In the
There has been a significant initiative in the oligoarthritis subtype, up to 30% of children can
pediatric rheumatology community to develop be affected with chronic anterior uveitis. This is
quality measures for the process of care in juve- asymptomatic and is detected by routine screen-
nile idiopathic arthritis (Lovell et al. 2011). ing by slit lamp exam. Most patients develop uve-
Pediatric Rheumatology—Care and Outcomes itis after the onset of arthritis, but uveitis activity
Initiative Network (PR-COIN) is a network of does not parallel activity of joint disease. The
Rheumatologists, Nurses, Therapists, Social highest risk of developing uveitis is within two
Workers and support staff at rheumatology cen- years of onset of arthritis, and virtually all who
ters who in partnership with families are all develop uveitis will do so within 4 years. There
working together to transform how care is deliv- are expert based consensus guidelines for the
ered to children with JIA. One of their initiatives screening of uveitis based on age of onset, ANA
is a shared decision-making tool to guide conver- status and onset type of JIA (Cassidy et al. 2006;
sations with families about initiation of medica- Heiligenhaus et al. 2012). Treatment recommen-
tions. As outlined (Fig. 21.2), the tool highlights dations have not yet been developed. Screening is
Things to Consider? Treatment Plan a
Avoid these medicines if you... You and your care provider have discussed
: have liver disease your arthritis treatment today.
: have TB (you may need to be tested)
While taking these medicines you should...

: not become pregnant
Juvenile
: not drink alcohol
: not receive live vaccines Idiopathic
Medications require blood test monitoring. Arthritis
Leflunomide
(Arava®)
Sulfasalazine
(Azulfidine®)
Medication
Choice
Notes
Methotrexate
(Rheumatrex® or Trexall®)
Etanercept Adalimumab Anakinra Canakinumab

(Enbrel®) (Humira®) (Kineret®) (Ilaris®)
Abatacept Infliximab Rituximab Tocilizumab

(Orencia®) (Remicade®) (Rituxan®) (Actemra®)
Read.
Ask Questions.
Think.
Decide.
©2013, Cincinnati Children’s Hospital Medical Center. All Rights Reserved.
This work is taken from or based upon information and data from sites contributing to the Pediatric
Rheumatology – Care and Outcomes Improvement Network (PR-COIN) www.pr-coin.org and may
not be used for commercial purposes.
Fig. 21.2 (a, b) The Arthritis Medication Choice Cards (From The Pediatric Rheumatology Care and Outcomes
Improvement Network (http://pr-coin.org))

b
How Soon? How Often? Cost?
These medicines do not work right away. In general, these Medications differ on how often they need to be given. What you pay will depend on your insurance. Patient
medicines begin to work between 2 and 12 weeks. There are assistance programs may be available.
ways to manage symptoms until these medicines start working.
Leflunomide Sulfasalazine Leflunomide Sulfasalazine Leflunomide Sulfasalazine

(Arava®) (Azulfidine®) (Arava®) (Azulfidine®) (Arava®)
MONTH MONTH
(Azulfidine®)
4–8 4–12 1x 2x
weeks weeks day day $
Methotrexate Methotrexate Methotrexate

(Rheumatrex® or Trexall®) (Rheumatrex® or Trexall®) (Rheumatrex® or Trexall®)
MONTH
4–6 1x
weeks week $
Etanercept Adalimumab Anakinra Canakinumab Etanercept Adalimumab Anakinra Canakinumab Etanercept Adalimumab Anakinra Canakinumab
(Enbrel®) (Humira®) (Kineret®) (Ilaris®) (Enbrel®) (Humira®) (Kineret®) (Ilaris®) (Enbrel®) (Humira®) (Kineret®) (Ilaris®)
MONTH MONTH MONTH MONTH
2–4 2–4 1–3 1–3 1–2x 2–4x 1x 1x

weeks weeks weeks weeks week month day month $$
Abatacept Infliximab Rituximab Tocilizumab Abatacept Infliximab Rituximab Tocilizumab Abatacept Infliximab Rituximab Tocilizumab
(Orencia®) (Remicade®) (Rituxan®) (Actemra®) (Orencia®) (Remicade®) (Rituxan®) (Actemra®) (Orencia®) (Remicade®) (Rituxan®) (Actemra®)
MONTH MONTH MONTH MONTH
2–12 2–4 2–4 2–4 1x 1x 2x in 1–2x

weeks weeks weeks weeks month month 1 month every
6 months month $$$
How Long? Side Effects?

Stopping or decreasing the medicine may be There is no way to predict which, if any, of these side effects you will experience
considered after the disease is well controlled.
Common: Uncommon:
Leflunomide • stomach upset • low blood counts • severe skin reaction
(Arava®) • diarrhea • severe liver injury (Sulfasalazine only)
• How long has the disease been under control?
Sulfasalazine • headache (Leflunomide only)
• Are there bothersome side effects?
• How often does arthritis remain well controlled (Azulfidine®) • cold symptoms
after stopping?
• What are the treatment options if the arthritis comes
back or flares? • mouth sores • abnormal liver test
Methotrexate • nausea • low blood counts
(Rheumatrex® or Trexall®) • stomach upset
• headache
Etanercept Anakinra • redness or soreness • stomach upset • TB may come back • development of
(Enbrel®) (Kineret®) where needle enters • headache • serious infection that autoantibodies
skin • itchy or allergic rash needs antibiotic • muscle inflammation
Adalimumab Canakinumab
• common cold • low blood counts • cancers like lymphoma
(Humira®) (Ilaris®)
• sinus infection
Abatacept Rituximab • common cold • TB may come back • development of

(Orencia®) (Rituxan®) • sinus or throat infection • serious infection that autoantibodies
• stomach upset needs antibiotic • cancers like lymphoma
Infliximab Tocilizumab • headache • low blood counts • severe infusion reaction
(Remicade®) (Actemra®)
(allergic reaction)
Fig. 21.2 (continued)
every 3 months for the young (<4 years at onset ing for growth disturbances (particularly leg
of disease), female, ANA-positive oligoarthritis length discrepancy and growth abnormalities of
patients. Morbidity from uveitis includes cata- the mandible), screening and awareness of ado-
racts, glaucoma, band keratopathy and loss of lescent issues (mental health, sexual activity, and
vision. Visual outcome has improved over the alcohol use due to the potential for liver toxicity
past 20 years; most children have a relatively and teratogenicity associated with the most com-
good prognosis if the disorder is detected and monly used DMARD, methotrexate).
treated early. However, uveitis in childhood A change in the treatment paradigm for JIA,
(including JIA) remains a leading cause of loss of including an early introduction of synthetic
vision and blindness worldwide (10–15%). DMARDs and biologic DMARDs has remark-
A team approach to surveillance for and pre- ably improved the outcomes for patients. The
vention of complications of JIA and its treatment goals of therapy to achieve remission, minimize
is essential. The following considerations in the medication toxicity, maximize function, optimize
management of JIA highlight the importance of a growth and development and improve quality of
team approach: adherence to uveitis screening life are achievable. Multinational collaborative
guidelines, necessary laboratory monitoring for efforts addressing issues of incorporation of
medications, vaccine counseling (live vaccines genetic and immunologic data to develop out-
prohibited while on immunosuppression and come based classification systems and personal-
annual infleunza vaccine encouraged), monitor- ized treatment plans, and the timing of initiation

and cessation of biologic therapies, are central or spreads diffusely. The patients can develop
and ongoing areas of study to further the advances significant disability to the point of becoming
in the management of children with JIA. immobile and unable to function physically.
Additionally, the pain can lead to social with-
drawal, missed school days, and isolation.
Update on Non-inflammatory There are regional and diffuse pain amplifica-
Musculoskeletal Pain tion syndromes. The classic regionalized pain
syndrome is complex regional pain syndrome
Musculoskeletal pain is one of the most common Type I (CRPS1 or reflex sympathetic dystrophy).
presenting symptoms to health care practitioners. This entity is characterized by chronic pain
Benign limb pain of childhood (growing pains), involving a peripheral extremity, often following
hypermobility, overuse syndromes, malignancy an injury that leads to immobilization. The main
and pain amplification syndromes are the most clinical features are pain and allodynia (a painful
commonly seen non-inflammatory causes. An response to a normally innocuous stimulus),
excellent comprehensive review on this topic was edema, changes in skin blood flow leading to dis-
published in 2012 and is suggested for further coloration, and/or abnormal sweating in the
information (Weiser 2012). region of pain secondary to sympathetic dysfunc-
Growing pains, which is a misnomer, usually tion. Motor impairment (e.g. weakness) can also
occur outside of major growth spurt periods, with be seen. With exclusion of other conditions that
an onset between 4 and 10 years of age. Growing could lead to the degree of pain and dysfunction
pains are characterized by a deep aching, crampy (infection, malignancy, fracture), the treatment
pain in the thighs or shins bilaterally. They usu- involves intense physiotherapy with manipula-
ally occur at night causing nocturnal awakenings. tion of the extremity with the goal of restoring
The pain occurs mostly in the calves with a peak function. Desensitization with manual therapy as
intensity of 10–15 min that slowly resolves over well as heat/cold therapy is a mainstay of treat-
an hour. Massage, heat and/or analgesia with ibu- ment. Mirror box therapy is a novel specialized
profen or acetaminophen may be helpful. approach to the treatment of CRPS1 that has
Typically symptoms resolve by the morning and shown promising results in terms of pain reduc-
children are asymptomatic during the day. There tion (Cacchio et al. 2009). This technique uses
are symptom free periods between the episodes visual feedback as a substitute for inappropriate
from days to weeks. Few studies exist looking at proprioceptive feedback with the understanding
the long-term outcome of this condition. Five- that pain in this syndrome may be induced by a
year follow up results suggest resolution in about mismatch between proprioceptive feedback and
half of the patients but the remainder have persis- motor action.
tent complaints into adulthood (Uziel et al. 2010). Juvenile fibromyalgia is characterized by gen-
Chronic pain syndromes and pain symptoms eralized MSK aches at ≥3 sites for ≥3 months in
can often be more debilitating and difficult to the absence of underlying conditions or causes,
treat than inflammatory disease. Many children and with normal laboratory tests. The physical
with chronic MSK pain do not have an identifi- examination shows ≥5 tender points (areas of
able cause. The prevalence of chronic MSK pain tenderness occurring in muscle, muscle-tendon
is variable. One-third of school-age children junction, bursa, or fat pads). It is associated with
reported pain lasting longer than 6 months, more fatigue, poor sleep, chronic anxiety, chronic
than half of which was described as MSK pain headaches, and irritable bowel syndrome.
(Roth-Isigkeit et al. 2005). Pain syndromes fre- Conversion symptoms are also not uncommon.
quently start following an inciting injury or ill- Onset of the illness may be triggered by a change
ness, but also seem to be related to emotional in physical activity due to injury or chronic ill-
stress such as the loss of a loved one or moving ness. Often there is a family history of pain and a
house. After onset, the pain either stays localized pain role model in the family. The pathogenesis is

