Jpog June 2014 Id

JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
INDONESIA
YOUR PARTNER IN PAEDIATRIC AND O&G PRACTICE MAY/JUN 2014 VOL. 40 NO. 3 ISSN 1016-0124
www.mims.com
MIMS mobile
FEVER IN THE
RETURNED CHILD
TRAVELLER
CME ARTICLE OBSTETRICS GYNAECOLOGY
Intrauterine Fetal Growth Management of Pain and Coping with Chronic
Restriction 5 SKP Fever during Pregnancy Vulvovaginal Candidiasis
JPOG_MayJun14_CVR_2.indd 5 6/4/14 6:53 PM

SGM Presinutri
Karena Nutrisi yang Anda Berikan di
Mendukung Kualitas Kehidupannya di Masa Depan
Hanya untuk Kalangan Medis

Dikembangkan oleh lebih dari 400 tim ahli
nutrisi dari Yogyakarta, Singapura, dan
Belanda dengan standard Internasional.
Lebih dari 60 tahun pengalaman dalam

menyediakan nutrisi Ibu dan Anak Indonesia.
Mendukung nutrisi yang tepat untuk

perkembangan otak, imunitas melalui
kesehatan saluran cerna dan
pertumbuhan fisik Ananda.1-7
Referensi:
1. Gluckman, Hanson, Cooper, & Thornburg. Effect of In Utero and Early-Life Conditions on Adult Health and Disease. N Engl J Med 2008; 359:61-73.
2. Koletzko, Berthold, et al. The roles of LC-PUFA in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations.
J. Perinat. Med 36 2008.
3. Georgieff, Michael K. Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr 2007;85(suppl):614S-20S.
4. Niness, Kathy R. 1999. Nutritional and Health Benefits of Inulin and Oligofrucose. J. Nutr. 129: 1402S-1406S.
5. Salgueiro et al. The Role of Zinc in the Growth and Development of Children. Nutrition 18:510-519, 2002.
6. Untoro, Juliawati, et al. 2005. Multiple Micronutrient Supplements Improve Micronutrient Status and Anemia But Not Growth and Morbidity of
Indonesian Infants. J. Nutr. 135: 639s-645s.
7. Vlaardingerbroek, H, et al. Amino Acids for the Neonate: Search for the Ideal Dietary Composition. NeoReviews 2011;12;e506-e516.
ASI adalah yang Terbaik

JPOG MAY/JUN 2014 i
90 92
MAY/JUN 2014 Vol. 40 No. 3
Editorial Board
Board Director, Paediatrics
Journal Watch
Professor Pik-To Cheung
Associate Professor
Department of Paediatrics 89
and Adolescent Medicine
The University of Hong Kong Link between cognition and anxiety in children may
vary with age
Board Director, Obstetrics and Gynaecology
Professor Pak-Chung Ho
Pre-term birth has long-term effects on motor
Head, Department of development, behaviour and school performance
Obstetrics and Gynaecology
The University of Hong Kong
90
Review of the evidence of a link between asthma
Professor Biran Affandi Professor Carmencita D Padilla
and air pollution in children
University of Indonesia University of the Philippines Manila Underutilization of interventions proven to manage
Dr Karen Kar-Loen Chan Professor Seng-Hock Quak pain during infant vaccinations
The University of Hong Kong National University of Singapore
Professor Oh Moh Chay Dr Tatang Kustiman Samsi
KK Womens and Childrens Hospital, University of Tarumanagara, Indonesia
Singapore 91
Professor Alex Sia
Associate Professor Anette Jacobsen KK Womens and Childrens Hospital, Growing-up milk supplement reduces the
KK Womens and Childrens Hospital, Singapore
Singapore incidence of infection in young children
Dr Raman Subramaniam
Professor Rahman Jamal Fetal Medicine and Gynaecology Centre, Long-term neuropsychological consequences of
Universiti Kebangsaan Malaysia
Malaysia opioid use in children
Dato Dr Ravindran Jegasothy
Professor Walfrido W Sumpaico
Hospital Kuala Lumpur, Malaysia
MCU-FDT Medical Foundation,
Professor Kenneth Kwek Philippines
KK Womens and Childrens Hospital,
92
Professor Cheng Lim Tan
Singapore KK Womens and Childrens Hospital, Education, cotinine levels linked to smoking
Dr Siu-Keung Lam Singapore
Prestige Medical Centre, Hong Kong cessation in women using NRT
Professor Kok Hian Tan
Professor Terence Lao KK Womens and Childrens Hospital, Optimized asthma management during pregnancy
Chinese University of Hong Kong Singapore
could affect childhood asthma risk
Dr Kwok-Yin Leung Professor Surasak
The University of Hong Kong Taneepanichskul
Chulalongkorn University, Thailand
Dr Tak-Yeung Leung
Chinese University of Hong Kong Professor Eng-Hseon Tay
Thomson Women Cancer Centre,
Professor Tzou-Yien Lin
Singapore
Chang Gung University, Taiwan
Professor Somsak Lolekha Professor PC Wong
Ramathibodi Hospital, Thailand National University of Singapore
Professor Lucy Chai-See Lum Adjunct Professor George SH Yeo

University of Malaya, Malaysia KK Womens and Childrens Hospital,
Singapore
Professor SC Ng
National University of Singapore Professor Hui-Kim Yap
National University of Singapore
Professor Hextan
Yuen-Sheung Ngan Professor Tsu-Fuh Yeh
The University of Hong Kong China Medical University, Taiwan
JPOG_MayJun_2014_Final_TOC.indd 1 6/4/14 2:58 PM

JPOG MAY/JUN 2014 iii
93 103
Review Article
Publisher Ben Yeo
Publication Manager Marisa Lam
Managing Editor Greg Town
Designers Agnes Chieng, Sam Shum
Production Edwin Yu, Ho Wai Hung, Steven Cheung
Circulation Christine Chok
paediatrics
Accounting Manager Minty Kwan
Advertising Coordinator Jasmine Chay 93
Published by:
Fever in the Returned Child Traveller
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Fever is common in children after overseas travel. Although usually
Tel: (852) 2559 5888 | Email: enquiry@jpog.com a symptom of a nonspecific self-limiting condition, it can signify
a serious illness such as malaria, dengue fever, enteric fever,
rickettsial disease, tuberculosis, yellow fever or hepatitis. A detailed
travel history and examination for specific symptoms and signs can
help guide investigations and the decision to refer to hospital.
Enquiries and Correspondence
Ameneh Khatami, David Isaacs, Ben Marais
China Philippines
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Management of Pain and Fever during
Korea
Choe Eun Young Vietnam Pregnancy
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Email: inquiry@kimsonline.co.kr Nguyen Thi My Dung
Tel: (84 8) 3829 7923 Pregnant women do not need to suffer unnecessary pain or
Indonesia Email: enquiry.vn@mims.com
Duma Evi Ulina Silalahi potentially dangerous fever for fear of their taking medica-
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Email: enquiry.id@mims.com Kristina Lo-Kurtz tions that may be harmful to their unborn baby. Healthcare
Tel: (852) 2116 4352 providers should be confident when prescribing appropriate
Malaysia Email: kristina.lokurtz@mims.com
Meera Jassal, Lee Pek Lian,
Sheena Subash, Grace Yeoh
treatment to such women during pregnancy.
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Debra Kennedy
PUBLISHER: Journal of Paediatrics, Obstetric & Gynaecology (JPOG) is published 6 times a year by MIMS Pte Ltd. CIRCULATION: JPOG is
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Review Article JPOG welcomes papers in the

following categories:
Gynaecology Review Articles
112 Comprehensive reviews providing the latest clinical information
on all aspects of the management of medical conditions affecting
Coping with Chronic Vulvovaginal Candidiasis children and women.
Acute vulvovaginal candidiasis (VVC) is common and usually
easily treated but some women develop chronic symptoms that Case Studies
do not respond to conventional anti-Candida treatment. Recently Interesting cases seen in general practice and their management.
proposed diagnostic criteria may help clinicians identify women
with chronic VVC. Evidence is mounting that it represents a
Pictorial Medicine
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Cystoscopic Mapping to Ensure Optimal
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Menelik MH Lee, Charles J Carter, Tyrone T Carpenter
Continuing
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125
Intrauterine Fetal Growth Restriction 5 SKP
Intrauterine fetal growth restriction is a placental function disorder

in which Doppler ultrasound has a major role in fetal surveillance.
Sequential changes in Doppler velocimetry of the umbilical
artery, middle cerebral artery and ductus venosus can be seen
in progressively worsening placental dysfunction. Management The Cover:
requires balancing the risk of prematurity and the risk of intrauterine Fever in the Returned Child Traveller
asphyxia. 2014 MIMS Pte Ltd
May Li Lim, Kenneth Kwek, Kok Hian Tan, George SH Yeo
Lisa Low, Illustrator

JPOG-thru-MIMS_0314.pdf 3 4/3/14 10:55 AM
JOURNAL WATCH peer reviewed JPOG MAY/JUN 2014 89
P havioural disturbance were determined school-age children remains unclear. A

using standard questionnaires. Assess- recent systematic review has, however,
ments were also made of the childrens indicated that children born before term
Paediatrics expectations and their responses to hy- are more vulnerable to impaired motor
pothetical ambiguous scenarios; all eval- development and poor behaviour and
Link between cognition and uations were compared among groups. school performance.
anxiety in children may There was no indication of a differ- The review identified 3,153 obser-
vary with age ence in threat interpretation among clini- vational and experimental studies pub-
cally anxious and control patients at any lished in Portuguese, Spanish or English
age. Moreover, among children aged between January 2002 and February
79, there was no evidence of reduced 2012 that were included in the MEDLINE/
coping expectation and little evidence PubMed, MEDLINE/BVS, LILACS/BVS,
of social anxiety-specific responses. IBECS/BVS, Cochrane/BVS, CINAHL,
In contrast, and unexpectedly, among Web of Science, Scopus, or PyscNet
children aged 1012, those with social databases. It assessed motor develop-
anxiety had significantly higher scores ment and/or behaviour and/or academic
for non-social threat interpretation than performance among children aged 810
the other clinically anxious group. Both years. The quality of the articles was as-
groups of clinically anxious children in sessed with Strengthening the Reporting
this age group also reported reduced of Observational Studies in Epidemiol-
expectations of social and non-social ogy (STROBE) and Physiotherapy Evi-
control compared with the non-anxious dence Database (PED) criteria, and only
children. studies with a score 80% were included
The researchers comment that their (n=33). All of these were observational.
findings challenge current cognitive ther- In total, 54% of the included studies
apeutic approaches. They suggest that evaluated data from children born at <32
there is no need to focus on changing weeks gestation, 9% evaluated those
childrens cognitions in mid-childhood born at 3236 weeks gestation, 6% in-
and that promotion of perceptions of cluded both age groups, and 30% only
control rather than a focus on reducing stated that the children were born at <37
threat interpretation may be more appro- weeks gestation. Seven of 11 assess-
The characteristic thinking styles of clin- priate in late childhood. ments of motor development, 13 of 20
ically anxious children appears to vary assessments of behaviour, and 12 of 16
Cresswell C et al. Interpretation and expectation in childhood
with age and may not be focused on anxiety disorders: age effects and social specificity. J Abnorm assessments of academic performance
Child Psychol 2014;42:453465.
threat interpretation, say UK-based re- reported an association with preterm
searchers. birth. Only four studies found no effect
Their study involved 120 children of prematurity on the studied outcomes.
aged 712 years (53% female) who were The researchers conclude that
diagnosed with social anxiety disorder Pre-term birth has longer-term follow-up of preterm children
(n=40), another anxiety disorder with- long-term effects on motor is needed.
out social anxiety (n=40), or no anxiety development, behaviour and
disorder (controls, n=40). The children school performance Moreira RS et al. Effect of preterm birth on motor development,
behavior, and school performance of school-age children: a
systematic review. J Pediatr (Rio J) 2014;90(2):119134.
and their parents participated in struc-
tured diagnostic interviews during which The early effects of pre-term birth are
symptoms of anxiety, low mood, and be- well known, but the long-term impact on
JPOG_MayJun_2014_Final_Combine.indd 89 6/5/14 8:32 PM