complex and likely related to abnormal pain pro- complicating sJIA has been proposed (Ravelli
cessing and central amplification. et al. 2016).
Effective treatment is through a multi- The main clinical manifestations of MAS are
disciplinary approach with the goal to focus on sustained fever (compared with the quotidian
pain control but also on regaining function and fever of sJIA), hepatosplenomegaly, anemia, liver
returning to regular daily activities. The three P’s function abnormalities, rash, coagulopathy, and
of pain management are pharmacological, physi- central nervous system dysfunction (lethargy,
cal and psychological and includes education, irritability, disorientation, headache, seizure or
sleep hygiene, exercise, physiotherapy, cognitive coma). Laboratory features suggestive of MAS
behavioral therapy for management of stress and include falling white blood cell count and plate-
pain triggers. As the primary care provider seeing lets, falling erythrocyte sedimentation rate
these patients, it is important to limit investigations
(secondary to hypofibrinogemia), significantly
and referrals to other specialists once the diagnosis increased ferritin level (>5000–10,000 ng/ml gen-
is clear. Additional excellent online resources for erally but should at least consider the diagnosis
patients, families and care providers are www. when the ferritin is >1000 ng/ml), elevated transa-
stopchildhoodpain.org and www.rsds.org. minases, hypertriglyceridemia, hypofibrinoge-
mia, elevated lactate dehydrogenase (LDH),
elevated d-dimers, and evidence of hemophago-
Macrophage Activation Syndrome cytosis on bone marrow aspirate (positive only in
60%) (Minoia et al. 2014). Although the ESR
Macrophage activation syndrome (MAS) is a decreases, the C-reactive protein level continues
potentially life-threatening complication of rheu- to increase in worsening MAS (Petty et al. 2016).
matic diseases (particularly systemic JIA) char- Elevated markers of T cell activation, including
acterized by activation of T cells and macrophages, soluble IL-2 receptor alpha chain and soluble
leading to an overwhelming inflammatory CD163, have good sensitivity. They are helpful in
response. Complete understanding of the patho- detecting subclinical disease and following
physiology is lacking but it is clear that the dys- response to treatment (Bleesing et al. 2007);
functional immune response is similar to that however, they are challenging to access given that
seen in other forms of hemophagocytic lympho- are only performed in specialized laboratories.
histiocytosis (HLH). MAS is classified as an A prolonged fever is defined as a single illness in
acquired cause of HLH, along with other acquired which duration of fever exceeds that expected for
causes such as infection, endogenous tissue dam- the clinical diagnosis (e.g. >10 days for a viral URI)
age (e.g. sepsis) and malignancy; whereas, in pri- (Long 2005). The most common rheumatic causes
mary HLH, the causes are genetic or of prolonged fever are KD, sJIA, systemic lupus
immunodeficiency related. erythematosus (SLE) and acute rheumatic fever
MAS can be a complication of a known case (ARF). However, MAS must be considered in this
of systemic JIA (sJIA) but can also be the initial context particularly because the presentation is
presentation of the disease. The incidence of often acute and may be severe with rapid develop-
MAS in sJIA is unknown but it is estimated that ment of multiorgan failure that requires the admis-
around 10% of children develop overt MAS. It is sion of the patient to the intensive care unit (Petty
abundantly clear that MAS occurs much more et al. 2016). In the context of a patient with pro-
commonly than thought, more recent data sug- longed fever a rheumatic cause should be consid-
gests that up to 30–40% of patients with sJIA will ered in the presence of the following: isolated fever
develop subclinical or MAS in a milder form >5 days in young infant (<6 months), presence of
(Behrens et al. 2007). Kawasaki disease (KD) arthritis/arthralgia, presence of a rash, presence of
and systemic lupus erythematosus (SLE) are also serositis, presence of cytopenias, culture negative
associated with MAS but not as frequently as sepsis, and/or recurrent and periodic episodes of
sJIA. A set of classification criteria for MAS fever (see Autoinflammatory disease below).

Early diagnosis and aggressive management Table 21.3 Differential diagnosis of periodic fever in
childhood
of MAS are necessary to avoid significant mor-
bidity and mortality. High-dose corticosteroids Infectious disease • Recurrent upper respiratory
and supportive care are the first-line therapies; tract infections
• Urinary tract infections
intravenous immunoglobulin and anakinra are • Viral infections (EBV,
also frequently used (particularly in MAS com- Parvovirus B19, HSV1 and
plicating sJIA) as well as cyclosporine and HSV2)
etoposide. • Bacterial infections (Borrelia,
Brucella, Salmonella,
tuberculosis, Yersinia)
• Parasitic disease (malaria,
Autoinflammatory Disease toxoplasmosis)
(Periodic Fever syndromes) Congenital immune • Primary immunodeficiencies
defects • Cyclic neutropenia
Fever syndromes • Familial Mediterranean fever
The autoinflammatory (AID) conditions are
• Cryopyrin associated periodic
caused by dysregulation in the innate immune sys- syndromes
tem (e.g. neutrophils, monocytes/macrophages). • Tumour necrosis factor
Typically, the AID are characterized by recurrent receptor associated periodic
syndrome
episodes of fever, systemic inflammation, multi-
• Mevalonate kinase deficiency
system involvement and possible end-organ dam- (includes Hyper-IgD
age. Periodic fever syndromes, the former term for syndrome)
this group of diseases, is not adequate because • PFAPA
• Periodic fever, aphthous
most syndromes are not truly periodic, and fever is
stomatitis, pharyngitis and
not a necessary feature. The definition of a peri- adenitis (PFAPA)
odic fever is recurring episodes of illness for which Neoplastic disease • Acute lymphoblastic
fever is the cardinal feature, and other associated leukemia
symptoms are similar and predictable, and the • Acute myeloid leukemia
• Lymphoma (Pel Epstein
duration is days to weeks, with intervening inter- fever)
vals of weeks to months of complete well being Autoimmune • Systemic lupus
(Long 2005). The main causes of periodic fever in erythematosus
childhood are outlined in Table 21.3. • Systemic JIA
The AIDs often presents a diagnostic chal- • Vasculitis
lenge to clinicians. Fever is a very common pre- Granulomatous • Blau syndrome
• Early onset sarcoidosis
senting symptom to health care professionals, the • Crohn disease
cause of which is rarely an AID. With multiple Adapted from Federici S and Gattorno M. A practical
febrile illnesses, the child is often evaluated by approach to the diagnosis of autoinflammatory disease in
several practitioners, leading to a delay in consid- children. Best Pract Res Clin Rheumatol 28, 263–276,
eration of an AID as the cause for the symptoms. 2014
The key to making the diagnosis is a careful his-
tory and physical examination. Important fea- well. If an AID is suspected, a fever and symp-
tures to consider narrowing the diagnosis of AID tom diary should be performed for at least
are the following: age at onset of the recurrent 6 months with consideration of referral to a pedi-
febrile episodes, ethnicity, family history, attack atric rheumatologist. Apart from familial
triggers, fever duration and periodicity, clinical Mediterranean fever (FMF), no validated diag-
manifestations, and response to therapy. nostic criteria are available (Yalcinkaya et al.
Investigations should be done when the patient is 2009). There is an evidence-based diagnostic
having an episode and also when well score that has been developed for the identifica-
(Table 21.4). In a typical AID, elevated inflam- tion of patients at a higher risk of carrying a caus-
matory markers are present with an attack but ative mutation in one of the genes associated with
normal blood work is seen when the patient is a periodic fever syndrome (Gattorno et al. 2008).

Table 21.4 Approach to periodic fevers and the most common cause of periodic fevers
History Physical examination (periodic fever, aphthous stomatitis, pharyngitis,
• Duration of febrile • Vital signs, growth and adenitis—PFAPA) will be reviewed. For a
episodes, regular or parameters full review of the AID, see 2012 paper by Hashkes
irregular and •H ead and neck exam—
and Toker (Hashkes and Toker 2012) and 2014
intervals mouth sores, pharyngitis,
• Associated cervical adenopathy paper by Federici and Gattorno (Federici and
symptoms • Rash Gattorno 2014).
• Full review of • Signs of serositis
systems • Hepatosplenomegaly
• Ill contacts • Other adenopathy
• Travel history • Joint abnormalities Familial Mediterranean Fever
• Pets •N eed to do full physical
• History of examination FMF was the first described (1945; Siegal 1949)
unpasteurized dairy,
and is the most common hereditary AID; it is inher-
uncooked meat, etc.
• Family and past ited in an autosomal recessive manner. It has been
medical history: linked to a genetic mutation in the MEFV gene
Ethnicity, encoding pyrin. There is an ethnic predilection in
consanguinity
Sephardic Jews, Arabic, Turkish and Armenian
Diseases in family:
renal transplants, populations. It is increasingly recognized in
hearing loss, early Ashkenazi Jews, Greeks and Italians and Japanese
deaths, amyloidosis (Ben-Chetrit and Touitou 2009).
• Past medical history:
FMF usually presents in childhood with 80%
appendectomy,
hearing loss of patients presenting prior to 10 years of age and
Investigations 90% by 20 years. The attacks are typically
• Complete blood count (CBC) 12–72 h in duration and can occur at variable
• Liver enzymes (AST, ALT) and Albumin intervals from every fews days to every few
• ESR, CRP months. Severe abdominal pain (caused by peri-
• Renal function
• Immunoglobulins G,A,M
tonitis), often mimicking appendicitis, accompa-
• Urinalysis (urine protein) nies fever in most patients. Pleuritis can occur in
• Immunoglobulin D up to one-third of patients. Monoarthritis and
• When indicated: rash (erysipelas-like rash on the shins and the
• Blood culture
• Viral testing, e.g. NP swab
dorsum of the feet) are additional characteristic
• Urine culture clinical features. Headaches related to aseptic
• If travel history, consider malaria smears meningitis may occur. In children younger than
• Tuberculin skin test 5 years of age, recurrent fever may be the only
• Imaging as directed by physical exam
• Serum amyloid A (done only in specialized
feature (Padeh et al. 2010).
laboratories) If left untreated, FMF can lead to renal failure
MVKD mevalonate kinase deficiency secondary to amyloidosis. There appears to be a
genotype-phenotype correlation with more
severe disease and amyloidosis occurring in
There is need to raise awareness of these con- patients with the M694V, M694I and M680I
ditions to decrease the delay in the time to refer- mutations (Gershoni-Baruch et al. 2003).
ral to a specialist in order to reduce associated Although an autosomal recessive condition, 30%
morbidity and to prevent any potential organ of patients who are diagnosed with definite FMF
damage. With a better understanding of the dis- by clinical criteria lack one or even two muta-
ease pathogenesis for many of the AID, there has tions, especially patients from Western Europe or
been an improvement in the diagnostic tests and the United States. There may be mutation or
therapeutic options for these patients. The fea- polymorphisms in genes other than MEFV gene
tures of the most common hereditary autoinflam- impacting on the development of FMF or the
matory disease (familial Mediterranean fever) severity of the disease. Further understanding of