90 JPOG MAY/JUN 2014 JOURNAL WATCH peer reviewed
Review of the evidence of a outdoors and engage in physical activ- these interventions and their actual clin-
link between asthma and air ities that increase their breathing rate, ical use is often reported by parents to
pollution in children which leads to larger deposits of environ- be due to a lack of knowledge. A recent
mental pollutants in the respiratory tract; study therefore evaluated the impact of
and young children are also generally an instructional pamphlet on managing
oral breathers, which means that more pain during infant vaccinations on par-
polluted particles can enter their lower ent knowledge and behaviour, but found
airways as they are not filtered out by the that the pamphlet had little effect.
nasal filter. The instructional pamphlet was devel-
Numerous epidemiological studies oped based on the new evidence-based
have shown that exposure to common clinical practice guideline for managing
air pollutants is associated with individ- acute pain during childhood vaccina-
ual susceptibility to respiratory infections tion. It recommended the use of topical
as well as the severity of these infections, anaesthetics, sugar water, breastfeed-
and air pollutants have been shown to in- ing or bottle feeding/sucking, holding,
duce airway inflammation and increase distraction, and acting calm to combat
asthma morbidity in children. Indeed, pain, and advised against the use of
exposure to traffic-related air pollutants oral analgesics and ice. The pamphlet
can increase airway inflammation and/or was passively distributed as part of a
oxidative stress. Asthma is closely cor- discharge package given to 354 new
related with pollution-induced oxidative mothers at two hospitals (intervention
stress, but there is hope that antioxidant and external control sites) following the
substances may reduce this stress and birth of an infant. A follow-up telephone
any consequent lung injury, which could survey evaluated maternal knowledge
decrease childrens susceptibility to air and self-reported use of pain manage-
Children are uniquely vulnerable to the pollution. However, further studies are ment interventions during routine infant
adverse effects of air pollution, and a needed to identify the specific mecha- 2-month vaccinations.
recent review has outlined these vulner- nisms of action of different air pollutants, The pamphlet did not improve pa-
abilities as well as summarized what is to identify genetic polymorphisms that rental knowledge or use of pain man-
currently known about possible molecu- modify airway responses to pollution, agement strategies after vaccination, but
lar mechanisms linking air pollution and and to clarify the role of epigenetics. only 21% of the mothers who were giv-
asthma in children. en the pamphlet actually read it. These
Esposito S et al. Possible molecular mechanisms linking air
The review included all studies in- pollution and asthma in children. BMC Pulmonary Medicine parents reported greater knowledge of
2014;14:31.
dexed in the PubMed database that analgesic efficacy, but not increased fre-
were published in English over the past quency of use. However, a >10% abso-
15 years. Searches were made using lute increase in the use of topical anaes-
the key words air pollution or carbon thetics and sugar water was noted. The
monoxide or particulate matter or Underutilization of interventions researchers advise against passive dis-
diesel exhaust particles and children proven to manage pain during tribution of such pamphlets and instead
or paediatrics. infant vaccinations suggest a number of ways in which par-
The authors note that children are ents can be advised of the benefits of
more vulnerable to air pollution than Pain-relieving interventions have been available interventions.
adults because their lungs are still grow- proven to reduce injection-induced pain
Taddio A et al. Impact of a parent-directed pamphlet about
ing and environmental pollutants can in children, but are commonly underuti- pain management during infant vaccinations on maternal
knowledge and behavior. Neonatal Network 2014;33(2):7482.
thus more easily alter lung development lized by parents. The reason for this
and function; they spend a lot of time gap between the known efficacy of

JOURNAL WATCH peer reviewed JPOG MAY/JUN 2014 91
Growing-up milk supplement Portugal or Thailand. The children were Recently, a systematic review of
reduces the incidence of randomized to receive the growing-up the literature was performed by search-
infection in young children milk supplement (n=388) or growing-up ing the Medline/PubMed, PsychInfo, CI-
milk alone (control group, n=379) for 52 NAHL, and Cochrane Library databases
In the first study to demonstrate that a weeks after a 4-week run-in period. The and Google Scholar for relevant studies
prebiotic mixture can influence the risk of analysis was based on data from the 697 published between January 1992 and
infections, researchers recently showed subjects who completed the study. Find- December 2012. Only four studies were
that growing-up milk supplemented with ings were compared with a reference identified that assessed the long-term
short-chain galacto-oligosaccharides/ group of 37 children from The Nether- impact of opioid use in neonates; the
long-chain fructo-oligosaccharides and lands who received cows milk. authors thus extrapolated findings from
n-3 long-chain polyunsaturated fatty ac- Compared with children allocated six studies of adult patients, four studies
ids reduces the incidence of infection in to the control group, children who re- of prenatal exposure, and four animal
young children. ceived the growing-up milk supplement studies.
had a significantly lower risk of devel- Among the four neonatal studies,
oping at least one infection (relative risk morphine exposure was found to result
[RR] 0.93, 95% CI 0.871.00, p=0.03). in poorer visual analysis skills in one
A post-hoc analysis also indicated that study, but none reported any significant
children who received the supplemented effects on intelligence, behaviour, vo-
version of the growing-up milk experi- cabulary or motor skills. In contrast, in
enced significantly fewer infections than the prenatal studies, illicit opioid expo-
the control group (RR 0.89, 95% CI 0.82 sure was found to have a negative effect
0.97; p=0.004). The reference group of on language, reading, arithmetic, im-
children who received cows milk ex- pulse control, visual attention span/se-
perienced significantly more infections quencing, and school readiness skills.
than children who received the grow- Some adults who were prescribed
ing-up milk supplement or growing-up opioids showed neuropsychological
milk alone (RR 1.15, 95% CI 1.041.28; impairments relating to memory, deci-
p=0.005). sion-making, attention, concentration,
information processing, psycho-motor
Chatchatee et al. Effects of growing-up milk supplemented
with prebiotics and LCPUFAs on infections in young children. speed, visuospatial skills, and hand-
JPGN 2014;58:428437.
eye coordination. However, other adult
patients did not show any such impair-
ments and some studies even reported
improved perceptual cognition. The
Long-term neuropsychological authors presume that the observed im-
consequences of opioid provement was due to the removal of
use in children pain as a stressor. They suggest that
the long-term negative cognitive effects
One of the primary concerns in paedi- of opioid use may be dependent on
The randomized, double-blind, atric pain management is the long-term whether these are used in the presence
controlled, parallel intervention study effect of opioid use in children since or absence of pain.
performed between September 2008 many opioid receptors are located in
Jain et al. Long-term neuropsychological effects of opioid
and May 2009 involved 767 healthy chil- brain regions that mediate or modulate use in children: a descriptive literature review. Pain Physician
2014;17:109118.
dren aged 1129 months who attended attention, memory and learning. Howev-
a day care centre at least twice a week er, data on the long-term effects of opioid
in Malaysia, The Netherlands, Poland, use in children are scarce.

92 JPOG MAY/JUN 2014 JOURNAL WATCH peer reviewed
O line cotinine levels (OR 0.96, 95% CI gorithm of clinical symptoms. Follow-up
0.920.99; p=0.010). of the infants born to women in each of
The researchers noted that al- these groups revealed no difference in
Obstetrics though cotinine levels are markers of the prevalence of wheeze, frequency of
exposure to tobacco smoke and not wheezing and coughing, triggers, or se-
Education, cotinine levels linked nicotine dependence, they have been verity. However, infants born to mothers
to smoking cessation in shown to be highly correlated with a val- from the FeNO group were significantly
women using NRT idated measure of nicotine dependence less likely to have recurrent episodes of
in pregnancy. bronchiolitis during their first year of life
Smoking during pregnancy is a signif- (odds ratio [OR] 0.08, 95% CI 0.010.62;
Vaz et al. Factors associated with smoking cessation in early
icant and much-studied public health and late pregnancy in the smoking, nicotine, and pregnancy p=0.016). There was also a trend for
trial: a trial of nicotine replacement therapy. Nicotine & Tobac-
problem, but the factors that influence co Research 2014;16(4):381389. these infants to experience fewer croup
smoking cessation among women who episodes (OR 0.12; 95% CI 0.010.99;
use nicotine replacement therapy (NRT)
p=0.050).
were unknown until a recent analysis of
data from the Smoking, Nicotine and Mattes et al. Prenatal origins of bronchiolitis: protective effect
of optimised asthma management during pregnancy. Thorax
Pregnancy (SNAP) trial suggested that Optimized asthma management 2014;69(4):383384.
education level and baseline cotinine during pregnancy could affect

levels are linked to successful cessa- childhood asthma risk
tion.
The SNAP trial was performed be- Asthma is a risk factor for bronchiolitis in
tween May 2007 and February 2010 and pregnancy and since recurrent episodes
involved 1,050 women aged 1645 years of bronchiolitis are associated with the
who were at 1224 weeks gestation, development of childhood asthma, opti-
smoked 10 cigarettes prior to pregnan- mal management of asthma during preg-
cy and 5 cigarettes currently, had ex- nancy may affect the risk of developing
haled carbon monoxide readings of >8 childhood asthma or even its severity.
parts per million (ppm), and were rand- To test this hypothesis, researchers
omized to NRT or placebo. followed-up infants born to 220 women
Data from this cohort of patients with asthma who participated in a dou-
were collected at baseline, 1 month after ble-blind, randomized, controlled trial for
the quit date and at delivery. Analyses optimizing asthma management during
revealed that the odds of smoking ces- pregnancy. The women were assigned
sation at 1 month were greater among to two groups, one in which treatment
women who had completed full-time ed- was adjusted with an algorithm based
ucation at >16 years of age (odds ratio on clinical symptoms and the other in
[OR] 1.82, 95% CI 1.242.67; p=0.002), which treatment was determined by the
but were lower among women who had fraction of exhaled nitric oxide (FeNO). A
higher baseline cotinine levels (OR 0.94, total of 146 infants were assessed at the
95% CI 0.910.96; p<0.001). At deliv- 12 month follow-up visit.
ery, the odds of cessation were great- During the trial, rates of asthma ex-
er among women who completed full acerbation were significantly reduced in
time education at >16 years (OR 1.89, women whose treatment was based on
95% CI 1.163.07; p=0.010) but were the FeNO value compared with those
inversely associated with higher base- whose treatment was based on the al-

PAEDIATRICS peer reviewed JPOG MAY/JUN 2014 93
Fever in the returned

child traveller
Ameneh Khatami BHB, MB ChB, DipPaeds; David Isaacs MD, FRACP, FRCP; Ben Marais MMed(Paeds), PhD
Fever is common in children after overseas travel. Although usually a symptom

of a nonspecific self-limiting condition, it can signify a serious illness such as
malaria, dengue fever, enteric fever, rickettsial disease, tuberculosis, yellow fever
or hepatitis. A detailed travel history and examination for specific symptoms and
signs can help guide investigations and the decision to refer to hospital.
Children represent a significant pro- ical advice for illness while abroad or af-
portion of international travellers, and the ter returning home.1 Fever occurs more
current ease and speed of international commonly in children than in adults, and
travel mean that children frequently pres- in particular is most common in children
ent to healthcare providers with illness younger than 5 years.2 Among child and
following recent travel. Up to 8% of trav- adolescent travellers who seek care, al-
ellers to developing countries seek med- most a third present with fever.3 Although

94 JPOG MAY/JUN 2014 PAEDIATRICS peer reviewed
Table 1. Common travel-associated infections in children: Preventive strategies*
Disease Immunisation and chemoprophylaxis Other preventive strategies

Influenza Immunisation >6 months of age Pay close attention to hand hygiene
(laboratory-
confirmed cases Immunisation recommended if travelling during Avoid close contact with ill individuals
are notifiable) influenza season at destination
Malaria Chemoprophylaxis Use topical insect repellents (e.g. DEET)

(see WHO and Chloroquine-susceptible areas:
Wear long-sleeved clothing
CDC websites chloroquine, once weekly from 1 week prior
for country- and until 4 weeks after travel Avoid outdoor activities at night
region-specific Chloroquine-resistant areas:
recommendations) atovaquone + proguanil daily from 1 to 2 days
prior to 7 days after travel, or
doxycycline (children >8 years) daily from 1 to
2 days prior to 4 weeks after travel, or
mefloquine once weekly from 2 to 3 weeks
prior to 4 weeks after travel
Dengue None Use topical insect repellents (e.g. DEET)
Wear long-sleeved clothing
Avoid activities near stagnant water,
especially in shaded areas, during
morning and late afternoon
Typhoid Polysaccharide vaccine >2 years of age Boil it, cook it, peel it or avoid it
Live oral vaccine >6 years of age Pay close attention to hand hygiene
Vaccine recommended for travel to endemic Use bottled water for drinking or
regions brushing teeth
Avoid ice cubes in drinks
Rickettsial None Use topical insect repellents (e.g. DEET)
infections
(Rickettsia Wear long-sleeved clothing during
prowazekii is bushwalking or hiking and perform
notifiable) regular self-inspection for ticks
many of these children have nonspecific, self-lim- on the area and duration of travel, possible expo-
iting febrile conditions, fever can be a marker of sures and specific signs and symptoms.
serious illness and requires timely assessment to
decide whether admission to hospital is required HISTORY TAKING
for further investigations or treatment. 3,4
Area of travel and exposures
The initial assessment of a returned child Likely infections vary according to the area of trav-
traveller with a fever requires a detailed history el.1,5 Thus it is important to take a detailed travel
and physical examination to narrow down the history, including areas visited, duration of stay,
long list of potential investigations (which are of- activities undertaken and potential exposures, in
ten time-consuming and expensive) to the most particular bites by insects or animals, injuries, ex-
relevant tests. These should be chosen based posures to open water (rivers, lakes, ponds or the

Table 1. Common travel-associated infections in children: Preventive strategies* continued
Disease Immunisation and chemoprophylaxis Other preventive strategies

Meningococcal Quadrivalent meningococcal A, C, W135, Y Avoid close contact with ill individuals
infection vaccine for children >9 months of age
Vaccine compulsory for travel to Saudi Arabia for
Hajj or Umra, especially recommended for travel
to sub-Saharan Africa (meningitis belt)
Hepatitis A Immunisation >1 year of age Boil it, cook it, peel it or avoid it
Immunisation recommended for travel to areas Pay close attention to hand hygiene
of moderate or high endemicity (all developing
Use bottled water for drinking, tooth
countries)
brushing
Avoid ice cubes in drinks
Tuberculosis (TB) Chemoprophylaxis: not indicated pre-travel; Avoid close contact with known TB
consider in vulnerable young children (<5 years) patients and individuals with suggestive
if documented TB exposure or infection (in the symptoms
absence of disease; adult pulmonary TB cases
are the most infectious)
Immunisation: BCG recommended (ideally 3
months prior to travel) for children aged <5 years
travelling for extended periods to countries with
high prevalence of TB
Japanese Immunisation >1 year of age Use topical insect repellents (e.g. DEET)
encephalitis
Immunisation recommended for travel for over a Wear long-sleeved clothing during
month in rural areas in high-risk endemic regions, bushwalking or hiking
especially if considerable outdoor activity
Yellow fever Immunisation >9 months of age Use topical insect repellents (e.g. DEET)
mmunisation recommended for travel to endemic Wear long-sleeved clothing, especially
areas, required for travel to or from certain during bushwalking or hiking
countries
Rabies Immunisation at any age Avoid close contact with animals,

especially dogs
Immunisation recommended based on risk of
exposure and access to postexposure prophylaxis Appropriate wound care of any animal bite
* See Communicable Diseases Intelligence for updates on infections in the Australian setting (www.health.gov.au/internet/main/publishing.nsf/Content/
cda-pubs-cdi-cdiintro.htm).

Nationally notifiable diseases unless otherwise stated. Contact the local public health unit or State/Territory authority for information on notification and public health
actions required.

Australian Technical Advisory Group on Immunisation. Australian immunisation handbook. 10th ed. Canberra: Australian Government Department of Health and Ageing;
2013.

Centers for Disease Control and Prevention. Malaria information and prophylaxis, by country. Available online at: www.cdc.gov/malaria/travelers/country_table/a.html
(accessed November 2013).
sea), animals, unpasteurised milk and sick con- measures taken (if any) and treatment received.
tacts. It is crucial to construct an accurate timeline Comparing this information with the known incu-
that includes the travel itinerary, likely exposures, bation periods of different infections may help to
symptom onset and progression, precautionary identify or exclude specific illnesses.

Table 2. Common travel-associated infections in children: Incubation periods and management
Common Incubation Investigations Treatment options15

infections period
Malaria
Plasmodium Usually <1 month Rapid antigen test Uncomplicated malaria: first-line artemether
falciparum + lumefantrine; or atovaquone + proguanil (if
Thick and thin blood films
not used for prophylaxis); or oral quinine +
Full blood count doxycycline or clindamycin
Severe malaria: IV artesunate or if parenteral
artesunate not available, IV quinine (needs
loading dose, monitor blood glucose) until stable
and able to tolerate oral treatment
P. malariae Usually <1 month Thick and thin blood films Oral chloroquine
Full blood count
P. ovale Up to 1 year Thick and thin blood films Oral chloroquine, followed by primaquine
for 14 days (check for glucose-6-phosphate
Full blood count
dehydrogenase (G6PD) deficiency prior to
administration)
P. vivax Up to 1 year Thick and thin blood films If acquired outside Indonesia and Pacific Island
nations: oral chloroquine
Full blood count
If acquired in Indonesia or Pacific Island
nations: atovaquone + proguanil; or mefloquine
(if not used for prophylaxis)
All treatment options to be followed by
primaquine for at least 14 days (check for G6PD
deficiency prior to administration)
Chemoprophylaxis and immunisations that malaria prophylaxis may delay the onset of
Children often travel with their families to visit symptoms of malaria.10 Child travellers may also
friends and relatives in their parentscountry of or- have incomplete routine childhood immunisa-
igin. In this group of travellers, there are low rates tions and may be at risk of vaccine-preventable
of malaria prophylaxis and pre-travel vaccine up- infections such as measles.3,8
take. Parents are often unaware of risks and may
6
Preventive strategies for common travel-as-
assume a degree of immunity based on previous sociated conditions are summarised in Table 1,
travel to the same area.5,7 This group is at higher including available chemoprophylaxis and immu-
risk of acquisition of infections as they are more nisation options.11,12
likely to travel to rural areas, to travel for longer pe-
riods, and to eat and drink local food and water.8,9 EXAMINATION: SYMPTOMS AND SIGNS
Multiple cultural and socioeconomic factors Fever in returned child travellers may be asso-
may also limit access to pre-travel health care.9 ciated with diarrhoea, which is one of the most
Even when appropriate prophylaxis is prescribed common symptoms in travellers but is more likely
(such as for malaria), adherence may not be to have a severe or protracted course in young
complete, particularly in children, so the clinician children.2,5,13 Diarrhoea may be accompanied
should ask about the exact type, duration and by blood in the stool. Causes of diarrhoea in re-
dosing regimen used. It is important to remember turning travellers include infections with viruses,

Table 2. Common travel-associated infections in children: Incubation periods and management continued
Common Incubation Investigations Treatment options15

infections period
Schistosomiasis 1 to 2 months or Full blood count and white Praziquantel. Repeat treatment 1 to 2 months
longer cell differential count after exposure
Stool and urine
examination for ova
(depending on species)
Serology
Hepatitis A 28 to 30 days Serology Supportive care
Leptospirosis <30 days (usually Culture from blood, IV penicillin, within 7 days, for severe cases
2 to 3 weeks) cerebrospinal fluid or urine
Oral doxycycline or, in young children,
Paired acute and azithromycin, for mild infections
convalescent phase
serology
Antigen detection in tissues
Rickettsial 1 to 3 weeks Paired acute and Oral doxycycline (10 days); or in children <8 years,
infections convalescent phase azithromycin (5 days)
serology
Severe disease may require IV tetracycline
Enteric fever 1 to 2 weeks (up Blood and stool culture Initially, a third-generation cephalosporin until
to 60 days) bacteraemia resolved and clinically improving
Completion of 2 to 3 weeks with an oral antibiotic
(ideally ciprofloxacin) depending on sensitivity
pattern
Dengue fever 4 to 7 days Paired acute and Supportive
convalescent phase
serology
RNA or antigen in blood
Full blood count
bacteria (commonly Campylobacter, Shigella, Es- nomegaly.14

cherichia coli and nontyphoidal Salmonella) and Specific signs that may help identify a tropi-
parasitic protozoa (most commonly Giardia lam- cal infection in a febrile child include:
blia and Entamoeba histolytica). Sometimes mul- rose spots, which may occur in a minority of
tiple pathogens are isolated and often no patho- patients with typhoid fever early in the course
gen can be identified. 5
of illness
In febrile children returning from the trop- skin lesions or an eschar, which may be seen
ics, examination findings are often nonspecif- in rickettsial infections such as African tick fe-
ic. Hepatomegaly, splenomegaly and jaundice ver and scrub typhus
may occur in malaria, hepatitis and enteric fever.
a nonblanching rash, which may be as-
However, the absence of these findings does not sociated with meningococcal disease,
exclude these conditions; around half of children rickettsial infection or viral haemorrhagic
with malaria may not have hepatomegaly or sple- fever.

Signs that require urgent intervention COMMON TRAVEL-ASSOCIATED

include respiratory distress, hypotension or FEBRILE ILLNESSES
poor perfusion, haemorrhagic manifestations, Malaria
confusion, stiff neck or focal neurological Malaria is a global tropical disease caused by
signs. Plasmodium, a parasitic protozoan that is spread
to humans by infected Anopheles mosquitoes,
INVESTIGATIONS which bite from dusk to dawn. In 2010 there were
All children with a fever after returning from an estimated 220 million cases of malaria and
the tropics should have a full blood count, an estimated 660,000 deaths (mainly in African
white blood cell differential count, stool and children).16 In recent years, 300 to 400 cases of
blood cultures and a blood film for malaria if imported malaria have been notified annually in
travel occurred in the preceding 12 months. 5
Australia, with 9 to 13% involving children aged
Investigations for respiratory and urinary tract under 15 years.17 Among children who present
infections should also be undertaken as ap- with a febrile illness after recent travel, malaria is
propriate for any child who presents with fe- the most common specific cause identified, par-
ver, including studies of a nasopharyngeal as- ticularly if travel was prolonged and the destina-
pirate, chest x-ray and urine dipstick test and tion was in sub-Saharan Africa.5
culture. Four main Plasmodium species cause malar-
Table 2 summarises incubation periods ia in humans: Plasmodium falciparum, P. vivax, P.
and management of some common travel-re- malariae and P. ovale. In a nonimmune individual
lated infections, including tests to perform and (young children or adults who have not lived in
treatment options.15 Additional investigations an endemic area), symptoms usually start one to
(e.g. specific nucleic acid amplification tests or two weeks after the infective mosquito bite and
serological assays) may be indicated according may initially be nonspecific (fever, headache,
to the travel and exposure history. chills and vomiting).
The most severe form of malaria is caused
SPECIALIST REFERRAL AND by P. falciparum, and the progression to severe
PUBLIC HEALTH NOTIFICATION anaemia, metabolic acidosis, hypoglycaemia,
Although many fever episodes in returned child seizures, coma or death can be rapid. Most pa-
travellers are likely to represent nonspecific tients with P. falciparum malaria present within
self-limiting illnesses, it is recommended that one month of exposure, although symptoms may
cases of moderate illness should be discussed be delayed if malaria prophylaxis is used.
with a paediatric infectious disease specialist For malaria caused by either P. vivax or P.
to ensure that appropriate investigations are ovale, clinical relapses may occur up to a year
carried out. Signs of severe infection (such as after the first infection, caused by the release of
respiratory distress, poor perfusion or neuro- dormant liver forms of the parasite known as hyp-
logical signs and symptoms) or complications nozoites (absent in P. falciparum and P. malari-
such as bleeding should prompt urgent refer- ae).18 Therefore, a complete travel history should
ral to hospital. Several infections require noti- include details of travel to malaria-endemic re-
fication to public health authorities, including gions in the previous 12 months.
malaria, typhoid fever, dengue fever and viral Diagnosis of malaria is based on detec-
hepatitis. A full list of notifiable diseases can tion of malaria antigen (highly reliable for P. fal-
be found at the Australian Government Depart- ciparum but not for other Plasmodium species)
ment of Health website (www.health.gov.au/ or parasites in the peripheral blood. Any patient
casedefinitions). who has spent time in a malaria-endemic region

and has a history of prolonged or recurrent fever The incubation period of dengue is short
should be tested for malaria, even if they are afe- (four to seven days), and patients usually pres-
brile at the time of review. Thick blood films are ent within the first week after travel to an endemic
more sensitive for diagnosing malaria, whereas area. Four serotypes of dengue virus can infect
thin films are more useful for identifying the para- humans, and prior infection with one serotype
site species. If results are initially negative, blood can cause subsequent infections to be more se-
films need to be repeated at least twice, ideal- vere. Symptoms may range from a mild influen-
ly during fever episodes, before malaria can be za-like illness with fever, headache and myalgia,
excluded with confidence in a febrile child who often associated with a maculopapular rash, to
has returned from any tropical area. Thrombocy- haemorrhagic complications or vascular leakage
topenia is common, and a platelet count above with shock, which can be fatal.
190 x 109/L makes malaria less likely (negative Initial diagnosis is clinical, with confirmation
predictive value of 97%).6 based on serological assays or detection of den-
Resistance patterns to antimalarial treat- gue virus RNA or antigen in the blood; however,
ment are variable, and up-to-date information for serology results are often negative during the
the area of travel can be obtained from the US acute illness and other results may not be avail-
Centers for Disease Control and Prevention.12 In able immediately. Treatment is supportive and
Australia, current recommendations for treatment mild cases resolve spontaneously, but vigilance
are given in Therapeutic Guidelines: Antibiotic. 15
is required for potential danger signs (severe ab-
Severe malaria requires intravenous treatment in dominal pain, persistent vomiting, blood in vomit,
hospital, but initial hospitalisation is recommend- bleeding gums, rapid breathing, fatigue, restless-
ed even for uncomplicated P. falciparum malaria ness). Patients with complications need to be
and also for severe cases of nonfalciparum ma- closely monitored in hospital, with special atten-
laria. In addition, eradication of liver hypnozoites tion to shock and fluid management.
is required for P. vivax and P. ovale malaria; glu-
cose-6-phosphate dehydrogenase deficiency Enteric fevers (typhoid and paratyphoid)
should be excluded before primaquine treatment Typhoid fever is caused by infection with the bac-
to avoid haemolysis. terium Salmonella enterica serovar Typhi (S. ty-
phi). With the exception of Western Europe, North
Dengue fever America, Japan, Australia and New Zealand, S.
Dengue fever is caused by a flavivirus transmit- typhi is endemic worldwide and recent data sug-
ted by the bite of Aedes aegypti mosquitoes. gest that the worldwide incidence of typhoid fever
These mosquitoes bite during the day, mostly is increasing.19,20
in the morning and afternoon, in cooler shaded S. typhi infects only humans and transmis-
areas and around stagnant water. Infection risk sion is via the faecaloral route. The incubation
is highest in the rainy season. In the past five period is usually one to two weeks but can be as
years, more than 1000 cases of dengue fever long as 60 days. Symptoms are generally non-
have been notified annually in Australia, with specific. Fever is the most common symptom, but
around 5% in children. Dengue is endemic in others include cough, headache, stomach pain,
most tropical regions and has important public constipation or diarrhoea, lethargy, and muscle
health implications for Australia. The mosquito and joint pains. In the youngest age groups, signs
vector is present in northern Queensland, and and symptoms are highly variable and nonspe-
local outbreaks have been attributed to travel- cific, making diagnosis particularly challenging.
lers returning with the disease from South-East Hepatomegaly and/or splenomegaly is a helpful
Asia. sign, but relative bradycardia is usually not seen