the pathogenesis of FMF has led to new thera- completely asymptomatic between episodes, nor-
peutic options. An appreciation of the interaction mal growth and development, and exclusion of
of the pyrin protein with the inflammasome, cyclic neutropenia.
which is responsible for activation of inflamma- The pathogenesis of PFAPA is multifactorial
tory processes and promotes the maturation the and possibly includes infection and abnormal
proinflammatory cytokine IL-1β, has led to the host immune responses, characterized by
discovery of the role of IL-1 as the key cytokine cytokine dysfunction. There is a strong familial
driving the FMF attacks. clustering suggesting a potential genetic origin
Colchicine is the mainstay of treatment for but no consistent mutations or polymorphisms
FMF which completely prevents attack in at least have been identified that are relevant to the dis-
60–70% of patients with an additional 20–30% ease etiology. Variants in the inflammasome
having a partial response; only about 5% are con- related genes, such as NLRP3 and MEFV (pyrin)
sidered non-responders. In colchicine failures, have been detected, which suggests an oligenic or
IL-1 inhibitors can be used. Serum amyloid A polygenic etiology. In one study nearly half of
(SAA) may be helpful in monitoring treatment PFAPA patients (38/84) had a positive family his-
efficacy. Ongoing debate exists both on how to tory for recurrent fever and 10 of those had been
manage asymptomatic patients with homozygous diagnosed with PFAPA (Cochard et al. 2010).
mutations and also on which asymptomatic rela- A proposed “diagnostic test” in PFAPA is the
tives of patients with genetically proven FMF dramatic response to one dose of prednisone
should genetic testing be performed. (1–2 mg/kg) given at the onset of the attack; a
positive response is typically seen within a few
hours. With prednisone therapy, the intervals
eriodic Fever, Aphthous Stomatitis,
P between the attacks may shorten. Studying the
Adenitis and Pharyngitis (PFAPA) efficacy of therapy in PFAPA is challenging
given the lack of diagnostic criteria (leading to
Periodic fever aphthous stomatitis, adenitis, and inclusion of patients in studies that do not have
pharyngitis (PFAPA) is the most common AID in PFAPA) and the natural history to outgrow this
childhood with onset typically before the age of 5 condition. Response to prednisone therapy is
(most frequently age 2–3). PFAPA is the only true likely complete in 80–90% (Ter Haar et al. 2013),
“periodic” AID with attacks occurring every occasionally a second dose is required 24 h later.
3–6 weeks (parents can very often predict the day Tonsillectomy (with or without adenoidectomy)
of the attack). Parents/patients report a glassy-eyed is curative in the majority of patients with a meta-
look and feeling unwell several hours before the analysis showing complete resolution in 83%
onset of the attack. Pharyngitis is the most com- (95% confidence interval, 77–89%) (Garavello
monly report symptom associated with the fever, et al. 2011). Tonsillectomy may be an option for
occurring in >90% of patients. Bacterial throat those needing frequent dosing of corticosteroids
swabs are repeatedly normal. Cervical lymphade- or those patients with a marked negative impact
nopathy occurs in 60–80% and aphthous stomatitis on quality of life. A recent Cochrane review on
in 40%. However, the full triad only occurs in 25% this use of tonsillectomy for PFAPA concluded
(Tasher et al. 2006). It is not uncommon for patients that children who had had surgery were about
to also complain of headache, abdominal pain, nau- four times more likely to be free of PFAPA symp-
sea, vomiting, arthralgias, and myalgia. The diag- toms from the point of surgery until the end of
nostic criteria proposed by Thomas et al. (Thomas the follow-up period for the study than those
et al. 1999) include regular recurring fevers with an children treated with medical therapy (Burton
early age of onset (<5 years of age), constitutional et al. 2014).
symptoms in the absence of an upper respiratory Although there is no known risk for the devel-
infection with at least 1 the 3 criteria list above, opment of amyloidosis or other long-term

sequelae, this relatively common AID has sig- Ben-Chetrit E, Touitou I. Familial mediterranean Fever in
the world. Arthritis Rheum. 2009;61:1447–53. https://
nificant morbidity, including absence at school/
doi.org/10.1002/art.24458.
daycare, work days missed for parents/other Bleesing J, et al. The diagnostic significance of soluble
caregivers, and frequent clinical symptoms. CD163 and soluble interleukin-2 receptor alpha-chain
Morbidity is one of the main reasons for treat- in macrophage activation syndrome and untreated
new-onset systemic juvenile idiopathic arthri-
ment. The frequency and severity of attacks
tis. Arthritis Rheum. 2007;56:965–71. https://doi.
tends to decrease with time and most will out- org/10.1002/art.22416.
grow this condition during the second decade of Broughton T, Armon K. Defining juvenile idiopathic
life. arthritis remission and optimum time for disease-
modifying anti-rheumatic drug withdrawal: why we
need a consensus. Paediatr Drugs. 2012;14:7–12.
https://doi.org/10.2165/11595980-000000000-00000.
Summary Burton MJ, Pollard AJ, Ramsden JD, Chong LY,
Venekamp RP. Tonsillectomy for periodic fever, aph-
thous stomatitis, pharyngitis and cervical adenitis
There have been significant advances in our under-
syndrome (PFAPA). Cochrane Database Syst Rev.
standing of the etiopathogenesis for many of the 2014;9:CD008669. https://doi.org/10.1002/14651858.
rheumatic diseases, with ensuring impressive CD008669.pub2.
additions to the armamentarium of treatment Cacchio A, De Blasis E, Necozione S, di Orio F,
options for rheumatic disease. Particularly for JIA, Santilli V. Mirror therapy for chronic complex
regional pain syndrome type 1 and stroke. N Engl
treating to remission of disease is an achievable J Med. 2009;361:634–6. https://doi.org/10.1056/
target and ultimately finding a cure for the disease NEJMc0902799.
is at the forefront of research agendas. The major Cassidy J, et al. Ophthalmologic examinations in children with
objectives for the pediatric rheumatology commu- juvenile rheumatoid arthritis. Pediatrics. 2006;117:1843–
5. https://doi.org/10.1542/peds.2006-0421.
nity are to increase awareness of the relatively Cochard M, et al. PFAPA syndrome is not a sporadic
uncommon pediatric rheumatic conditions and to disease. Rheumatology. 2010;49:1984–7. https://doi.
educate and empower community practitioners org/10.1093/rheumatology/keq187.
with skills to confidently assess MSK complaints Doherty M, Dacre J, Dieppe P, Snaith M. The ‘GALS’
locomotor screen. Ann Rheum Dis. 1992;51:1165–9.
and appropriately triage referrals to specialist care Federici S, Gattorno M. A practical approach to the diag-
when needed. Certainly in JIA, earlier referral and nosis of autoinflammatory diseases in childhood. Best
treatment has been linked to improved outcomes Pract Res Clin Rheumatol. 2014;28:263–76. https://
in terms of disease control and quality of life. With doi.org/10.1016/j.berh.2014.05.005.
Foster HE, Jandial S. pGALS – paediatric Gait Arms Legs
increasing awareness of the AIDs, previously and Spine: a simple examination of the musculoskel-
undiagnosed children have been identified and etal system. Pediatr Rheumatol Online J. 2013;11:44.
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to referral to specialist care and shortening this gap Foster HE, Kay LJ, Friswell M, Coady D, Myers
A. Musculoskeletal screening examination (pGALS)
has the potential to reduce morbidity and poten-
for school-age children based on the adult GALS
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org/10.1002/art.22230.
Foster H, Rapley T, May C. Juvenile idiopathic arthri-
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Index
A Acute urinary tract infection, 393

Abdominal pain, 275–276, 299 Acute viral bronchiolitis, 331
Abdominal trauma, 93, 102, 244 bronchodilators, 332–333
ABLE trial, 317 diagnosis, 332
Abnormal Involuntary Movement Scale (AIMS), 532 feeding and hydration, 334
Abusive head trauma, 97 hypertonic saline, 333
Acetaminophen, 236 oxygen management, 334–335
Acquired aplastic anemia, 325 prevention, 335
Acquired epileptic aphasia, 446–447 suctioning, 333–334
Acquired hyperthyroidism, 261–266 AD, see Atopic dermatitis (AD)
Acquired hypothyroidism, 261 Addiction, 519, 533
Acute acetaminophen (APAP) toxicity, 295 Adenosine deaminase (ADA), 375
Acute kidney injury (AKI) ADHD, see Attention deficit hyperactivity disorder
definition, 398–399 (ADHD)
epidemiology, 400 Adjunctive steroid therapy, 230
etiology, 399–400 Adolescence
indications and timing of RRT, 400–401 cognitive changes, 3
prognosis, 401 confidentiality, 5–8
treatment, 400 development, 1–3
Acute liver failure (ALF), see Pediatric acute liver failure early adolescence, 1
(ALF) emotional changes, 4
Acute lung injury (ALI), 122 healthcare, 31, 33
Acute lymphoblastic leukemia (ALL) late adolescence, 1
genetic features, 464 middle adolescence, 1
aneuploidy, 464–465 patient interviewing, 5–7
genomic profile, 466 prolonged adolescence, 1–2
structural alterations, 465 psychosocial changes, 4
immunophenotype, 461–462 resources for patients, 13
immunotherapy, 470–471 substance use, 8
antibody conjugates, 471 Adrenal cortisol, 252, 253
bispecific antibodies, 471–472 Adrenal insufficiency (AI)
engineered T cells, 472–473 etiology, 251–252
moving novel therapies into frontline treatment, 473 investigations, 252–253
precision medicine therapies, 470–471 primary, 251
prognostic factors secondary, 251
clinical features, 462–463, 466 symptoms, 252
early response to therapy, 463–464 treatment, 253–254
treatment for childhood, 466–467 Adrenocortical carcinoma, 504–505
CNS-directed therapy, 467–468 Adrenocorticotropin (ACTH), 251
hematopoietic stem cell transplantation, 468 Adult height therapy, 257
novel therapy approaches, 468–473 Age of blood, 317–318
risk-adapted therapy, 467 Aggression
Acute pancreatitis (AP), 299, 301 antipsychotics and, 530
Acute renal failure (ARF), 398 ASD, 215
Acute respiratory distress syndrome (ARDS), 122 AI, see Adrenal insufficiency (AI)