in young children. Rose spots (2 to 4 mm blanch- ic areas are particular risk factors for infection.
ing erythematous maculopapular lesions) may This group of infections includes Rocky Mountain
occur on the abdomen and chest in 5 to 30% of spotted fever (transmitted by brown dog ticks),
patients.21 The most serious complication is gas- epidemic typhus (transmitted by body lice), scrub
trointestinal perforation, which occurs in 1 to 2% typhus, murine typhus (transmitted to humans by
of hospitalised patients. Chronic carriage occurs rat or cat fleas) and African tick fever (associated
in 1 to 4% of those infected, with the risk increased with tick bites). Rickettsial infections are a com-
by pre-existing gallbladder disease. mon cause of fever in travellers who have gone
Diagnosis of typhoid is based on culturing the bushwalking in sub-Saharan Africa.1
organism from blood, stool or bone marrow, but The classic symptoms of rickettsial infection
sensitivity is generally poor (60% and 30% for blood comprise fever, rash (involving the palms of the
and stool, respectively, and up to 90% for bone hands), headache and myalgia. An eschar may
marrow).21 Samples from multiple sites should be be present at the bite site. Diagnosis can be con-
taken as soon as possible after presentation to op- firmed by serological testing of paired acute and
timise the yield. The Widal (serology) test performs convalescent phase blood samples, but if infection
poorly and should not be used in children. is suspected clinically, empiric treatment may be
Treatment with fluoroquinolones is highly ef- started. First-line treatment is usually doxycycline.
fective and safe in all age groups. It is associated Azithromycin can be used for young children. Spe-
with the highest cure rates (lower rates of relapse cialist advice should be sought for severe cases.15
or chronic carriage) if the organism is sensitive,
and the fastest time to resolution of fever com- Tuberculosis
pared with other antibiotics.21 However, reduced Mycobacterium tuberculosis infection (TB) has
susceptibility to fluoroquinolones is an emerging high prevalence in some parts of the world, with the
problem in Asia, and initial empiric treatment with risk of infection related to the proximity and duration
an intravenous third-generation cephalosporin in of exposure to people who are potentially infectious.
hospital is recommended until the organisms an- Children, especially infants, are more susceptible
tibiotic sensitivity profile is available.
22
than adults. Investigations for TB should be carried
Immunisation provides some protection out in any child who has stayed in areas of high
against typhoid fever and should be offered to endemicity and who presents with any symptom
travellers to areas of high endemicity for periods or sign compatible with TB, including fever, weight
of travel of 10 to 14 days or longer. An oral live loss, lethargy, persistent lymph node enlargement
attenuated vaccine is licensed for use in children or chronic cough. Discussion with a paediatric
over the age of 6 years, and a parenteral poly- infectious disease specialist is recommended to
saccharide vaccine is licensed for use in children ensure appropriate testing and management.
over the age of 2 years. Both of these vaccines
are around 60% effective.23,24 Antibiotic-resistant organisms
Paratyphoid fever is caused by other S. Globally the incidence of antibiotic-resistant or-
enterica serovars (Paratyphi A, B and C). The clin- ganisms is increasing. In recent years, a rapid
ical syndrome is indistinguishable from typhoid rise in infections caused by multidrug-resistant
fever, but typhoid vaccines do not protect against Gram-negative bacteria has been noted in almost
paratyphoid infection. every country. This is of particular concern in In-
dia and other Asian countries where widespread
Rickettsial diseases use of non-prescription antibiotics has led to sig-
Rickettsial diseases are transmitted by arthropods nificant selection pressure. The increase in re-
(usually ticks). Camping and hiking in endem- sistance in Gram-negative bacteria is mainly due

to mobile genes on plasmids that can be easily Key points

passed between bacterial populations. Increas-
High or persistent fever can be a marker of serious illness in
ing human migration and international travel al- children who have returned from overseas travel, and requires
low selected bacterial clones and plasmids to be prompt assessment.
rapidly transported between countries. A detailed history of travel, immunisations, prophylaxis and
Examples of antibiotic-resistant pathogens exposures, and thorough medical examination will help focus
that may be related to previous travel (or history of investigations.
travel in close contacts) include fluoroquinolone-re- First-line investigations include a full blood count, white blood
sistant S. typhi causing typhoid fever, and extended cell differential count, blood and stool cultures, blood films and
spectrum -lactamase (ESBL)-producing entero-
a rapid antigen test for malaria.
bacteria causing urinary tract infections. It is impor- Respiratory and urinary tract infections are common; consider
tant to be aware of the potential for drug-resistant viral studies of a nasopharyngeal aspirate, chest x-ray and
urine dipstick or culture.
pathogens and, where possible, to tailor antibiotic
use to culture and sensitivity results. Malaria should be ruled out in anyone presenting with
persistent or recurrent fever after travel to a malariaendemic
region in the previous year.
Other imported febrile illnesses
Other common infections in travellers include dengue fever,
Yellow fever and other viral haemorrhagic typhoid fever and rickettsial infections.
fevers. Yellow fever is caused by a flavivirus
Children who are systemically unwell with a fever require
transmitted by several mosquito vectors, includ- hospital admission.
ing Aedes species. The yellow fever vaccine is
very effective and is required for travel to most
countries in sub-Saharan Africa, and to Central (Katayama syndrome) can cause high persistent
and South America. It is contraindicated in chil- fevers that may last several weeks. Eosinophilia
dren younger than 9 months of age and in im- and urticarial rash are important clues to recent
munocompromised individuals as it is a live virus primary infection, although the incubation period
vaccine. Several other less common forms of vi- is relatively long with acute symptoms starting
ral haemorrhagic fever can occur as outbreaks, typically one to two months after exposure.25
usually in Africa. Up-to-date information regarding Hepatitis A and hepatitis E. These viral in-
recent outbreaks can be found on the websites of fections are endemic in most parts of the world
the Centers for Disease Control and Prevention and are usually contracted by exposure to con-
(www.cdc.gov) and World Health Organization taminated food or water. Both infections can
(www.who.int). manifest with diarrhoea and jaundice and rarely
Leishmaniasis. The causative protozoan of cause fever. The incubation period of hepatitis A
this disease is transmitted to humans by infect- is 28 to 30 days, and infection is often subclinical
ed sandflies that typically bite between dusk and in young children. Hepatitis A is preventable by a
dawn. Cutaneous and mucocutaneous forms (ul- highly effective vaccine.
cers on the skin or mucous membranes) occur Leptospirosis. This bacterial infection is
more commonly in the Middle East and Central and typically spread through contact of mucous
South America than visceral leishmaniasis (fever, membranes or broken skin with water contami-
anaemia and hepatosplenomegaly), which is more nated with animal urine. It causes an acute flu-like
common in Africa and the Mediterranean region. illness, sometimes associated with aseptic men-
Schistosomiasis. This parasitic disease is ingitis. The incubation period ranges from one to
widespread in Africa and infection with the caus- 30 days (usually two to three weeks), and most
ative trematodes occurs through exposure to infections cause mild symptoms and are self-lim-
fresh water (e.g. at Lake Malawi). Acute infection ited. Rarely, a rapidly progressive, multisystem

form (Weil syndrome) occurs, presenting with travel, including respiratory tract infections (e.g.
jaundice, haemorrhage, acute renal failure and/or pharyngitis, otitis media and influenza), urinary
pulmonary and cardiac involvement. tract infections, meningococcal disease, glandu-
Chikungunya fever. This disease is caused lar fever (caused by Epstein-Barr virus or cyto-
by an alphavirus transmitted by Aedes mosqui- megalovirus) and staphylococcal skin infections.
toes in tropical residential areas of Africa and
Asia. The incubation period is short (one to three CONCLUSION
days), and infected patients usually present Fever is a common complaint in children follow-
with fever and severe polyarthalgia and arthritis, ing overseas travel. Prompt evaluation, including
which can be severe and persistent over several a detailed travel history and thorough clinical
months. There is no specific treatment and most examination, will help guide investigations. First-
patients recover completely. line investigations for all febrile children returning
Herpes simian B virus infection. This her- from the tropics include a full blood count, stool
pes virus usually infects macaque monkeys but culture, blood culture and blood films for malaria,
can be transmitted to humans through bites, as well as urine dipstick and culture and a chest
scratches or mucous membrane exposures. x-ray, depending on signs and symptoms. Signs
Contact with monkeys around temples in South- that require urgent intervention include respirato-
East Asia can be a risk factor. The virus causes ry distress, hypotension, poor perfusion, haem-
severe and permanent neurological disease, with orrhagic manifestations, confusion, stiff neck or
case fatality rates up to 80% if untreated. Early focal neurological signs.
treatment with intravenous aciclovir can prevent
2013 Medicine Today Pty Ltd. Initially published in Medicine Today
severe disease. December 2013;14(12):27-38. Reprinted with permission.
COMMON CHILDHOOD INFECTIONS About the Authors

Dr Khatami is a Fellow in Infectious Diseases and Microbiology at The
Common infections of childhood, also referred Childrens Hospital at Westmead, Sydney. Professor Isaacs is Senior Staff
to as cosmopolitan infections, are frequently re- Specialist in Infectious Diseases and Microbiology at The Childrens Hos-
pital at Westmead and Clinical Professor in Paediatric Infectious Diseases,
sponsible for fever in returned child travellers, The University of Sydney, Sydney. Associate Professor Marais is Associate
Professor in Paediatrics and Child Health at The Childrens Hospital at West-
including those returning from tropical locations.6
mead, the Marie Bashir Institute for Infectious Diseases and Biosecurity and
Several infections occur more frequently after The University of Sydney, Sydney, NSW.
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6. West NS, Riordan FA. Fever in returned tion. Malaria information and prophylaxis, by 18. Brabin BJ, Ganley Y. Imported malaria in 25. Ross AG, Vickers D, Olds GR, Shah SM,
travellers: a prospective review of hospital country. Available online at: www.cdc.gov/ children in the UK. Arch Dis Child 1997; 77: McManus DP. Katayama syndrome. Lancet
admissions for a 2(1/2) year period. Arch Dis malaria/travelers/country_table/a.html (ac- 7681. Infect Dis 2007; 7: 218224.

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OBSTETRICS peer reviewed JPOG MAY/JUN 2014 103
Management of pain and

fever during pregnancy
Debra Kennedy MB BS, FRACP
Pregnant women do not need to suffer unnecessary pain or potentially danger-

ous fever for fear of their taking medications that may be harmful to their unborn
baby. Healthcare providers should be confident when prescribing appropriate
treatment to such women during pregnancy.
Pain and fever are two of the most com- injury, or it may be specifically related
mon symptoms affecting the commu- to pregnancy, for example, ligamentous
nity at large regardless of sex or, in the back and pelvic pain.
case of women, pregnancy status. Pain It is important that pain be ade-
during pregnancy may be due to acute quately evaluated so that women receive
conditions such as injury or infection, or appropriate treatment for their stage of
secondary to underlying medical disor- pregnancy. Acute (and potentially treat-
ders such as rheumatoid arthritis or past able) conditions such as cholecystitis or

104 JPOG MAY/JUN 2014 OBSTETRICS peer reviewed
Women with chronic pain syndromes should

ideally have a comprehensive holistic pain man-
agement plan implemented by their GP or a spe-
cialist. Medications should be optimised before
a planned pregnancy and consideration given to
nonpharmacological modes of treatment, includ-
ing physiotherapy and acupuncture.
Like pain, fever is common during pregnan-
cy and can indicate the presence of infection or
inflammation and requires appropriate investi-
gation and treatment where necessary. It is also
important to recognise that sustained high fever
(above 39C for more than 48 hours) may be
associated with adverse pregnancy outcomes
including miscarriage or birth defects, and thus
needs to be managed appropriately.
Overall, appropriate therapeutic doses of the
commonly used analgesics, including paraceta-
mol, aspirin, NSAIDs and narcotics, have not
been associated with an increased incidence of
birth defects. Thus, pregnant women can be reas-
sured that they need not suffer unnecessarily and
their healthcare providers should be confident in
prescribing pain relief to women during pregnan-
cy and lactation (Table).
PARACETAMOL
Paracetamol is probably the analgesic and anti-
pyretic agent most widely used in the Australian
Fever is common during pregnancy and can indicate the presence of infection community and certainly in the pregnant popula-
or inflammation. tion. In its unconjugated form paracetamol readi-
ly crosses the placenta and in therapeutic doses
intracranial pathology must be sought and active- does not appear to increase the risk of birth de-
ly treated. This means that necessary investiga- fects or other adverse pregnancy outcomes.
tions, including x-rays, are not withheld merely on Despite its widespread use there are, some-
the grounds of pregnancy. In general, diagnostic what surprisingly, no prospective controlled stud-
radiation (even pelvic x-ray or intravenous pyelo- ies about its use in human pregnancy. Retrospec-
gram) will not result in dangerous radiation levels tive studies have found an increased risk of some
for the developing embryo or fetus. birth defects, including gastroschisis and head
It is also well recognised that inadequate and neck anomalies, but the data are difficult to
management of patients with chronic pain can interpret due to methodological problems. In a
result in depression, anxiety and hypertension, registry-based study from Denmark, more than
which may all impact on a womans physical and 26,000 children were exposed to paracetamol in
psychological wellbeing and can have a poten- the first trimester and there was no increase in
tially adverse effect on her pregnancy outcome. either the specific or overall rate of birth defects

Table. Analgesic and antipyretic medications suitable for use in women who are pregnant*
Medication Indication Comments

Paracetamol Mild pain and fever Use in recommended doses to avoid hepatotoxicity
(same doses as nonpregnant population)
Aspirin and other NSAIDs, e.g. Mild pain and fever Some data suggest aspirin and other NSAIDs may be
ibuprofen, diclofenac, indomethacin associated with increased risks of miscarriage in first
trimester. Aspirin and other NSAIDs should be avoided
in the third trimester because of premature closure of
ductus arteriosus
Codeine and other opioids, e.g. More severe pain Can cause nausea and constipation, which may be
pethidine, oxycodone, tramadol exacerbated in pregnancy. Chronic use results in
tolerance and dependence in mother as well as
risks of withdrawal in infants. Women with CYP2D6
polymorphisms (and their babies) may be at greater risk
of toxicity with codeine
Tricyclic antidepressants, e.g. Chronic pain Reassuring data with regard to pregnancy and longer-
amitriptyline (off-label use) term infant neurodevelopmental outcomes.
May reduce need for opioids
*Doses are the same as for nonpregnant women.
in exposed children compared with unexposed children. Further studies are needed to confirm
controls. 1
these concerning but somewhat implausible
A large population-based case-control study findings.5
from the US National Birth Defects Prevention
Study investigated whether exposure to single-in- NSAIDS
gredient paracetamol (acetaminophen) during Aspirin
the first trimester of pregnancy increased the risk Aspirin (acetylsalicylic acid) is the oldest of the
of major birth defects. The prevalence of first-tri-
2
NSAIDs and is used to treat patients with mild
mester single-ingredient paracetamol use was pain and fever. It is also prescribed in doses be-
common in women in the case group and those tween 40 and 150 mg/day by some obstetricians
in the control group, 46.9% (n = 5440) and 45.8% to improve pregnancy outcomes in women at risk
(n = 2059), respectively. Overall, paracetamol for certain complications, including pre-eclamp-
was not associated with an increased risk of any sia and intrauterine growth restriction.
birth defect. In fact, it appeared to be protective in Most prospective studies of aspirin use dur-
reducing the risk of certain birth defects, including ing pregnancy have involved these lower doses
anencephaly, encephalocoele, cleft lip/palate and of less than 150 mg/day rather than analgesic
gastroschisis, in those women reporting a first-tri- doses of 300 mg every four to six hours. Over-
mester infection and fever.2 all, aspirin is not associated with an increased
There have been conflicting reports about risk of congenital malformations, although one
maternal use of paracetamol during pregnancy meta-analysis suggested an association between
and an association between childhood asthma first trimester aspirin use and increased risk of
and wheezing. 3,4
gastroschisis.6 There is a theoretical concern
A recently published study has suggested about premature closure of the ductus arterio-
that long-term exposure (longer than 28 days) sus with use of aspirin (and other NSAIDs) after
to paracetamol during pregnancy is associat- about 30 weeks gestation, although there are no
ed with adverse neurodevelopmental effects in reported cases of closure of the ductus arteriosus

Inadequate pain management during pregnancy can have a negative impact on pregnancy outcomes.
in humans specifically following third trimester aspirin (100 mg/day) improves implantation and
aspirin use. pregnancy rates in patients undergoing in vitro
fertilisation.
Other NSAIDs NSAIDs appear to increase the incidence
NSAIDs such as ibuprofen, naproxen, indometha- of luteinised unruptured follicle (LUF) syndrome,
cin and diclofenac are widely used to treat mild to a condition (also reported in rats and rabbits)
moderate pain and fever. NSAIDs have not been where an anovulatory cycle results due to failure
Appropriate therapeutic doses of the commonly used

analgesics, including paracetamol, aspirin, NSAIDs and
narcotics, have not been associated with an increased
incidence of birth defects.
shown to increase the risk of structural birth de- of normal follicular wall rupture despite normal
fects or other adverse outcomes such as preterm ovarian follicular development and elevation of
delivery or low birthweight. There are both animal serum progesterone. Cyclooxygenase-2 (COX-2)
and human studies suggesting that NSAIDs may is active in the ovaries during follicular develop-
be associated with an increased risk of infertility ment and thus inhibition via COX-2 inhibitors is
and miscarriage.7 However, somewhat confus- thought to result in LUF. Although similar findings
ingly, there are also data reporting that low-dose have been reported for both COX-1 and COX-2

Use of NSAIDs after 30 weeks gestation is contraindicated.
NSAIDs, a more recent paper suggested the risks dence of other adverse pregnancy outcomes. A
were greater in patients with inactive disease major flaw in this study, however, was that it was
and in those taking the selective COX-2 inhibitor prescription-based and retrospective and did not
etoricoxib rather than nonselective COX inhibitors control for the indications of use of NSAIDs (such
such as ibuprofen. 8
as underlying fever or viral illness).9
The phenomenon is reversible with normal A study from Kaiser-Permanente in California
ovulation documented following drug withdrawal. showed an 80% increase in the risk of miscarriage
Thus the prolonged use of NSAIDs, which may oc- associated with first trimester use of both aspirin
cur in the treatment of patients with chronic pain and NSAIDs but failed to show this association
or inflammation of rheumatological conditions, with paracetamol.10
is more likely to be associated with this effect on To confuse things even more, a recently
fertility rather than occasional or intermittent use. published study from Israel failed to show an in-
Two studies that primarily involved NSAIDs creased incidence of miscarriage following first
other than aspirin have reported findings that sug- trimester use of most NSAIDs apart from indo-
gest a possible increased risk of miscarriage when methacin.11
these agents are taken around the time of concep- Use of NSAIDs after 30 weeks gestation
tion or for more than one week. 9,10
A two-armed is contraindicated because of their potential to
(case-control and population-based observational cause premature closure of the fetal ductus arte-
cohort) study from Scandinavia demonstrated an riosus and persistent pulmonary hypertension.
increased risk of spontaneous abortion with use High doses of NSAIDS in the third trimes-
of NSAIDs in the first trimester but with no evi- ter may also cause reduction in perfusion of the

Using NSAIDs such as ibuprofen and diclofenac post-partum may reduce need for narcotic analgesics.
fetal kidneys with resultant decrease in fetal NSAIDs such as ibuprofen and diclofenac
urine output. This latter effect is occasional- are considered to be compatible with breastfeed-
ly used therapeutically in fetal medicine to try ing as the relative infant doses for these agents
and reduce liquor volume and the chances of are 0.65% and 1%, respectively, even in women
cord entanglement in cases of mono-amniotic taking extremely high doses, such as 75 mg di-
twin pregnancy. Most cases of reduced renal clofenac suppositories.14 The advantage of using
perfusion and fetal urine output are reversible these drugs, especially in the immediate postpar-
but there have been reports of only partial res- tum period is the reduction in narcotic require-
olution and even of death due to anuric renal ments and therefore reduction in the associated
failure. 12,13
risks of opioid use.
Paracetamol should still be recommended as first-line

treatment of fever and pain during all stages of pregnancy
As with the older NSAIDs, the main con- Women with inadvertent NSAID use in ear-
cerns with the COX-2 inhibitors such as celecox- ly pregnancy should be reassured about their
ib, meloxicam and piroxicam are effects on the exposure but paracetamol should still be recom-
ductus arteriosus as well as perfusion of the fetal/ mended as first-line treatment of fever and pain
neonatal kidney and gut. during all stages of pregnancy (with the addition

Narcotic analgesics are used to treat women with moderate to severe pain.
of codeine or another narcotic analgesic for more concern about these drugs is that chronic use
severe pain). may lead to dependence and tolerance in the
mother, with resultant withdrawal in the neonate
NARCOTIC ANALGESICS (neonatal abstinence syndrome). Some com-
Narcotic analgesics, including morphine-like mon pregnancy symptoms that are recognised
(opioid) agonists (codeine, oxycodone, hydro- side effects of narcotics include nausea, pos-
morphone, hydrocodone and morphine) as well tural hypotension and constipation, and these
as the synthetic opioids such as pethidine and may significantly limit a womans ability to tol-
tramadol are used to treat women with moderate erate narcotic analgesics during pregnancy. A
to severe pain. Codeine is also widely used as an new combination of oxycodone and naloxone (a
antitussive in various over-the-counter prepara- competitive opioid antagonist) has been devel-
tions. oped to improve tolerability of chronic narcotic
Although some studies have suggested an pain relief but there is limited pregnancy safety
increased risk of some birth defects including information available specifically about this com-
cardiac defects, gastroschisis and spina bifida bination.
with the use of narcotic analgesics,15 overall they Cytochrome P450 (CYP) 2D6 catalyses the
have not been associated with an increased in- O-demethylation of codeine to morphine and du-
cidence of birth defects or other adverse preg- plication of the gene for this enzyme results in
nancy outcomes such as miscarriage. There is ultrarapid metabolism of codeine and thus sig-
also reassuring longer-term neurodevelopmen- nificantly increased production of morphine from
tal follow-up data in exposed infants. The main codeine. In adults this can result in significant

Key points than those with the more common UGT287*1

allele and are thus at greater risk of prolonged
Pain during pregnancy should be appropriately evaluated so
effects from exposure to the pharmacologically
that women receive appropriate treatment for their stage of
pregnancy. active morphine metabolite.
Caution, therefore, needs to be exercised in
It is important to exclude acute (and potentially treatable)
conditions. terms of breastfeeding and minimising the risk
of opioid toxicity in both mothers and babies.
Overall, appropriate therapeutic doses of the commonly used
analgesics have not been associated with an increased Short-term opioid use is unlikely to pose a sig-
incidence of birth defects. However, narcotic and NSAID use in nificant risk but longer-term or chronic use can
later pregnancy may be associated with withdrawal/adaptation be potentially dangerous, particularly in those
problems and other sequelae, respectively.
people who are ultrarapid metabolisers due to
Sustained high fever in early pregnancy should be treated the CYP2D6 duplication. Mothers and babies
because it increases the risk of miscarriage and certain birth
should be carefully observed and monitored for
defects.
evidence of opioid toxicity. In most cases, signs
of central nervous system depression with opi-
opioid toxicity despite small doses of drug, and oids is consistent between mother and baby
thus infants of such patients are also at risk of (although babies appear to be more sensitive to
serious toxicity if breastfed. A case report of a the effects of narcotics). Therefore, if a mother
breastfed neonate who died following maternal appears to have effects of opioid toxicity there
codeine use postpartum highlighted the risks should be a low threshold for examining the
of opioid toxicity in patients with duplication of baby and excluding toxicity.
Women with chronic pain syndromes who may require high

doses of narcotics during pregnancy should seek advice about
optimising their pain management before pregnancy.
the CYP2D6 gene.16 The incidence of this gene If longer-term pain relief is required in breast-
duplication varies in different populations: from feeding women then agents other than opioids
about 1% in Denmark and Finland to 10% in such as NSAIDs should be considered as first-
Greece and Portugal and up to 30% in Ethiopia. line treatment.
Although genetic testing for this polymorphism Women with chronic pain syndromes who
is not routinely available, it could be considered may require high doses of narcotics during preg-
in hospital and other settings where chronic or nancy should seek advice about optimising their
high-dose opiate use is likely. pain management before pregnancy. It is of con-
Another enzyme, uridine diphosphate-de- cern that worldwide there has been a significant
pendent glucuronyltransferase 287 (UGT287), increase in the prescription and use of opioids
catalyses the formation of the metabolites mor- such as oxycodone, with attendant risks of tol-
phine-3-glucuronide (M3G) and morphine-6-glu- erance, dependence and abuse in mothers and
curonide (M6G) from morphine. M6G is a highly risks of withdrawal in neonates.17
active metabolite of morphine that is almost ex-
clusively catalysed by UGT287. Some individuals ANTIDEPRESSANTS
with a genetic polymorphism (UGT287*2) have Alternative agents including tricyclic antidepres-
higher levels of the more active metabolite, M6G, sants (used off label) may be useful in controlling

chronic pain and reducing narcotic expo- but no longterm neurodevelopmental follow-up
sure. Tricyclic antidepressants have not data are available as yet.
been associated with an increased rate of
birth defects and longterm neurodevelop- CONCLUSION
mental studies have been reassuring. 18
As It is important that pain be adequately evaluated
mentioned above, their use in chronic pain and treated so that women receive appropriate
management is off label. management for their stage of pregnancy. There
are safe options for the management of acute and
ANTICONVULSANTS chronic pain during pregnancy and breastfeed-
Although gabapentin and pregabalin (both ing. It is important that women are given reassur-
gamma-aminobutyric acid [GABA] ana- ing and evidenced-based information about their
logues with anticonvulsant and anxiolytic pain management options by healthcare provid-
properties) are being increasingly pre- ers who are confident in their knowledge and un-
scribed for the treatment of neuropathic derstanding of these options.
pain, there are extremely limited data about
2014 Medicine Today Pty Ltd. Initially published in Medicine Today May
their use in pregnancy. Therefore their use 2014;15(5):18-23. Reprinted with permission.
in pregnancy should not be advocated, and