S. Piteau (ed.), Update in Pediatrics, https://doi.org/10.1007/978-3-319-58027-2

554 Index
AID, see Autoinflammatory disease (AID) ARFID, see Avoidant/restrictive food intake disorder
Air entrapment, 233 (ARFID)
Airway management ARIPI trial, 317
pediatric emergency medicine, 223 Aromatase inhibitors, 257
transport team, 233 Array comparative genomic hybridization (aCGH), 369
trauma, 239 Arrhythmias, 66
AKI, see Acute kidney injury (AKI) ASD, see Autism spectrum disorder (ASD)
Alert, verbal, pain, unresponsive (AVPU) scale, 241 Askin tumor, 493
ALF, see Acute liver failure (ALF) Assisted reproductive technique (ART), 431
Alfa-fetoprotein (AFP), 500 Asunra®, 316
Allergic rhinitis, 49 Atopic dermatitis (AD)
Alpha-thalassemia, 316 calcineurin inhibitors in, 48–49
Alport syndrome, 373 food allergy risk with, 47–48
Alprolix®, 322 updates in, 45–46
ALPS, see Autoimmune lymphoproliferative syndrome Atrial septal defects (ASDs), 62, 64, 73
(ALPS) Atrioventricular septal (canal) defects (AVSDs), 62
ALTE, see Apparent life-threatening event (ALTE) Atropine, 225
Alveolar RMS, 497 Attention deficit hyperactivity disorder (ADHD), 110,
Ambulatory blood pressure monitoring (ABPM), 404 215, 515
American Academy of Pediatrics (AAP), 10 clinical point, 519
American College of Critical Care Medicine (ACCM), diagnosis, 517
228–230 prevalence, 517
American College of Medical Genetics (ACMG), 374 treatment, 517–518
American Heart Association, 66 Attenuated psychosis syndrome (APS), 516
Aminocaproic acid, 23 Atypical hemolytic uremic syndrome (aHUS), 405
Aminosalicylate (ASA), 280 Auditory brainstem response (ABR), 419
Amplatzer device, 73 Autism and Developmental Disabilities Monitoring
Analgesia, in procedural pain, 423 (ADDM) Network, 208
Anaphylaxis Autism Diagnostic Observation Schedule 2nd Edition
clinical presentation, 52–53 (ADOS-2), 213
definition, 51–52 Autism spectrum disorder (ASD), 387, 433, 515
diagnosis, 53–54 ADHD, 215
epidemiology, 52 anxiety, 216
management, 54–55 assessment/evaluation, 212–213
sign and symptom, 51 behavioral intervention, 214
Anemia, 15 biomedical interventions, 214–215
aplastic, 325–326 causes, 209–210
iron-deficiency (see Iron-deficiency anemia) DCD, 217
Aneuploidy, 464 definition, 207–208
Anogenital examination, 106 dyspraxia, 217
Antibiotic Stewardship, 355–357 gastrointestinal disorders, 216
Antibody conjugates, 471 genetics, 210–211
Anticoagulation therapy, 323–324 intellectual disability, 217
Anticonvulsants, 15 investigations, 213–214
Antidepressant, 521 irritability/aggression, 215–216
Antihistamine, 55 prevalence, 208–209
Antipsychotics, 529 risk-factors, 210
Anti-tissue transglutaminase (TTG), 272 seizures, 216
Anxiety sleep problems, 217
ASD, 216–217 tics and Tourette syndrome, 218
diagnosis, 523–524 treatment options for, 214
prevalence, 523 Autoimmune lymphoproliferative syndrome (ALPS),
treatment, 524–525 319, 324–325
Aplastic anemia, 325 Autoinflammatory disease (AID), 548–549
Apparent life-threatening event (ALTE), 338, 339 Autosomal dominant polycystic kidney disease
Applied behavioral analysis (ABA), 214 (ADPKD), 405, 406
ARDS, see Acute respiratory distress syndrome (ARDS) Avoidant/restrictive food intake disorder (ARFID), 516
ARF, see Acute renal failure (ARF) Axial skeletal tumors, 496

Index 555
B differential diagnosis, 91
Bacteremia documentation of physical findings, 92
epidemiology, 338 history, 91
time to blood culture positivity, 338 physical examination, 92
urinary tract infection, 337 testing for occult injuries, 93
Bag mask ventilation (BMV), 224, 225 Burns, 103–105
B-ALL, 461, 462
clinical features, 462–463, 466
CNS-directed therapy, 467–468 C
genetic features, 464–466 Calcineurin inhibitors, 48
hematopoietic stem cell transplantation, 468 Canadian Cardiac Disease in Pregnancy (CARPREG)
immunotherapy, 470–473 registry, 66
moving novel therapies into frontline treatment, 473 Canadian College of Medical Genetics (CCMG), 374
novel therapy approaches, 468–473 Cannabis, 533
precision medicine therapies, 470–471 Capnography, 118–119
risk-adapted therapy, 467 Carcinoma, hepatocellular, 502
Balloon enteroscopy, 303 Cardiac computed tomography (CT), 72
Basic life support (BLS) algorithm, 124 Cardiac MRI, 69–71
Bayley Scales of Infant Development, 64 Cardiac output (CO), 229
Benign epilepsy with centro temporal spikes (BECTS), Cardiopulmonary resuscitation (CPR), 99, 123, 225–226
450 Cardioversion, 226
Benign familial infantile seizure (BFIS), 443 CAR-expressing T cells, 472
Benign familial neonatal seizure (BFNS), 442–443 Catecholaminergic polymorphic ventricular tachycardia
Benign familial neonatal-infantile seizure (BFNIS), 443 (CPVT), 75, 76
Benign neonatal sleep myoclonus (BNSM), 457 Catheter based interventions, 72–73
Beta-thalassemia, 316 Catheter-associated blood stream infections (CLABSI),
Bidentate chelator, 316 128
Biliary atresia, 287 cCMV, see Congenital CMV (cCMV)
Bioinformatics, 119 Celiac disease
Bipolar disorder (BD) definition, 271
diagnosis, 526 diagnosis, 272
prevalence, 525–526 epidemiology, 271
safety, 527 genetics and risk facor, 271–272
treatment, 527 pathogenesis, 271
Bispecific antibodies, 471 treatment, 272
Bispecific T-cell engagers (BiTE), 471 Cell culture cytotoxicity neutralization assay (CCNA),
Bleeding disorder, see Hemophilia 354
Blinatumomab, 471 Central line associated infection (CLABSI), 286
Bone marrow replacement, 461 Central precocious puberty (CPP), 258
Bone mineral density (BMD), 14 Central venous catheter (CVC), 342
Bone tumors Centrosome, 406
epidemiology and genetic predisposition, 493–494 Cervical intraepithelial neoplasia (CIN), 349
histology and molecular profile, 494 CHD, see Congenital heart disease (CHD)
pathophysiology, 493–494 Chemical dependency professional (CDP), 12
staging, 494–496 Child maltreatment
symptoms, 494 abdominal trauma, 101–103
treatment and outcomes, 496–497 bruising, 89–91
Bortezomib, 468–469 cause of, 93
Breastfeeding, 429 differential diagnosis, 91
benefits, 416, 417 documentation of physical findings, 92
contraindications, 416 history, 91–92
supplement with, 416–417 physical examination, 92
Breathing, transport team, 233 testing for occult injuries, 93
Brief resolved unexplained event (BRUE), 339–341 burns, 103–104
Bronchiolitis, 331–335 differential diagnosis, 104
Bronchodilators, 332 documentation, 104–105
Bruising, child maltreatment, 89 history, 104
cause of, 93 medical testing, 105

556 Index
Child maltreatment (cont.) Cirrhosis, 293

physical examination, 104 CKD, see Chronic kidney disease (CKD)
definition, 84 Clinical genetics, 369–370
discharge and follow-up, 109 Clinical-decision support tools, 119
emergency contraception, 109 Clofarabine, 469
fractures, 93–94 Clostridium difficile infection (CDI), 353–355
cause of, 96 CMA, see Chromosomal microarray (CMA)
differential diagnosis, 94–95 CNS-directed therapy, acute lymphoblastic
history, 95 leukemia, 467
medical testing, 95–96 CNV, see Copy number variant (CNV)
physical examination, 95 Coagulopathy, 320
head and spine injuries, 97–98 Coarctation of the aorta (CoA), 62
cause of, 101 Cofactor therapy, 385
differential diagnosis, 98–99 Colchicine, 550
history, 99–100 Cold shock, 227, 228, 230
medical testing, 100–101 Colonoscopy, 303
physical examination, 100 Compensated shock, 226
HIV post exposure prophylaxis, 109 Complex regional pain syndrome Type I (CRPS1), 546
identifying, 86 Conduct disorder (CD), 515
neglect, 109 Congenital adrenal hyperplasia (CAH), 251, 252
physical abuse, 89 Congenital anomalies of the kidney and urinary tract
physical injuries (CAKUT), 408
developmental history, 87 Congenital cardiac disease, 421
documentation, 89 Congenital CMV (cCMV) infection, 359–360
general approach, 86 Congenital heart disease (CHD)
history, 87–88 cardiac CT, 72
non-judgemental and supportive style, 88 cardiac MRI, 69–70
physical examination, 88–89 catheter based interventions, 72–74
risk factors, 87 echocardiography, 71
psychosocial support, 109 epidemiology, 61–62
sexual abuse and assault exercise in, 65
documentation, 107 genetic syndrome, 64
forensic evidence collection, 108 heart transplantation, 63
history, 106 late outcomes, 62–63
interpretation of findings, 107 mortality rate, 61, 63
physical examination, 106–107 neonatal oximetry screening, 68
timing of examination, 105–106 neurodevelopmental outcomes in, 63–65
sexually transmitted infections, 108–109 pregnancy in, 66–68
terminology, 85–86 quality of life in, 65
United States, 83 survival rates for, 61
Child-centred approach, 236 termination rates, 61
Childhood absence epilepsy (CAE), 450–451 WHO Class I/IV, 67
Children’s Hospital of Eastern Ontario pain scale, 235 Congenital hypothyroidism, 259–261
Children’s Oncology Group (COG) MRD assay, 463 Constipation, 274, 276
Chimeric antigen receptor (CAR), 472 Continuous antibiotic prophylaxis (CAP), 395
Chlamydia, 108 Continuous EEG (cEEG) monitoring, 119
Choosing Wisely®, 344 Continuous renal replacement therapy (CRRT), 401
Chromosomal karyotyping, 448 Contraception
Chromosomal microarray (CMA), 213, 369–371, 448 conversation, 13
Chromosome variant, 370 decision-making, 14–15
Chronic kidney disease (CKD), 401 eligibility for various methods, 13–14
estimation GFR, 402 emergency contraception, 16–18
progression, marker, 402–403 LARC, 15
Chronic lymphocytic thyroiditis, 261 non-LARC option, 16
Chronic pain syndrome, 546 options to teens, 15
Chronic pancreatitis, 301 Copper intrauterine device (IUD), 17
Ciliopathies, 406 Copy number variant (CNV), 210, 370
Circulation Cornell Assessment for Pediatric Delirium (CAPD), 121
hemorrhage, 240 Coronary artery abnormalities, 66
transport team, 233 Corticosteroid therapy, 230, 280