certainly not as first-line treatment for pain About the Author
Dr Kennedy is Director of MotherSafe at the Royal Hospital for Women, Syd-
in pregnancy. The limited data suggest no
19
ney; and Conjoint Lecturer in the School of Womens and Childrens Health
significantly increased risk of birth defects at the University of NSW, Sydney, NSW.
REFERENCES
1. Rebordosa C, Kogevinas M, Horvath-Puho 6. Kozer E, Nikfar S, Costei A, Boskovic R, study. BMJ 2001;322:266270. 15. Broussard C, Rasmussen SA, Reefhuis J,
E, et al. Acetaminophen use during pregnan- Nulman I, Koren G. Aspirin consumption 10. Li DK, Liu L, Odouli R. Exposure to et al; National Birth Defects Prevention Study.
cy: effects on risk for congenital abnormalities. during the first trimester of pregnancy and non-steroidal anti-inflammatory drugs during Maternal treatment with opioid analgesics
Am J Obstet Gynecol 2008;198:178.e1e7. congenital anomalies: a meta-analysis. Am J pregnancy and risk of miscarriage: popula- and risk for birth defects. Am J Obstet Gyne-
2. Feldkamp ML, Meyer RE, Krikov S, Botto Obstet Gynecol 2002;187:16231630. tion based cohort study. BMJ 2003;327:368. col 2011;314:e1e11.
LD. Acetaminophen use in pregnancy and 7. Smith G, Roberts R, Hall C, Nuki G. Re- 11 Daniel S, Koren G, Lunenfeld E, Bilenko N, 16. Koren G, Cairns J, Chitayat D, Gaedigk
risk of birth defects: findings from the Na- versible ovulatory failure associated with Ratzon R, Levy A. Fetal exposure to nonster- A, Leeder SJ. Pharmacogenetics of mor-
tional Birth Defects Prevention Study. Obstet the development of luteinised unruptured oid anti-inflammatory drugs and spontaneous phine poisoning in a breastfed neonate
Gynecol 2010;115:109115. follicles in women with inflammatory arthritis abortion. CMAJ 2014;186:E177E182. of a codeine prescribed mother. Lancet
3. Shaheen SO, Newson RB, Sherriff A, et taking non-steroidal anti-inflammatory drugs. 12. Gloor JM, Muchant DG, Norling LL. Pre- 2006;368:704.
al. ALSPAC Study Team. Paracetamol use in Br J Rheumatol 1996;35:458462. natal maternal indomethacin use resulting 17. Kellogg A, Rose CH, Harms RH, Watson
pregnancy and wheezing in early childhood. 8. Micu MC, Micu R, Ostensen M. Luteinized in prolonged neonatal renal insufficiency. J WJ. Current trends in narcotic use in preg-
Thorax 2002;57:958963. unruptured follicle syndrome increased by Perinatol 1993;13:425427. nancy and neonatal outcomes Am J Obstet
4. Kang EM, Lundsbert LS, Illuzzi JL, Brack- inactive disease and selective cyclooxygen- 13. van der Heijden BJ, Carlus C, Narcy F, Gynecol 2011;259:e1e4.
en MB. Prenatal exposure to acetaminophen ase 2 inhibitors in women with inflammatory Bavoux F, Delezoide AL, Gubler MC. Per- 18. Nulman I, Rovet J, Stewart DE, et al.
and asthma in children. Obstet Gynecol arthropathies. Arthritis Care Res (Hoboken) sistent anuria, neonatal death, and renal Neurodevelopment of children exposed in
2009;114:12951306. 2012;63:13341338. microcystic lesions after prenatal exposure utero to antidepressant drugs. N Engl J Med
5. Brandlistuen RE, Ystrom E, Nulman I, 9. Nielsen GL, Sorensen HT, Larsen H, Ped- to indomethacin. Am J Obstet Gynecol 1997;336:258262.
Koren G, Nordeng H. Prenatal paracetamol ersen L. Risk of adverse birth outcome and 1994;171:617623. 19. Fujii H, Goel A, Bernard N, et al. Preg-
exposure and child neurodevelopment: a miscarriage in pregnant users of non-ste- 14. Hale T. Medications and mothers milk: nancy outcomes following gabapentin use:
sibling-controlled cohort study. Int J Epide- roidal anti inflammatory drugs; population a manual of lactational pharmacology. 15th results of a prospective comparative cohort
miol 2013;42:17021713. based observational study and case-control ed. Texas: Hale Publishing;2012. study. Neurology 2013;80:15651570.

IL-CON-001_Jpog_OP.pdf 1 5/19/14 7:09 PM
STRATEGIES TO
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Find out what these experts have to say about factors that cause infertility
in females and males, and how upcoming treatments can overcome this
Professor Kolibianakis Dr Nicolas Zech Professor Ben-Rafael

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stimulation and managing excess fertilization and overcoming male infertility and how management
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MIMSmobileapp206x276_0314.indd 1 3/10/14 2:23 PM
112 JPOG MAY/JUN 2014 GYNAECOLOGY peer reviewed
Coping with chronic

vulvovaginal candidiasis
Gayle Fischer MB BS, MD, FACD
Acute vulvovaginal candidiasis (VVC) is common and usually easily treated but
some women develop chronic symptoms that do not respond to conventional
anti-Candida treatment. Recently proposed diagnostic criteria may help clinicians
identify women with chronic VVC. Evidence is mounting that it represents a hyper-
sensitivity response to commensal Candida spp. It usually responds to long-term
antifungal treatment.
Acute vulvovaginal candidiasis (VVC) is rences of VVC.2,3 Four or more episodes

a common condition that affects 70% of microscopically proven candidiasis
to 75% of women at least once in their per year has been defined as recur-
lives. It is usually easy to diagnose and
1
rent vulvovaginal candidiasis.4 There
treat in general practice. However, about are also women who do not have recur-
5% of women have very frequent recurrent symptoms but have disease that

GYNAECOLOGY peer reviewed JPOG MAY/JUN 2014 113
is chronic, continuous and unremitting. Women Box 1. Diagnostic criteria for chronic vulvovaginal candidiasis5
such as these are common patients in practices
that specialise in vulval diseases. Their symptom A patient presenting with chronic nonerosive erythematous vulvo-
complex includes itch, pain and dyspareunia that vaginitis with any five of the following characteristics is likely to
have chronic VVC.
worsen premenstrually and remit during menstru-
ation and are associated with an erythematous Previous response, even if brief, to antifungal treatment
vulvovaginal eruption. History of a positive vaginal swab for Candida spp. at any time
while symptomatic
There is no international consensus on a
Cyclical symptoms: build-up before menses, improvement
name for this form of candidiasis and until now during menses
it has come under the umbrella of recurrent VVC. Discharge: usually nonoffensive, mucoid
A recent study has, however, proposed a set of Exacerbation with antibiotics
diagnostic criteria for what is termed chronic vul-
Dyspareunia
vovaginal candidiasis (Box 1).5
Soreness
Recent research suggests that chronic VVC
Vulval oedema, including after coitus
is not due to opportunistic infection or host im-
munodeficiency but is likely to be a hypersensi-
tivity response to a commensal organism. This variable discharge, soreness, irritation, burning,
response may be genetically determined. Fur- dyspareunia and dysuria with a premenstrual ex-
thermore, chronic VVC, like acute VVC, does not acerbation.1 These are also features of chronic
occur before menarche or after menopause un- VVC (Box 1). Most patients report that their male
less the patient is taking hormone replacement partner has no symptoms, but postcoital penile
therapy and, although it may commence at any erythema and irritation occurs in about 10% of
stage of reproductive life, it is most common in men with a partner with untreated vaginal can-
young adults.6,7 It thus appears that oestrogen didiasis.1 Examination reveals vaginal erythema,
plays an essential permissive role and in healthy a nonoffensive mucoid discharge and erythema
non-diabetic patients, no forms of VVC occur in of the labia minora and majora, perineum and
the absence of oestrogen, whether endogenous sometimes perianal skin, which may be compli-
or exogenous. The nature of this relationship with cated by oedema and painful fissuring.
oestrogen has not been established. Patients with chronic VVC are typically sys-
VVC, including chronic VVC, imposes a sig- temically well. They show no evidence of immu-
nificant burden on health resources and, like any nosuppression, and oral and oesophageal in-
chronic disease, has a large impact on quality volvement is the exception. The latter do occur in
of life, particularly as it occurs in an area of the individuals with VVC who are immunosuppressed
body that many are too embarrassed to present or have diabetes, but this group appears distinct
to their doctor. Self-diagnosis and the availability from the otherwise healthy women who have
of over-the-counter medication make it difficult to chronic VVC.
estimate this burden accurately; however, VVC It is not uncommon for patients with chronic
has been estimated to cost one billion dollars per VVC to have a negative vaginal swab for Can-
year in the USA. 4
dida at presentation.5 There are several possible
A typical case of chronic VVC is described causes of false negatives. They are most likely
in Box 2. the result of self-medication with over-the-coun-
ter antifungals, but sampling errors and the limi-
CLINICAL FEATURES tations of current detection methods may also be
The typical clinical features of recurrent VVC are implicated. Patients with this condition find that
well described in the medical literature as itch, antifungals afford some relief, even if temporary

Box 2. A typical case of chronic vulvovaginal candidiasis or partial, and use them frequently. There are
no data on how long after antifungal treatment
Jenna is a healthy 22-year-old woman who presents with one should wait before trying to isolate Candida
vulvovaginitis. Her first attack occurred soon after she started from the vagina of a patient with chronic VVC.
taking the oral contraceptive pill (OCP) and concurrently became
In my experience, swab results may still be neg-
sexually active at the age of 18 years. She was too embarrassed
to visit her family GP, who had known her all her life, but went ative several months after the last treatment. A
instead to a pharmacist who provided her with a course of positive culture result for group B streptococci
antifungal suppositories. Her symptoms improved rapidly but she
should be ignored, as in any other nonpregnant
had frequent recurrences, responsive to topical therapy.
At the age of 21 years, Jenna had an appendectomy and patient.
was treated with intravenous antibiotics. While in hospital, Despite negative culture results for Candida,
she developed severe vulvovaginitis. She again self-medicated patients with a typical history and examination
with topical antifungals but this time without a response. At
this point she consulted her GP. A vaginal swab was negative results for chronic VVC usually respond to oral
for Candida spp. but showed group B streptococci. At a loss to antifungal therapy. Although short-term manage-
explain her problem, her GP prescribed a course of amoxycillin. ment of recurrent VVC with oral fluconazole is well
Her symptoms of itch, dyspareunia and discharge worsened
described, data on the long-term outcome of this
and she was then empirically treated with two single doses of
fluconazole 150 mg. After each dose, her symptoms remitted but treatment are lacking, with the longest follow-up
rapidly returned. period being 12 months.
Each month Jenna noted a premenstrual flare of symptoms,
and the only time she felt well was while menstruating. Stopping
the OCP made no difference to her symptoms and extensive HOW COMMON IS CHRONIC VCC?
investigations for sexually transmitted infections, iron deficiency Chronic VVC is common but we do not know pre-
and impaired glucose tolerance gave negative results. A cisely how common or what proportion of women
referral to an immunologist did not reveal anything to suggest
immunodeficiency. have acute versus recurrent and chronic disease.
Examination revealed nonspecific vulvovaginal erythema All attempts to define the prevalence of chronic
extending to the labia minora and the sulcus between the labia VVC have been hampered by the lack of definition
minora and majora, accompanied by a nonoffensive mucoid
discharge. A repeat vaginal swab revealed no abnormality. of the condition, diagnostic inaccuracy, variabili-
Jenna was referred to a vulval disease clinic, where she was ty of clinical presentation and self-diagnosis and
diagnosed with chronic VVC. She gradually became asymptomatic self-treatment with antifungals.1,8
over a three-month course of continuous treatment with oral
fluconazole.
DIFFERENTIAL DIAGNOSIS
Commentary The differential diagnosis of VVC includes a range
This young womans story is typical of the history and evolution of conditions that cause persistent erythematous
of chronic VVC over time. Many similar patients present at vulval
dermatology clinics. Patients are usually aged in their late teens vulvovaginitis (Box 3). Of these many conditions,
to early 20s and at symptom onset have recently become sexually VVC is the only one that is causally related to
active. They are otherwise healthy with no factors to suggest Candida albicans and the only one that responds
immunodeficiency. Because sexual activity often coincides with
commencing the OCP, the latter is usually implicated, but patients to antifungal medication alone. It is an important
find no change in symptom severity whether they are taking or not practice point that common skin conditions caus-
taking the OCP. ing vulvitis such as dermatitis and psoriasis are
Attacks are initially sporadic and readily treated with antifungal
not associated with a vaginitis but may resemble
medication. With time, they become progressively more frequent,
treatment resistant and finally chronic with a premenstrual flare. VVC externally and may coexist with it.9 Patients
The typical appearance of acute candidiasis is replaced by a low- with psoriasis or dermatitis may have signs of
grade chronic erythema involving the vagina, introitus and vulva.
these conditions on other parts of their skin and
The dominant symptoms are pain, dyspareunia and itch with a
definite but not cheesy discharge. Oral antibiotics are frequently it is always worth scanning patients for such ev-
associated with flares, and patients learn to avoid them. Single- idence on first examination. Patients who have a
dose antifungals bring only brief relief. dermatosis, rather than chronic VVC, generally
give a very different history that does not include

a previous good response to antifungal treatment, Box 3. Causes of chronic vulvovaginitis9*

discharge, dyspareunia or a premenstrual flare.
Although burning as a symptom is certainly Common
seen in chronic VVC, it is rarely the only symp- Recurrent vulvovaginal candidiasis (VVC)
tom. Nevertheless, chronic pain syndromes that Recurrent bacterial vaginosis
can cause burning can occur concurrently, and if Uncommon
a patient has not responded to antifungal therapy Desquamative inflammatory vaginitis
then these should be considered. Intravaginal foreign body (e.g. retained tampon)
Chronic fixed drug eruption
HOW CAN GPS CONFIDENTLY Allergy: contact dermatitis to intravaginal substance
Rare
DIAGNOSE CHRONIC VVC?
Mucosal lichen planus
Acute VVC appears to be overdiagnosed, par-
Oestrogen hypersensitivity vulvovaginitis
ticularly by patients themselves who frequently
Very rare
assume that most vulvovaginal complaints are
Crohns disease
due to thrush. The chronic form of VVC appears,
Immunobullous disease
however, to be significantly underdiagnosed ow-
Graft versus host disease
ing to its lack of definition and the insistence of
* Fischer G, Bradford J. Practice pointer: persistent vaginitis. BMJ 2011; 343: d7314.
previous definitions of recurrent VVC that the
diagnosis cannot be made in the absence of a
positive culture result at presentation. As there is no definitive diagnostic test for
The difficulty with this concept is that even chronic VVC, the diagnosis rests on:
a positive culture result for Candida does not al- a typical history
ways confirm the diagnosis. Around 10 to 15% nonerosive vulvovaginitis seen on examina-
of asymptomatic women are colonised by Can- tion (although this can be nonspecific and
dida, and conversely many women with signifi- vary with the menstrual cycle) and
cant chronic symptoms have negative cultures at a convincing objective return to a normal

presentation.5 In these patients it is necessary to vulvovaginal appearance and self-reported
rely on clinical judgement irrespective of whether symptomatic response to antifungal therapy.
there is a positive culture result. Previous studies have demonstrated the un-
It is not known why so many women with reliability of clinical diagnosis, but diagnostic ac-
significant long-term symptoms present with a curacy can be improved by ensuring that patients
negative result for Candida on culture and even satisfy at least five of the diagnostic criteria listed
polymerase chain reaction (PCR) testing. Never- in Box 1.5,10 A vaginal swab positive for C. albicans
theless, in my experience, most patients relate or a non-albicans Candida species supports the
if questioned that culture has been positive for diagnosis but does not confirm it, and a negative
Candida at some stage while they were sympto- swab does not rule it out.
matic in the past.
Biopsy shows only nonspecific inflammatory WHY DO HEALTHY PATIENTS DEVEL-
changes and usually does not demonstrate the OP CHRONIC VVC?
presence of yeast in the epidermis. Microscopy Candida is a dimorphic yeast, a commensal of the
is time-consuming and difficult for practitioners genital and gastrointestinal tracts. Many studies
and, as stated above, is not always positive. The have shown it is responsible for VVC and that in
pH of vaginal discharge, which is normal in VVC, approximately 85 to 95% of cases, C. albicans is
serves only to differentiate VVC from bacterial isolated on culture. In the other 5 to 15% of cases,
vaginosis. 1,8
other Candida species are isolated, with the most

Box 4. Triggering factors in vulvovaginal candidiasis have been successful. Why or how a commen-
sal organism that is tolerated by most individu-
Relevant factors als evolves to cause severe symptoms in a few
Endogenous and exogenous oestrogen otherwise healthy women is unknown. Our under-
Alteration of normal flora by antibiotics standing of pathogenesis involving organisms of
Systemic immunosuppression the normal microbiota (the community of organ-
Sexual activity isms making up a tissue microbiome) is in its in-
Uncontrolled diabetes fancy. As tissue microbiomes become better un-
Intrauterine device derstood some of the paradoxes of this condition
Nonrelevant factors may be better explained.
Species of Candida Symptom severity and signs of inflammation
Virulence factors in VVC appear to be unrelated to the severity of in-
Tissue invasion fection. Some patients who are heavily colonised
Host receptors by Candida remain asymptomatic, while others
Humoral immunoglobulin with low or negative colony counts may display
Systemic cell-mediated immunity severe symptoms.
Iron deficiency anaemia
Colonisation of the male partner Predisposing and trigger factors
Factors of undetermined relevance Although there is much we do not know about the
Genetic susceptibility cause of VVC, there are factors that have been
High carbohydrate diet shown to play a role, others that may play a role
High-oestrogen oral contraceptive pill and some that have been shown not to play a role
Tight occlusive clothing and pads (summarised in Box 4).9
Pregnancy Recent evidence points to two aetiological
HIV infection factors that appear to be the most important in
susceptibility to chronic VVC: host immune re-
sponse and oestrogen. Other factors that are well
frequent being Candida glabrata.1,8 In certain geo- recognised to predispose to or trigger attacks in-
graphic areas, non-albicans species are isolated clude antibiotics and sexual activity, although the
at higher rates than 5 to 15% but this is not true of condition is not sexually transmitted and treating
the Australian population.11 An important practice the male partner does not enhance treatment
point is that non-albicans species are azole-re- response.8 After menopause, hormone replace-
sistant, although susceptible to topical boric acid ment therapy can trigger VVC but studies have
and to oral voriconazole, an antifungal drug that not shown that the OCP has any effect on it. There
recently became available.12,13 The prevalence of are reports implicating progesterone-releasing
non-albicans strains appears to be increasing. 8
intrauterine devices, and my experience corrob-
Most diseases caused by commensal or- orates this.15
ganisms occur in patients who are immunosup-
pressed or have diabetes, so it is of great interest Host immune response
that chronic VVC is an exception. The role of the Cell-mediated and humoral immunity
organism itself has been studied; virulence fac- In the past, Candida-specific cell-mediated im-
tors are not relevant, which possibly explains the munity has been considered to be the most likely
rarity of drug resistance. 14
host defence mechanism against mucosal Can-
Many studies have attempted to discover dida infection. However, studies using mouse
an immune deficiency underlying VVC but none models as well as cross-sectional clinical studies

have convincingly ruled out a role for either local bility.20 Vaginal cells in these patients both lacked
or adaptive immunity in VVC. Humoral immunity anti-Candida activity and were highly intolerant
similarly has not been shown to play a role. No to the presence of Candida, generating an exag-
study has been able to demonstrate a difference gerated immune response triggered by very low
in total or Candida-specific antibodies in sera or numbers of the organism.
vaginal secretions between women with recurrent A study that evaluated vaginal epithelial cell
VVC and control women. 16
anti-Candida activity prior to intravaginal chal-
It is now accepted, therefore, that system- lenge showed that cells in women who develop
ic immunity is not relevant and the problem is symptoms have significantly lower activity com-
specific to the vagina. This is supported by the pared with those in women who do not develop
observation that women with recurrent VVC are symptoms. This suggests an inherent but as yet
almost never susceptible to oral candidiasis, and not elucidated protective mechanism at the level
conversely that immunosuppressed women with of the vaginal epithelial cell.21
HIV disease are susceptible to oral but not vaginal T cells can be demonstrated in large numbers
candidiasis.17 in the vagina in candidiasis and appear to migrate
in response to local antigenic stimuli or inflammato-
Local immunoregulatory mechanisms ry chemokines. Their exact role in VVC is unclear.22
Data suggest that host-specific innate immu- A study examining immune mediators found
noregulatory mechanisms play a role in sus- elevated levels of prostaglandin as well as Can-
ceptibility to VVC. The concept that symptoms dida-specific intravaginal IgE. This study also
are the result of an allergic reaction mediated postulated a hypersensitivity response.23
by Candida-specific IgE has been explored by a It thus appears that VVC is associated with
number of researchers and does appear relevant signals following interactions between Candida
in a small number of patients.18 Interestingly, ato- and vaginal epithelial cells that promote a non-
py has been shown to be more prevalent in this protective inflammatory response, which results
group than in the general population.19 in symptoms. Resistance to disease is associat-
Much of our data come from murine experi- ed with a lack of these signals. Vaginal cells in
ments, but in 2004 a breakthrough study used an VVC patients have a low tolerance for even small
intravaginal challenge with C. albicans in healthy numbers of organisms (theoretically so small in
human volunteers. 20
This study demonstrated some cases that they are not able to be cultured)
that, counterintuitively at first, susceptibility to and signal an inflammatory response. The thresh-
acute symptomatic candidiasis was associated old above which this signalling takes place varies
with a brisk inflammatory leukocyte response, from patient to patient. It is possible also that, giv-
while protection from symptoms was associated en the numbers of women with significant symp-
with lack of inflammation. Patients with a previ- toms despite negative culture, the inflammatory
ous history of candidiasis were more suscepti- response continues after initiation in the absence
ble than those without. Vaginal lavage fluid from of detectable antigen.16
women with symptomatic infection had the abili- These studies raise a paradigm for under-
ty to stimulate neutrophil migration in vitro. standing chronic VVC, suggesting a host-mediat-
This same study demonstrated that inocula- ed individual genetic susceptibility to a commen-
tion of Candida into the vagina was much more sal organism that is tolerated by most women.24
likely to result in colonisation in women with a This may explain the paradoxes that have so far
previous history of recurrent attacks of candidia- confounded investigators, including lack of lo-
sis than in those without such a history, thus sug- cal or systemic immune deficiency, the fact that
gesting an individual, possibly genetic suscepti- chronic VVC is no more common in HIV-infected

Oestrogen
The role of oestrogen appears obvious but is
largely unexplored. Chronic VVC is usually char-
acterised clinically by oestrogen-related cyclic-
ity. Most patients report that symptoms worsen
after ovulation when oestrogen levels are high-
est, peak in the premenstrual week and rapidly
decrease during menstruation. Similarly, clinical
appearance varies over the menstrual cycle and
is often near to normal during menstruation and
for a few days after.
A 2001 study suggested that postmenopau-
sal women could become susceptible to candid-
iasis as a result of hormone replacement thera-
py.11 Among 339 consecutive patients aged 55
years or over presenting to a dermogynaecology
clinic, 26% of women using oestrogen had a pos-
itive vaginal swab for C. albicans as opposed to
4% in the group not using oestrogen.
A more recent study supports these findings.
It demonstrated that after menopause, VVC oc-
curs almost exclusively in women using oestro-
gen (but not progesterone) replacement therapy
and that most of these patients were suscepti-
ble to it before menopause, thus demonstrating
the importance of oestrogen in the aetiology of
chronic VVC.7
Healthy patients with chronic VVC typically
do not have oral or oesophageal involvement, in
Acute VCC affects 70% to 75% of women at least once in their lifetime. contrast to immunosuppressed and diabetic indi-
viduals who often do. This fact may support the
patients than in healthy patients, the lack of oral contention that the pathology of VVC is particu-
involvement and irrelevance of infection of the lar to the vaginal microenvironment and that the
male partner. pathogenesis in healthy people differs from that
This may also explain why continuous sup- in those who are immunocompromised. The dif-
pression is required in patients with chronic VVC ference may be related to the density or type of
to keep the levels of Candida in the vagina be- oestrogen receptors.
low the threshold for inflammation and why some
patients need more suppression than others. It CURRENT RECOMMENDED
is of interest here to compare chronic VVC with MANAGEMENT OF CHRONIC VVC
autoimmune conditions where the antigenic stim- There is a paucity of grade A evidence for
ulus is not known. In these conditions, treatment treatment of chronic VVC. A recent systematic
requires nonspecific suppression of the immune review identified only two studies suitable for
system. In chronic VVC we need to suppress only meta-analysis in the past 10 years.25 Both these
the known antigen. trials examined long-term maintenance therapy

with fluconazole 150 mg per week. However, my improvement, but some degree of persistent er-
experience is that weekly regimens often fail in ythema in the sulcus between the labia minora
patients with chronic VVC, a point that was not and majora is common. Although patients taking
addressed in the review. Long-term treatment these medications almost always have negative
regimens have all tended to recommend oral cultures while on treatment, relapse is common
azoles, because long-term use of pessaries is after the medications are ceased. Relapse ap-
difficult to comply with and often causes irritant pears not to be caused by drug resistance as
skin reactions that complicate the assessment of re-treatment is usually effective.
treatment response.
Oral antifungal agents
Principles of treatment The antimycotic agents itraconazole and flu-
The principles of treating chronic VVC are as conazole are well tolerated with low rates of side
follows. effects. Unlike ketoconazole, which has been
Commence therapy with an induction course, associated with drug-induced hepatitis in 10%
usually with an oral antifungal medication of patients, itraconazole and fluconazole very
such as fluconazole or itraconazole taken rarely affect the liver and are safe to take orally
daily. Continue until the patient is asympto- long term. Neither drug is supported by the PBS
matic and vulval appearance on examination for the indication of chronic VVC, but the cost
is essentially normal, other than erythema of of fluconazole has reduced significantly recent-
the sulcus between the labia minora and ma- ly and the costbenefit ratio is good. In general,
jora. The usual dose is fluconazole 50 to 100 antifungal resistance is rare although recently
mg daily or itraconazole 100 mg daily. reported.26
Where C. glabrata is found and the patient fits
the diagnostic criteria, boric acid supposito- Natural therapies
ries 600 mg daily are used. If patients are un- Patients often request natural therapies for treat-
able to tolerate boric acid then oral voricona- ment of candidiasis, which have been reviewed
zole is an alternative although this drug has recently.27 The role of diet and probiotics is as yet
potential toxicities not shared by fluconazole undetermined. In my experience, although many
or itraconazole. women express reservations about long-term
For the next six months after symptom re- antifungal therapy with fluconazole and itracona-
mission is achieved, maintenance therapy zole, fuelled largely by unsubstantiated reports of
should be undertaken as about 50% of pa- liver toxicity, they are sufficiently frustrated with
tients relapse soon after the induction course other treatment options to embark on it and hap-
is ceased. The dose required differs between py to remain on it once they realise its efficacy.
patients. For most, a twice weekly dose of
fluconazole 50 to 100 mg or itraconazole 100 Antifungal pessaries
mg is adequate, but some cannot reduce from In theory, antifungal pessaries containing azoles
daily dosing without a relapse of symptoms. such as miconazole and clotrimazole, nystatin or
If relapse occurs after maintenance therapy boric acid may be used with once-daily dosing.
is ceased, long-term maintenance may be Indeed, where swabs have demonstrated atypi-
needed. cal candidiasis, caused most commonly by C.
Signs and symptoms usually resolve with glabrata, boric acid suppositories 600 mg daily
these regimens, so much so that response be- are indicated as this organism is generally resist-
comes a diagnostic test in itself. Once symp- ant to azoles. The problem with long-term use of
toms have resolved there is usually an objective pessaries is poor adherence.