Index 557
Corticotropin-releasing hormone (CRH), 251 Dysmorphic syndrome, 386

Cortisol, 252, 253 Dyspraxia, 217
CPP, see Central precocious puberty (CPP)
CPR, see Cardiopulmonary resuscitation (CPR)
CRAFFT screening, 11, 533 E
Craniopharyngioma, 252 Early infantile epileptic encephalopathy (EIEE), 443
Critical congenital heart disease (CCHD), 68, 421 Early myoclonic encephalopathy (EME), 444
Cross-Canada Anaphylaxis Registry (C-CARE), 52 Early T cell precursor (ETP) ALL, 462
Crushing head trauma, 99 Early-onset sepsis (EOS), 424
Culture-negative sepsis, 227 Echocardiography, CHD, 71
Cyberbullying, 28 Eculizumab, 406
CYP2D6 polymorphisms, 236 Edible marijuana, 9
Cytokine release syndrome (CRS), 471 Educational neglect, 110
Cytopenia, 325 EGD, see Esophagogastroduodenoscopy (EGD)
Cytotoxic agents, 468–470 E-learning, 129
Elimination diet, 43
Eloctate®, 321
D Embryonal tumors, 497
Decompensated shock, 226 Emergency contraception (EC), 16, 109
Deferasirox, 316 Emergency medical services (EMS), 232, 234
Deferiprone, 316 Emergency Triage Assessment at Treatment (ETAT), 128
Defibrillation, 225 Emerging genetic technology, 448–449
Delirium, 121 Emollients, 46
Denys-Drash and Fraiser syndrome, 490 Emotional development, 139, 141, 144, 147, 152, 156,
Depression, 14, 516 160, 165, 170, 174, 179, 184, 188, 193, 198
clinical point, 522–523 Emotional neglect, 110
diagnosis, 519–520 Encephalopathy, epileptic, 447, 451
prevalence, 519 Endoscopic retrograde cholangiopancreatography
safety, 522 (ERCP), 303
Desferal®, 316 Endoscopy, 301
Desferrioxamine, 316 Engineered T cells, 472
Developmental coordination disorder (DCD), 217 Enquiring about Tolerance (EAT) study, 44
Dextrose gel, 428 Enteroscopy, balloon, 303
Diabetes mellitus, 14, 530–531 Environmental peanut exposure (EPE), 48
Diagnostic and Statistical Manual of Mental Enzyme immunoassay (EIA), 354
Disorders , fifth edition (DSM-V), 25, 28, 457, Enzyme replacement therapy (ERT), 380
513–517, 520, 522, 524–526, 529, 532 EOS, see Early-onset sepsis (EOS)
Diaper dermatitis, 418 Eosinophilic esophagitis (EoE)
Diarrhea, 273 management, 270
DIC, see Disseminated intravascular diet, 270
coagulation (DIC) dilation, 271
Digital rectal exam (DRE), 241 drug, 270–271
Dilated cardiomyopathy (DCM), 75 pathogenesis, 269
Disability presentation, 269–270
GCS, 241 therapy, 270
transport team, 234 Epigenetics, 134
Disease-modifying therapy for IEM, 385 Epilepsy, 440
Disorders of sexual development (DSD), 24 diagnosis, 441
Disruptive mood dysregulation disorder (DMDD), focal, 441
516, 526 Epileptic aphasia, 446
Disseminated intravascular coagulation (DIC), 240, Epileptic encephalopathy, 443, 447, 451
319–321 Epileptic seizures, 439
DNA-based tests, 384, 421 Epileptic syndrome, 452
Domestic violence, 84 Epileptogenic lesion, 441
Dravet syndrome, 443, 446 Epinephrine, 54
Dronabinol, 9 ERCP, see Endoscopic retrograde
Duchenne muscular dystrophy, 371 cholangiopancreatography (ERCP)
Dysbiosis, 210 Esophagogastroduodenoscopy (EGD), 301, 302
Dyserythropoiesis, 316 Etonorgestrel (ENG) implant, 17
Dyslipidemeia, 531 ETV6-RUNX1 (TEL-AML1) gene fusion, 465

558 Index
European Registry on Pregnancy and Cardiac Disease medical testing, 95

(ROPAC) registry, 66 physical examination, 95
European Society of Human Genetics (ESHG), 374 Functional constipation (FC), 274, 276
Evans syndrome, 319 Functional diarrhea, 273–274
Ewing sarcoma, 493, 495 Functional gastrointestinal disorder (FGID), 272–273
Exercise, in CHD, 65–66
Exjade®, 316
Extracorporeal Liver Assist Device (ELAD), 299 G
Extracorporeal membrane oxygenation (ECMO), 415 Gastroesophageal reflux disease (GERD), 267, 268, 417
Extragonadal tumors, 501 Gastrointestinal bleeding, 301–303
Extrauterine growth failure, 432 Gastrointestinal disorder, 216, 273
Extremely preterm infant (EPT), 430 Gastroschisis, 284
Ex utero intrapartum treatment (EXIT), 416 GCTs, see Germ cell tumors (GCTs)
Eye injury, 99 Gender dysphoria (GD), 211
Eye tumors, 504 management of, 26
referral and treatment, 25–26
Gender expression, 25
F Gender identity, 25
Familial Mediterranean fever (FMF), 549–550 Gender identity disorder (GID), 211
Family history (FHx) Gene panel, 373
fracture, 95 Gene therapy, 375
physical injuries, 87 Generalized epilepsy with febrile seizures plus (GEFS+),
Feminizing hormones, 26 445–446
Fentanyl, 236 Genetic disease management, 375
Ferriprox®, 316 Genetic syndrome, 64, 66, 386
Fetal growth, 254 Genetic testing, in pediatric cardiology, 74
Fetal teratomas, 500 Genomic technology, 466
FGID, see Functional gastrointestinal disorder (FGID) Germ cell tumors (GCTs)
Fibrolamellar HCC, 503 histology and molecular profile, 500–501
Filaggrin (FLG), 46–47 staging, 501
Fine motor development, 139, 142, 146, 150, 154, 158, symptoms, 500
163, 168, 173, 177, 181, 186, 190, 195, 200 treatment and outcomes, 501–502
Fluid Expansion as Supported Therapy (FEAST) Germline mutations, 493
trial, 127 Gestational age (GA), 431
Fluid resuscitation, 240 Gestational alloimmune liver disease (GALD), 296
Fluorescence in situ hybridization (FISH), 465 Glasgow Coma Scale (GCS)
FMF, see Familial Mediterranean fever (FMF) disability, 241
Focal epilepsy, 441 transport team, 234
Focal segmental glomerulosclerosis (FSGS), 405 Glomerular disease, 396–398, 405–406
Focal seizure, 441, 444 Glomerular filtration rate (GFR), 402
Focused assessment of sonography in trauma (FAST), Glomerulonephritides, 396
241, 242 Glomerulonephritis (GN)
Food allergy clinical manifestation, 397
clinical presentation, 41 diagnosis, 397
diagnosis, 42–43 epidemiology, 397
management, 42–43 management, 397–398
pathophysiology, 40 prognosis, 398
physical examination, 42 Glucocorticoid, 251, 253
prevalence, 39 Glucocorticoid (steroid)-resistant nephrotic
prevention and new research, 44–45 syndrome, 405
risk factors, 40–41 Glucose monitoring, 428
risk with atopic dermatitis, 47–48 Glycemic control, 125
Western lifestyle, 40 Gonadotropin- releasing hormone (GNRH), 257
Food protein-induced enterocolitis syndrome Gonorrhea, 108
(FPIES), 41 Gore Septal Occluder device, 73
Foreign body ingestion, 301 GPO-L-ONE®, 316
Fractures, child maltreatment, 93 Graft-versus-host disease (GVHD), 468
cause of, 96 Grastek®, 50
differential diagnosis, 94 Gross motor development, 139, 142, 145, 149, 154, 158,
history, 95 162, 167, 172, 176, 182, 187, 191, 196, 201

Index 559
Group B Streptococcus (GBS), 338 Hepatosplenomegaly, 287

Growing pain, 546 Hereditary renal cystic disease, 406, 407
Growth failure, 255–256 Hexadentate chelator, 316
Growth hormone, 256–257 HIE, see Hypoxic ischemic encephalopathy (HIE)
Gut dysbiosis, 210 High frequency oscillatory ventilation (HFOV), 123
High value care, 344–347
Hirschsprung’s disease, 285
H Histamine2 receptor antagonist (H2RA), 268
Hair removal, 26 History of Presenting Illness (HPI), 87
Hashimoto’s thyroiditis, 261 HIV post-exposure prophylaxis (PEP), 109
Head and spine injuries, child maltreatment, 97 HIV/AIDS, 15
cause of, 101 HMB, see Heavy menstrual bleeding (HMB)
differential diagnosis, 98 Horner’s syndrome, 486
history, 99 HSCT, see Hematopoietic stem cell transplantation
medical testing, 100 (HSCT)
physical examination, 100 HTS, see Hypertonic saline (HTS)
Head injury, 93 Human leukocyte antigen (HLA), 271
Healthcare, 31 Human papillomavirus (HPV), 349–351
Hear screening program, 419 Hydrocortisone, 253
Heart failure, 62 Hydromorphone, 236
Heart transplantation, 63 Hydroxyurea, in sickle cell disease, 315
Heavy menstrual bleeding (HMB), 18–19 Hyperbilirubinemia, 286
additional treatment considerations, 23–24 Hyperdynamic shock, 227
evaluation, 19–20 Hyperglycemia, 125
history of, 19–21 Hyperlipidemia, 14
internal exam, 21 Hypertension, 14
laboratory and imaging studies, 22 diagnosis, 404
management, 21–22 epidemiology, 403
medical options for, 22–23 evaluation of target organ damage, 404
physical exam, 21 treatment, 404
testing, 21–22 Hyperthyroidism, acquired, 261
HEEADSSS mnemonic, 5 Hypertonic saline (HTS), 333
Hematology, 126 Hypertrophic cardiomyopathy (HCM), 74–75
Hematopoietic stem cell transplantation (HSCT), 380, Hypoglycemia
382, 465, 468 insulin induced, 252
Hemoglobin (Hb) disorder, 315 neonatal, 427
Hemoglobinopathy, 314 Hypoplastic left heart syndrome (HLHS), 63
Hemophagocytic lymphohistiocytosis (HLH), 547 Hypotension, orthostatic, 455
Hemophilia Hypothalamus, 251, 257, 259
gene therapy, 322–323 Hypothermia
treatment, 321 neuroprotective effects, 226
FIX-albumin fusion, 322 post-cardiac arrest, 226
FIX-Fc fusion, 322 therapeutic, 427
FVIII with pegylated liposomes, 322 Hypothyroidism
FVIII-Fc fusion, 321 acquired, 261
pegylated FIX, 322 congenital, 259
Hemorrhage Hypoxia, 233
circulation, 240 Hypoxic ischemic encephalopathy (HIE), 424
fluid resuscitation, 240 diagnosis, 425–426
Hemostasis, 324 management, 426–427
Hepatic encephalopathy (HE), 296 pathophysiology, 425
Hepatitis, viral, 292 prognosis, 427
Hepatitis B vaccine, 109
Hepatitis B virus (HBV), 293
Hepatitis C virus (HCV), 293–294 I
Hepatoblastoma (HB), 502 IBD, see Inflammatory bowel disease (IBD)
Hepatocellular carcinoma (HCC), 293, 502 Ibuprofen, 236
Hepatocellular carcinoma not otherwise specified (HCC Idelvion®, 322
NOS), 502 Idiopathic short stature (ISS), 256
Hepatoportoenterostomy, 288 IgA nephropathy, 397, 398

560 Index
Ileoanal pull-through with anal anastomosis (IPAA), 282 surgical management, 281–282
Immune thrombocytopenia (ITP), 318 pathophysiology, 277
Immunoglobulin A (IgA), 272 Infliximab block, 281
Immunoglobulin E (IgE), 40, 51 INFORM trial, 317
Immunology, 126 Inhaled steroids, 256
Immunomodulator, 281 Inheritance, 442
Immunophenotype, acute lymphoblastic leukemia, 461 Inherited arrhythmias, 75–76
Immunotherapy, acute lymphoblastic leukemia, 470–473 Inotuzumab ozogamicin, 471
Inborn errors of metabolism (IEM), 375 Insulin, induced hypoglycemia, 252
disease-modifying therapy for, 385 Insulin like growth factor (IGF), 256
small-molecule, 376–378 Intellectual development, 139, 141, 145, 149,
Indirect calorimetry, 125 153, 157, 161, 167, 171, 176, 180, 185,
Inertial trauma, 99 190, 195, 200
Infant Intellectual disability (ID), 217, 515
developmental phase, 136, 201 International Cardiac Collaborative on
emotional development, 141, 144, 147, 150, 152, Neurodevelopment (ICCON), 64
160, 165, 170, 174, 179, 184, 188, 193, 198 International Liaison Committee on Resuscitation
fine motor development, 142, 146, 150, 154, 158, (ILCOR), 421, 422
168, 173, 177, 181, 186, 190, 195, 200 International Neuroblastoma Pathology Classification
gross motor development, 142, 145, 149, 154, (INPC), 487
158, 162, 167, 172, 176, 182, 187, 191, International Neuroblastoma Risk Group Staging System
196, 201 (INRGSS), 488, 489
intellectual development, 141, 145, 149, 153, 157, International Neuroblastoma Staging System (INSS),
161, 167, 171, 176, 180, 185, 190, 195, 200 488
language development, 148, 152, 157, 161, 166, Interpersonal therapy (IPT), 521
171, 175, 180, 184, 189, 194, 199 Inter-pregnancy intervals (IPIs), 210
research for clinicians and practitioners, 203–204 Intestinal dysmotility, 285
serve and return interaction shapes brain Intestinal failure
circuitry, 135 causes, 285
social development, 140, 143, 147, 151, 155, 159, diagnosis, 284
164, 169, 173, 178, 183, 188, 192, 198 management, 284
social emotional development, 136–139 central access presrvation, 286
stress, 202–203 enteral nutrition, 285
formula, 417 parenteral nutrition, 284
mental health, 133–135 surgery, 286
prevention/management of procedural pain, 422–424 transplantation, 286
Infantile spasm (IS), 444–445 Intrachromosomal amplification of chromosome 21
Infant-parent interaction, 415–416 (iAMP21), 465
Infectious disease, 126 Intravenous antimicrobial therapy, 230
Clostridium difficile infection, 353 Intravenous epinephrine, 54
human papillomavirus, 349–351 Iron chelation, in thalassemia, 316–317
measles, 352–353 Iron-deficiency anemia
meningococcal disease, 360–361 definition, 313
MRSA infection, 357 development, 314
Zika virus infection, 361 diagnosis, 313–314
Inflammatory bowel disease (IBD) treatment, 314–315
clinical presentation, 277 Iron refractory iron deficiency anemia (IRIDA), 315
diagnosis, 278 Irritability, ASD, 215
epidemiology, 276–277 Irritable bowel syndrome, 275
evaluation, 277–279 ISS, see Idiopathic short stature (ISS)
extra-intestinal manifestation, 277
histology, 279–280
management, 280 J
aminosalicylate, 280–281 Jaundice, 296
biologic therapies, 281 Juvenile fibromyalgia, 546
corticosteroid, 280 Juvenile idiopathic arthritis (JIA), 542–546
immunomodulator, 281 Juvenile myoclonic epilepsy (JME), 452
outcome, 282

Index 561
K driving, 9–10
Kawasaki disease (KD), 547 lung disease, 9
Kelfer®, 316 mental health, 10
Ketamine, 225, 229, 237 testicular cancer, 9
Kidney tumors dabbing, 9
histology and molecular profile, 491 edible marijuana, 9
staging, 491–492 epidemiology, 8
symptoms, 490–491 forms of use, 9
treatment and outcomes, 492–493 inhaled use, 9
Kupffer cell, 295 medical marijuana, 9
pharmaceutical cannabinoids, 9
policy and legal considerations, 10
L screening and history, 10–11
Landau-Kleffner syndrome (LKS), 446 and sexual health, 10
Language development, 139, 148, 152, 157, 161, 166, synthetic marijuana, 9
171, 175, 180, 184, 189, 194, 199 MAS, see Macrophage activation syndrome (MAS)
LARC, see Long-acting reversible contraception (LARC) Masculinizing hormones, 26
Learning Early About Peanut (LEAP) study, 44 Massively parallel DNA sequencing, 369
Left ventricular mass index (LVMI), 404 Measles, 352
Left-sided obstructive lesions, 66 Measles-mumps-rubella (MMR) vaccine, 209
Lennox Gastaut syndrome, 451–452 Media and adolescents
Lesion, epileptogenic, 441 benefits, 29
Levonorgestrel (LNG) IUD, 17–18 guidance for parents and patients, 30
LGBTQ teens risks, 28–29
caring for, 24 Medical marijuana, 9
health considerations in, 27 Medical neglect, 110
sensitive care, 27 Medication, 33, 224
terminology, 24–25 Meningococcal B vaccine, 360
Li Fraumeni Syndrome, 490, 497 Meningococcal disease due to serogroup B (MenB), 360
Liletta®, 17 Mental Development Index (MDI), 64
Liver-based small-molecule IEM, 385 Mental health, 513, 521, 532
Liver progenitor cell (LPC), 296 Mental retardation (MR), 515
Liver tumors Mental status, assessment, 242
histology and molecular profile, 502–503 Metabolic Red Flags, 387
staging, 503 Metabolics, 369, 375–376
symptoms, 502 clinical paradigm, 376–383
treatment, outcomes, and surveillance, 503–504 disease-modifying therapy for IEM, 385
Long-acting reversible contraception (LARC), 15–17 DNA-based test, 384–385
Loss of heterozygosity (LOH), 371 newborn screening, 383
l-thyroxine, 261 Metabolism
Lutenizing hormone (LH), 18 clinical paradigm, 376
Lymphoblast, malignant B, 461 high-value ‘routine’ laboratory findings in, 380–381
Lymphoproliferative disease, 324 syndromic presentations in, 382–383
therapeutic approaches in, 381
Metabolomics, 386
M Metaiodobenzylguanidine (MIBG) imaging, 487
Macrophage activation syndrome (MAS), 547–548 Methicillin-resistant Staphylococcus aureus (MRSA)
Major depressive disorder (MDD), 520 infection, 357–359
Malignant B lymphoblast, 461 Microbiology, sepsis, 227
Malignant GCTs, 500 Midazolam, 237
Malignant migrating partial seizures of infancy Migraine headaches, 15
(MMPSI), 444 Minimal residual disease (MRD), 463
Malnutrition, 283 Mircoarray, chromosomal, 370
Maple syrup urine disease (MSUD), 419 Mirena®, 17
Marijuana, 533 Mirror box therapy, 546
adverse effects Mixed lineage leukemia (MLL) gene, 465
addiction, 9 Molecular Absorbent Recirculating System (MARS),
cognitive development, 10 299

562 Index
Movement disorder, 531 factors that affect neutrophil count, 326

Moxetumomab pasudotox, 471 management, 326–327
MR spectrometry (MRS), 100 sign and symptom, 326
Multidimensional Anxiety Scale for Children (MASC), New York Heart Association (NYHA)/Ross
524 classification, 62
Multiple intraluminal impedance (MII), 268 Newborn
Multisystemic therapy, 517 blood spot screening, 419
Musculoskeletal (MSK) assessment tool, 537–542, 546 care, 416
Myocardial viability, 70 cleaning, 418
diaper care, 418
routine bathing, 418
N skin, 418
NAFLD, see Nonalcoholic fatty liver disease (NAFLD) Newborn intensive care unit (NICU), 231
NAS, see Neonatal abstinence syndrome (NAS) Newborn screening (NBS), 383–384, 418–420
Natural moisturizing factors (NMFs), 47 Nexplanon®, 17
Nausea, 274–275 Next generation sequencing (NGS), 369, 371
Near-infrared spectroscopy (NIRS) monitoring, 117 N9-GP®, 322
Neglect, 109–111 Non-acidic reflux, 268
Nelarabine, 469–470 Nonalcoholic fatty liver disease (NAFLD)
Neoadjuvant treatment, 485 diagnosis, 290
Neonatal abstinence syndrome (NAS), 428 histologic evaluation, 291
clinical manifestation, 429 laboratory evaluation, 291
drugs, 430 management, 292
in infants, 430 radiologic evaluation, 291
management, 429–430 pathogenesis, 290
pathophysiology, 429 presentation, 290
Neonatal cholestasis screening, 291–292
diagnosis, 288 Nonalcoholic steatohepatitis (NASH), 289
etiology, 287 Nonepileptic paroxysmal events, 439
management, 288–289 benign neonatal sleep myoclonus, 457
pathogenesis, 286–287 breathholding spells, 456
presentation, 287 non-epileptic seizure, 458–459
Neonatal encephalopathy, 424 orthostatic hypotension, 455
Neonatal hypoglycemia, 427–428 postural orthostatic tachycardia syndrome, 455
Neonatal intensive care unit (NICU), 432–437 pseudosyncope, 456
Neonatal nutrition, 416 reflex anoxic seizure, 455
Neonatal oximetry screening, 68–69 self-induced syncope, 455
Neonatal resuscitation, 421–422 stretch syncope, 455
Neonatal sepsis, 424 syncope, 453, 456–457
Neonatal-perinatal medicine, 415 tic disorder, 457–458
Neonate functional gastrointestinal disorder, 273 vasovagal syncope, 453–455
Neonatology, 415 Non-epileptic seizure, 458
Nephroblastomatosis, 490 Non-IgE mediated food allergy, 40
Nephrogenic rests, 490 Non-inflammatory musculoskeletal pain, 546–547
Nephrolithiasis, 408–413 Non-rhabdomyosarcoma (non-RMS), 497, 498
Nephrology, 391 Nonsteroidal anti-inflammatory drug (NSAID)
Nephrotic syndrome, 391 , 21, 23, 543
Neuroblastoma Non-suicidal self-injury (NSSI), 516, 522–523
histology and molecular profile, 487 Non-syndromic hearing loss, 373
retroperitoneal, 488 Noonan’s syndrome, 255
staging for, 487–488 Novel therapy approach, acute lymphoblastic
symptoms, 486–487 leukemia, 468
treatment and outcomes, 488–490 Nucleic acid amplification test (NAAT), 108, 354
Neurocritical Care Society, 122 Nutrition, 282–283
Neurodevelopmental disorder, 515 guidelines, 124
Neurology neonatal, 416–417
delirium, 121
status epilepticus, 122
traumatic brain injury, 120 O
Neutropenia Obesity, 14

Index 563
Obsessive compulsive disorder (OCD), 525 Pediatric Confusion Assessment Method (pCAM-ICU),
Obstructive shock, 240 121
Ohtahara syndrome, 443–444 Pediatric critical care
Oligonucleotide array, 371 ARDS, 122–123
One-way valve effect, 239 bioinformatics, 119
Opioid agents, pain, 236, 237 capnography, 118–119
Oppositional defiant disorder (ODD), 515 cardiopulmonary resuscitation, 123–124
Oral allergy syndrome, 41 cEEG monitoring, 119
Oral analgesics, pain, 236 education
Oral anticoagulant, 323 courses, 128
Oral food challenge, 43 e-learning, 129
Orchiectomy, 500 simulation, 128–129
Organellar disease, 378–379, 382–383 glycemic control, 125
Orthostatic hypotension, 455 hematology
Osteomyelitis, 341 thromboprophylaxis, 126
oral vs. intravenous antibiotic therapy, 342–343 transfusion strategies, 126
transition to oral antibiotics, 343 indirect calorimetry, 125
Osteosarcoma, 493–496 neurology
Otoacoustic emission (OAE), 419 delirium, 121
Ovarian GCTs, 501 status epilepticus, 122
Ovulation, 18 traumatic brain injury, 120–121
Oxyhemoglobin, 117 NIRS monitoring, 117–118
nutritional guidelines, 124–125
patient care bundles, 128
P patient monitoring, 117
Paediatric BASIC, 128 post-cardiac arrest management, 124
Pain sepsis, 126–127
assessment, 235 standardized handover tools, 127
non-pharmacologic management, 236 ultrasound technology, 119
opioid agents for, 236, 237 Pediatric cuffed endotracheal tubes, 224
pharmacologic management, 236–237 Pediatric early warning scores (PEWS), 127–128
topical agents, 238 Pediatric emergency medicine, 227
PALF, see Pediatric acute liver failure (PALF) airway management, 223–224
PALISI guidelines, 123 equipment for intubation, 224
Pancreatitis, 299 medication, 224–225
anatomic/obstructive risk factor, 300 post-cardiac arrest hypothermia, 226
environmental risk factor, 300 resuscitation, 223
etiology, 300 sepsis (see Sepsis)
genetic risk factor, 300 Pediatric Fundamental Critical Care Support (PFCCS),
management, 300–301 128
metabolic risk factor, 300 Pediatric gait arms legs and spine (pGALS), 537
presentation, 299–300 Pediatric intensive care unit (PICU), 232
ParaGuard®, 17 Pediatric nephrology, 391
Paraneoplastic syndrome, 486 Pediatric Rheumatology—Care and Outcomes Initiative
Parenteral nutrition associated liver disease (PNALD), 285 Network (PR-COIN), 544
Paroxysmal events, 439 Pegylation, 321
Past medical history (PMHx) Periodic fever, 548, 549
fracture, 95 Periodic fever aphthous stomatitis, adenitis, and
physical injuries, 87 pharyngitis (PFAPA), 550–551
Patch testing, 43 Peripheral neurologic exam, 242
Patient monitoring, 117 Peripheral precocious puberty (PPP), 258
Pediatric acute liver failure (PALF), 292, 122 Peripherally inserted central catheter (PICC), 341
diagnosis, 296–297 Pervasive developmental disorder, not otherwise
management, 297–299 specified (PDD-NOS), 208
pathogenesis, 295–296 Phalates, 259
presentation, 296 Pharmaceutical cannabinoids, 9
Pediatric Advanced Life Support (PALS) Phenylketonuria, 418
algorithms, 223 Philadelphia chromosome (Ph), 465
Pediatric cardiology, genetic testing in, 74 Physical abuse, 84, 89
Pediatric chest pain, 76 Physical injuries, 86–89

564 Index
Physical neglect, 110 Rapid sequence intubation (RSI), 224, 225

PICC, see Peripherally inserted central catheter (PICC) Rapidly progressive renal dysfunction (RPGN), 397
Pituitary gland, 251 Rare tumors, 500–504
Pleomorphic RMS, 497 RCC, see Renal cell carcinoma (RCC)
Post-cardiac arrest hypothermia, 226 Recombinant growth hormone, 257
Post-cardiac arrest management, 124 RECSS trial, 317
Post-streptococcal glomerulonephritis, 397, 398 Recurrent respiratory papillomatosis (RRP), 349
Posttraumatic stress disorder (PTSD), 516 Red cell transfusion trigger, 317
Postural orthostatic tachycardia syndrome (POTS), 455 Reflex anoxic seizure, 455–456
PPI, see Proton pump inhibitor (PPI) Reflex sympathetic dystrophy, 546
PPP, see Peripheral precocious puberty (PPP) Reflux, 267
Precocious puberty, 258 diagnostic considerations, 268
Prednisone poor response (PPR), 463 management, 268–269
Pregnancy, in CHD, 66–68 Renal cell carcinoma (RCC), 490, 493
Pre-hospital care trauma, 239 Renal dysfunction, 298
Prematurity, 430–431 Renal Fanconi syndrome, 406
Pre-oxygenation, 224 Renal replacement therapy (RRT), 400
Preschool Confusion Assessment Method Renal tubular disorder, 406–407
(psCAM-ICU), 121 Renal tumors, 490, 493
Procedural pain, 236 Renin-angiotensin system, 491
Progressive myoclonic epilepsy (PME), 452 Respiratory syncytial virus (RSV), 332
Prokinetic agent, 268 Resuscitation, 223
Prolonged fever, 547 Retinal hemorrhage, 99
Prophylactic antibiotics, 336–337 Retinoblastoma, 504
Prophylaxis, 126 Retroperitoneal neuroblastoma, 488
Propofol, 225 Return of spontaneous circulation (ROSC), 124
Propylthiouracil (PTU), 262 Rhabdoid tumors, 493
Proton pump inhibitor (PPI), 268, 270 Rhabdomyosarcoma (RMS), 497, 499
Pruning, 133 Rheumatology, 537
Pseudosyncope, 456 Risk-adapted therapy, acute lymphoblastic leukemia, 467
Psychiatric illness, 513, 514, 534 RMS, see Rhabdomyosarcoma (RMS)
Psychogenic pseudosyncope (PPS), 456 Rocuronium, 225
Psychomotor Development Index (PDI), 64 RSV, see Respiratory syncytial virus (RSV)
Psychosis, 533–534 Russel Silver syndrome, 255
Psychosocial support, 109
Psychostimulant, 518, 519
Psychotherapy, 26 S
Psychotic spectrum disorder Sarcomas, 493–500
diagnosis, 528 SBI, see Serious bacterial infection (SBI)
prevalence, 527–528 SCD, see Sickle cell disease (SCD)
treatment, 528–529 Schizophrenia, 528
PTSD, see Posttraumatic stress disorder (PTSD) Screen for Child Anxiety and Related Emotional
Pubertal delay, 258–259 Disorder (SCARED), 524
Puberty Screening, brief intervention and referral to treatment
blockers, 26 (SBIRT), 11
control, 257–258 Seizures, 216
definition, 257 Selective serotonin reuptake inhibitors (SSRIs), 21, 521,
environmental exposures and, 259 522, 525
precocious, 258 Self-induced syncope, 455
Pulmonary vascular disease, 66 Self-reported food allergy, 39
Pulse oximetry screening, 69 Sensorial stimulation (SS), 423
Sensorineural hearing loss (SNHL), 359
Sentinel chromosome translocation, 465
Q Sentinel node biopsy, 498
Quality of life (QOL), 65 Sepsis, 126, 425
cold shock, 228
definition, 226
R diagnosis, 228
Radial orchiectomy, 500 epidemiology and risk factors, 226–227
Randomized Intervention for Children with etiology, 227
Vesicoureteral Reflux (RIVUR) trial, 336 management, 228–230

Index 565
microbiology, 227 imaging, biopsy, and surgical considerations,

pathphysiology, 227–228 485–486
warm shock, 228 survivorship/late effects, 505
Septic shock, 226 Spinal cord injury without radiographic abnormality
clinical presentation, 228 (SCIWORA), 242
cold vs. warm, 228 Splenectomy, 318, 319
diagnosis, 228 SSTI, see Skin and soft tissue infection (SSTI)
mortality, 227 Standardized handover tools, 127
treatment, 228, 229 Status epilepticus, 122
Sequencing-based technology Steroid, inhaled, 256
gene panel, 373 Stevens Johnson syndrome, 527
principles, 371–372 Stress, developmental phase, 202
whole-exome sequencing, 373 Stressor-related disorder, 515
Serious bacterial infection (SBI), 338 Stretch syncope, 455
Serum-specific IgE testing, 43 Subacute sclerosing panencephalitis (SSPE), 209
Severe myoclonic epilepsy of infancy (SMEI), 446 Subcutaneous immunotherapy (SCIT), 49
Severe sepsis, 226 Subdural hemorrhage, 98
Sexual abuse, 84 Sublingual immunotherapy (SLIT), 49–51
Sexual abuse and assault, 105–108 Suboptimal communication, 127
Sexual attraction, 25 Substance use, see also Marijuana
Sexual health, marijuana use and, 10 adolescents, 8
Sexual maturity rating (SMR), 106 behavioral treatment, 12–13
Sexual orientation, 25 detox/withdrawal, 12
Sexually transmitted infections (STI), 108 disclosure of, 12
Second generation antipsychotics (SGA), 528 SBIRT, 11
diabetes, 530 support groups, 12–13
dyslipidemeia, 531 treatment, 12
movement disorder, 531–532 Substance use disorder (SUD)
Shaken Baby Syndrome, 97 clinical point, 533–534
Shimada system, 487 diagnosis, 532–533
Shock, see Specific types of shock prevalence, 532
Short gut syndrome treatment, 533
central access preservation, 286 Substrate reduction therapy (SRT), 385
definition, 283 Succinylcholine, 225
enteral nutrition, 285–286 Sucrose, 237–238
parenteral nutrition, 284–285 Sudden cardiac death, 75–76
surgery, 286 Suicide, 521
transplantation, 286 Surface tumors, 494
Short stature, 255 Synapses, 133
Sickle cell disease (SCD), 315–316 Synaptogenesis, 133
Single nucleotide polymorphism (SNP) array, 371 Synthetic marijuana, 9
Skeletal injury, 93 Systemic inflammatory response (SIRS), 226
Skin and soft tissue infection (SSTI), 358 Systemic JIA (sJIA), 547
Skin prick testing, 42 Systemic lupus erythematosus (SLE), 547
Skylaa®, 17 Systemic vascular resistance (SVR), 227
Sleep problems, 217
Small-molecule disorder, 376–382
Smoking, 14 T
SNHL, see Sensorineural hearing loss (SNHL) T-ALL, 461–463
Social development, 139, 140, 143, 147, 151, CNS-directed therapy, 468
155, 159, 164, 169, 173, 178, genetics of, 466
183, 188, 192, 198 novel therapy for, 469
Social emotional development, 136–139 risk-adapted therapy, 467
Social media, 28–30 T cell, engineered, 472
Social Responsiveness Scale (SRS), 211 T-cell receptor gamma delta (TCRγδ), 272
Soft tissue sarcomas T cell receptor (TCR) gene, 463
histology and molecular profile, 497–498 T lymphoblast, 462
staging, 498 TCIs, see Topical calcineurin inhibitors (TCIs)
symptoms, 497–498 TCSs, see Topical corticosteroids (TCSs)
treatment and outcomes, 498–500 Team composistion, 231–232
Solid tumors Teratomas, 500

566 Index
Testicular GCTs, 500 AVPU scale, 241

Tetralogy of Fallot (TOF), 62, 74 brain injury, 243–244
TEWL, see Transepidermal water loss (TEWL) breathing, 239–240
Thalassemia, iron chelation in, 316 circulation and hemorrhage control, 240
Therapeutic hypothermia, 427 exposure and temperature control, 241
Thoracic trauma, 244 fluid resuscitation and hemorrhage, 240–241
Thrombocytopenia, immune, 318–319 GCS, 241
Thrombogenic mutation, 14 pre-hospital care, 239
Thrombopoietin (TPO) receptor agonist, 318 panel, 242
Thromboprophylaxis, 126 primary survey, 241–242
Thrombosis, 319, 323 scope of, 238–239
Thymic stromal lymphopoietin (TSLP), 466 secondary survey, 242–243
Thyroid disease, 259 thoracic, 244
Thyroid stimulating hormone (TSH), 259 Traumatic brain injury (TBI), 118, 120
Thyrotropin-releasing hormone (TRH), 259 TRICC trial, 317
Tic disorder, 457 TRIPICU trial, 317
Tics and Tourette syndrome (TS), 217–218 Trisomy 21, 255
Toddler functional gastrointestinal disorder, 273 Tube thoracostomy, 233
Toddler’s fracture, 95 22q11 microdeletion syndrome, 64
Topical agents, pain, 238 Tyrosine kinase inhibitor (TKI), 465
Topical calcineurin inhibitors (TCIs), 46, 48
Topical corticosteroids (TCSs), 46, 48
Total iron binding capacity (TIBC), 314 U
Tourette Syndrome International Database Consortium Ulcerative colitis, 279
Registry, 217 Ulipristal acetate (UPA), 18
Tracheal intubation, 223 Ultrasound technology, 119–120
Tranexamic acid (TXA), 23, 240 Umbilical cord core, 418
Transepidermal water loss (TEWL), 45 Undifferentiated syndrome, 386
Transferrin saturation (TS), 314 Upper gastrointestinal series (UGI), 278
Transfusion associated necrotizing enterocolitis Urinary tract infection (UTI)
(TA-NEC), 318 bacteremic, 337–338
Transfusion medicine, 317 clinical presentation, 393
Transfusion strategies, 126 diagnosis, 335–336, 393
Transient loss of consciousness (TLOC), 456 pathogenesis, 392
Transitional cell tumors, 502 treatment, 393
Transitioning patients urinary tract imaging, 393–394
to adult healthcare, 31 Ursodeoxycholic acid (UDCA), 289
with chronic disease, 31–32 Uveitis, 544
in clinical practice, 31
completion, 32
health values, 31 V
health-related skills and knowledge, 31–33 Vaccine
planning, 32 hepatitis B vaccine, 109
policy for, 31 human papillomavirus, 349–351
readiness, 32 meningococcal B, 360
tracking and monitoring, 32 MMR vaccine, 209
transfer of care, 32 Vasovagal syncope, 453
Transport modes, 232–233 Ventricular septal defects (VSDs), 62, 64
Transport team Vernix caseosa, 418
airway and breathing considerations, 233 Very preterm infant (VPT), 430
circulatory considerations, 233–234 Vesicoureteral reflux (VUR)
composistion, 231 antibiotic prophylaxis, 395
disability and exposure considerations, 234 definition, 394
supplies and equipment, 234–235 diagnosis, 394–395
Transposition of the great arteries (TGA), 63 prophylactic antibiotics in children with, 336
Trans Student Educational Resources (TSER), 24 surgical intervention, 395
Trauma, 515–516 Video capsule endoscopy (VCE), 279
ABCDE approach, 239, 240 Viral hepatitis, 292–293
abdominal, 244 Viral lower respiratory tract pathogens, 331
airway, 239 Visceral hypersensitivity, 275

Index 567
Voice and communication therapy, 26 Whole-exome sequencing (WES), 369, 373–374

Volumetric capnography, 119 Whole-genome sequencing (WGS), 211, 374
Vomiting, 274, 275 Wilms tumors, 490–491
von Willebrands disease, 491
Y
W Yolk sac tumors, 500
WAGR syndrome, 490 Yupze method, 18
Warfarin, 323
Warm shock, 227, 228
Wear and tear effect, 202 Z
Weight loss surgery (WLS), 292 Zika virus (ZIKV), 361–362
West syndrome, 444

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Shalea Piteau

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

ISBN 978-3-319-58026-5 ISBN 978-3-319-58027-2 (eBook)

Library of Congress Control Number: 2017964312

© Springer International Publishing AG, part of Springer Nature 2018

Printed on acid-free paper

FB:Cardiologia Siglo XXI

Pediatrics is evolving with new advancements in knowledge, research, and

ON, Canada Shalea Piteau

FB:Cardiologia Siglo XXI

1 Update in Adolescent Medicine���������������������������������������������������� 1

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11 Update in Pediatric Hematology�������������������������������������������������� 313

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Sabina Abidi, M.D., F.R.C.P.C. Department of Psychiatry at IWK, Halifax,

FB:Cardiologia Siglo XXI

Lisa A. DelSignore, M.D. Division of Critical Care Medicine, Department

FB:Cardiologia Siglo XXI

Madhavi Moharir Infant Mental Health Promotion, HSC, Toronto, ON,

FB:Cardiologia Siglo XXI

Adjunct Lecturer, Lawrence S. Bloomberg Faculty of Nursing, The University

FB:Cardiologia Siglo XXI

Introduction including healthcare. Providers can help shep-

© Springer International Publishing AG, part of Springer Nature 2018 1

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

accompanied by increased myelination and Confidentiality

FB:Cardiologia Siglo XXI

Table 1.2 The HEEADSSS assessment: a psychosocial interview tool

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

Table 1.3 Indications for breaking confidentiality

Adolescents are very likely to try illicit drugs as

FB:Cardiologia Siglo XXI

Forms of Use Medical Marijuana: At the time of this publi-

FB:Cardiologia Siglo XXI

Sexual Health Providers should screen children and teenagers

FB:Cardiologia Siglo XXI

LSD/acid, non-prescribed medications (such as severity of substance use. Brief Intervention is

The CRAFFT Screening Interview

Fig. 1.1 The CRAFFT Part B No Yes

FB:Cardiologia Siglo XXI

While not recognized as evidence-based treat-

FB:Cardiologia Siglo XXI

chemical dependency. Youth-specific groups are Starting the Conversation

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

 escribing Contraceptive Options

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

Table 1.8 Long-acting reversible contraceptive options

Etonorgestrel Inserted into arm, Thickened cervical mucus 3 years Radio-opaque

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

FB:Cardiologia Siglo XXI

prescribed iron regimens is variable; patients Caring for LGBTQ Teens

ON, Canada Shalea Piteau

1 Update in Adolescent Medicine�� 1

11 Update in Pediatric Hematology�� 313

Introduction including healthcare. Providers can help shep-

accompanied by increased myelination and Confidentiality

Forms of Use Medical Marijuana: At the time of this publi-

Sexual Health Providers should screen children and teenagers

chemical dependency. Youth-specific groups are Starting the Conversation

escribing Contraceptive Options

prescribed iron regimens is variable; patients Caring for LGBTQ Teens

Sensitive Care offered PrEP, a medication which can be taken

Media and Adolescents An increasing body of international literature

Clinicians can be involved in several aspects of ransitioning Patients with Chronic

Medication Adherence Finding an Adult Healthcare Provider

Food Allergy Prevalence

Introduction The prevalence of food allergy is a challenging

Pathophysiology Risk Factors

Epidemiology Anaphylaxis can present with a wide variety of

ongenital Heart Disease: Current

Cardiac Imaging Cardiac MRI is now considered the ‘gold stan-