Key Points oestrogen replacement therapy and has not

ceased it during the induction course.
Vulvovaginal candidiasis (VVC) covers a disease spectrum, The patient has a progesterone-releasing in-
from a single episode to chronic disease with unremitting
symptoms. trauterine device in situ. In these situations,
The concept of chronic VVC was recently described; it is a specialist referral is suggested.
common cause of chronic nonerosive vulvovaginitis in women
presenting at vulval disease clinics.
PRACTICE POINTS FOR CLINICIANS
Evidence suggests chronic VVC is a hypersensitivity response
to commensal Candida spp. At present, the diagnosis of chronic VVC is not de-
In healthy non-diabetic patients, chronic VVC, like acute VVC, fined. I suggest, based on the criteria presented
occurs only in the presence of oestrogen. in Box 1, the following guide to diagnosis.
Chronic VVC may be diagnosed based on clinical features and a Patients who have a nonerosive chronic vul-
history that satisfies specific criteria; diagnosis is supported by,
but does not require, a positive swab result for Candida spp. at vovaginitis that worsens premenstrually and
presentation. also with antibiotic treatment, who have had a
Patients with chronic VVC respond well to oral antifungal positive culture result for Candida at any time
therapy, which may be needed long term.
while they were symptomatic and who have
a history of a positive response to antifungal
Ancillary treatments medication are likely to have chronic VVC.
Ancillary treatment, including topical corticoster- These patients are likely to benefit from a trial
oids and avoidance of soap and irritants (includ- of oral antifungal medication. The optimum
ing pads, liners, perfumed sprays and G-string duration and frequency of treatment are yet
underwear) is helpful, particularly in patients who to be determined, but the guidelines outlined
have a concurrent atopic or psoriatic tendency above are a good starting point. My practice
is to initiate treatment with a minimum of three
WHAT TO DO IF TREATMENT FAILS months of continuous oral antifungal medica-
If the diagnosis is correct then there is usually a tion, continued until the patient is completely
rapid and pleasing response with significant im- asymptomatic and objectively appears close
provement in quality of life score by three months to normal (many patients always retain slight
of treatment. If treatment fails then the possibili- erythema in the sulcus between the labia mi-
ties are as follows. nora and majora).
The diagnosis was incorrect, and other pos- Fluconazole is significantly cheaper than itra-
sibilities should be considered (see Box 3). conazole and has less potential for drug inter-
The diagnosis was correct but comorbidities actions. If swabs show C. glabrata then boric
such as pain syndromes, pelvic floor spasm acid pessaries should be used instead. Most
or dermatoses have prevented a complete patients given a choice indicate they would
symptom response. Patients are usually rather take oral medication than use pessa-
much improved but still have residual com- ries. C. glabrata is sensitive to voriconazole
plaints. but this drug is potentially more toxic than
The patient is not absorbing the medication. fluconazole and itraconazole.
This may indicate celiac disease, although Maintenance therapy is then continued for

not invariably. a minimum of six months, using a reduced
The organism is either resistant to the medi- dose usually twice a week. Some patients
cation or has an unusually high minimum in- require continued maintenance therapy for
hibitory concentration, and a higher dose is many years.
required. There are no data at present on how many

The patient is postmenopausal and taking patients are able to completely withdraw from

therapy without relapse in the long term. A study proposed a definition and diagnostic criteria for
suggested 50% can do so, but follow up was of chronic VVC.5 Over the past 10 years there have
short duration.23 The safety of maintenance ther- been only two well-controlled trials to determine
apy appears high despite the requirement for the best evidence-based treatment regimen.25 Us-
long-term oral antifungal medication using either ing our criteria, the probable response to a trial of
fluconazole and itraconazole, akin to long-term oral antifungal treatment can be predicted, even
antiviral therapy for genital herpes. To date no when a vaginal swab on presentation is not pos-
more effective treatment has been identified. itive for Candida. In most cases, oral antifungal
treatment is effective and safe but may need to
CONCLUSION be prolonged, and a significant although undeter-
There is still much that we do not know about mined number of patients require ongoing main-
chronic VVC. Research suggests it is an oestro- tenance therapy, in some cases until menopause.
gen-related hypersensitivity response, which may
2014 Medicine Today Pty Ltd. Initially published in Medicine Today
be genetic, and which appears to best explain the February 2014;15(2):33-40. Reprinted with permission.
clinical features. As none of the clinical features

of chronic VVC are highly specific or sensitive, di- About the Author
Associate Professor Fischer is an Associate Professor of Dermatology, Syd-
agnosis has required the development of a set of ney Medical School, The University of Sydney, and a Visiting Medical Officer
at the Royal North Shore Hospital, Sydney, NSW, where she runs a vulval
diagnostic criteria. Recently, our research group dermatology clinic.
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122 JPOG MAY/JUN 2014 CASE STUDY peer reviewed
Cystoscopic Mapping to Ensure

Optimal Laparoscopic Excision of
Bladder Endometriosis
Menelik MH Lee, MBBS, MRCOG, FHKCOG, FHKAM; Charles J Carter, MBChB, FRCS(urol); Tyrone T Carpenter, MBBS, BSc, MRCOG, MD
ABSTRACT The new technique described allows precise mapping

Laparoscopic partial cystectomy is established as the opti- of the lesion ensuring complete excision and close dissec-
mal treatment of full thickness bladder endometriosis. Com- tion around the ureteric offices without risking occlusion,
plete excision of the lesion is essential however over excision and also preserves maximum bladder capacity.
risks unnecessary reduction in bladder volume and may risk
ureteric obstruction. The following case demonstrates a new HISTORY, PRESENTATION AND EXAMINATION
technique of cystoscopic mapping and laparoscopic resec- A 41-year-old woman with a long standing history of endo-
tion of bladder endometriosis, allowing complete removal of metriosis complained of severe menorrhagia, bladder pain,
the endometriotic nodule while sparing maximum bladder strong desire to void and nocturia 4-5 times per night during
capacity and minimising risk of injury to the ureteric orifices. her menstruation. Examination revealed a nodule in the up-
per third of her vagina.
INTRODUCTION
Bladder endometriosis affects approximately 1-6% of all pa- DIAGNOSIS
tients with endometriosis. 1,2
Symptoms occur in 61.9% of Ultrasound and MRI imaging confirmed a 2x3x5cm endome-
such cases.1 Frequency and dysuria are the main symptoms triotic nodule within the posterior bladder wall that extend-
with severity worse with increasing diameter of lesion and ed inferiorly to the level of the intra-ureteric bar. The ureters
basal endometriotic nodules.3 were not obstructed.
Conventional cystoscopic diagnosis and subsequent In view of this finding a combined procedure with a gy-
laparoscopic partial cystectomy to remove the endometri- naecologist and urologist was undertaken.
otic nodules appears to be the treatment of choice.4-6 Two
studies also showed no recurrence of bladder endometriosis TREATMENT PROCEDURE AND TECHNIQUE
after 50.9 months7 and 36 months8 of follow-up, respectively. Laparoscopic entry into the abdomen was undertaken by
Trans-urethral resection of these lesions provide inadequate two gynaecologists in the usual manner and the posterior
treatments with studies suggesting a recurrence rate of 35% bladder endometriotic nodule with anterior wall uterine ad-
after 3 years. 8,9
hesions were identified and adhesiolysis performed.
Laparoscopic partial cystectomy for bladder endometri- Concurrently a cystoscopy was done by a urologist to
osis generally involves the use of peri-operative cystoscopy identify the pathology (Figure 1). The lesion extended below
to diagnose the position of bladder endometriosis and in- the intra-ureteric bar and was seen to be in immediate prox-
sertion of ureteric stents. Laparoscopic partial cystectomy imity to the left ureteric orifice (Figure 2). The ureters were
is subsequently performed by excising the lesion transab- then stented and margins of the lesion were then circum-
dominally. However excising the lesion with exact margins scribed with a Collins knife introduce via a 26F continuous
is difficult. The resulting bladder capacity will be reduced flow resectoscope to a depth just short of the serosal surface
but this may be exacerbated due to over excision of normal (Figure 3). This was aided by the laparoscopic view to pre-
bladder adjacent to the endometrial nodule. vent full thickness penetration (Figure 4).

CASE STUDY peer reviewed JPOG MAY/JUN 2014 123
Figure 1 Figure 3
CYSTOSCOPIC VIEW OF BLADDER ENDOMETRIOTIC NODULE MINIMAL MARGIN USING COLLINS KNIFE (CYSTOSCOPIC VIEW)
Figure 2 Figure 4
BLADDER
ENDOMETRIOTIC NODULE
URETERIC STENT
CYSTOSCOPIC MAPPING OF BLADDER LAPAROSCOPIC VIEW OF BLADDER DURING CYSTOSCOPIC

ENDOMETRIOSIS MAPPING OF BLADDER ENDOMETRIOTIC NODULE
Once the margins of the lesion had been fully mapped, direct vision and the bladder was then closed laparoscopi-
a full thickness incision was made through the bladder at cally with a continuous 2.0 vicryl suture (PIC if space) (Fig-
the most uppermost point of the margin to guide entry into ure 6). The specimen was retrieved via Endocatch bag and
the bladder form the laparoscopic approach. This caused port sites closed in the usual manner. The procedure was
leakage of 1.5% glycinine into the plane under the uterove- completed in 120 minutes without complications and the pa-
sical fold of peritoneum, following which the bladder was tient was discharged the next day without any further man-
immediately emptied. agement.
The partial cystectomy was started laparoscopical- The patient went home with the suprapubic catheter
ly at the superior margin of the endometriotic nodule left on free drainage for 2 weeks and then removed after a
through the opening created at the end of cystoscopy. cystogram confirmed bladder integrity. The ureteric stents
Excision was performed using the harmonic scalpel fol- were removed at 4 weeks. Pathology confirmed the bladder
lowing the mapped margin created during cystoscopy nodule as endometriosis and margins were clear. The pa-
(Figure 5). tient did not show clinical recurrence at follow-up and had
A supra pubic catheter was sited in the bladder under normal bladder function.

124 JPOG MAY/JUN 2014 CASE STUDY peer reviewed
COMMENT Figure 5
The laparoscopic management of deep bladder endometri-
osis is technically challenging with the competing require-
BLADDER
ment for complete excision to reduce recurrence and the
need to leave as much functional capacity of the bladder
as possible. This is further compounded by the need to dis-
sect extremely close to the ureteric orifices in some cases.
This technique allows precise mapping of the bladder en-
dometriotic nodule thereby completely excising the lesion
but preserving as much bladder capacity as possible and BLADDER ENDOMETRIOTIC
NODULE
preventing inadvertent ureteric obstruction or incomplete
treatment in this area. The ability to trace the predefined
EXCISION OF BLADDER ENDOMETRIOTIC NODULE VIA CYSTOSCOPIC
margins laparoscopically also makes the procedure both MAPPED MARGIN (LAPAROSCOPIC VIEW)
simpler and quicker.
Although this case represents a successful and poten-
Figure 6
tial new technique for future bladder endometriosis nodule
resection, larger series and long-term data will be required
to assess the difference between this technique and conven-
tional laparoscopic partial cystectomy.
About the Authors

Dr Menelik Lee is a Specialist in the Department of Obstetrics and Gynaecology, Queen Eliz-
abeth Hospital, Hong Kong. Dr Charles Carter is a Consultant in the Department of Obstetrics
and Gynaecology, Royal Bournemouth Hospital, Bournemouth, UK. Dr Tyrone Carpenter is a BLADDER SUTURED LAPAROSCOPICALLY (LAPAROSCOPIC VIEW)
Consultant in the Department of Obstetrics and Gynaecology, Poole Hospital NHS Foundation
Trust, Longfleet Poole, Dorset, UK.
REFERENCES
1. Salvatores M, Landi S, Ceccaroni M, et 3. Villa G, Mabrouk M, Guerrini M, et al. ment and follow-up. Eur J Obstet Gynecol of associated posterior deep lesions. Hum
al. The Laparoscopic Treatment of Blad- Relationship between site and size of endo- Reprod Biol 2008;140:114117. Reprod 2010; 25:884889.
der Endometriosis. A retrospective analy- metriotic nodules and severity of dysuria. J 6. Schornman R, Dotan Z, Weintraub AY, 8. Sanchez Merino JM, Guillan Maquieira
sis of 21 cases. Minerva Ginecol 2007;59: Minim Invasive Gynecol 2007;14:628632. et al. Deep endometriosis inflicting the blad- C, Garcia Alonso J. The treatment of blad-
1925. 4. Tai HC, Chung SD, Wang SM, et al. Lap- der: long-term outcomes of surgical man- der endometriosis. Spanish literature review.
2. Chapron C, Fauconnier A, Vieira M, et al. aroscopic partial cystectomy for various agement. Arch Gynecol Obstet 2013;288: Arch Esp Urol 2005;58:189194.
Anatomical distribution of deeply infiltrating bladder pathologies. BJU Int 2007;100: 13231328. 9. Le Tohic A, Chis C, Yazbeck C, et al. Blad-
endometriosis: surgical implications and 382385. 7. Chapron C, Bourret A, Chopin N, et al. der endometriosis: diagnosis and treatment.
proposition for a classification. Hum Reprod 5. Granese R, Candiani M, Perino A, et al. Surgery for bladder endometriosis: long- A series of 24 patients. Gynecol Obstet Fertil
2003;18:157161. Bladder endometriosis: laparoscopic treat- term results and concomitant management 2009;37:216221.

SPONSORED SYMPOSIUM HIGHLIGHTS
At a Menarini-sponsored symposium during the 19th World Congress on Gynecology and Infertility held at the Venetian Macau Hotel
last February 22, 2014, experts discussed the latest information about Asian scar management, with particular emphasis on the recently
published Asian scar treatment guidelines.
Updates on Asian Scar Management and Treatment Guidelines

Marie Socouer Medina-Oblepias, MD EE Cherk Cheong, MD
Consultant Dermatologist Consultant, Plastic, Reconstructive
Research Institute for Tropical Medicine and Aesthetic Surgery
Philippines Tan Tock Seng Hospital
Singapore
The Asian Scar Treatment Guidelines
Scar prevention post-surgery
A combination of prolonged inflammation, increased tension and
genetic predisposition may lead to excessive scarring.1 Ethnicity Prevention is always better than treatment, and in terms of scars,
may also be an important factor. Specifically, Asians have been good and early wound management yields better scar outcomes.
described to have unique skin characteristics that predispose Planning the incision, with the consideration of several factors,
them to scarring. They exhibit a thicker dermis with greater also determines the resulting scar. Factors to note are as follows:
collagen density and propensity to fibroblast proliferation. Asians anatomic site of injury, symptoms involved, degree of psychological
also have larger melanosomes that make them more prone to distress and functional impairment.
hyperpigmentation after a cutaneous injury. Thus, to manage scars
in Asians, expectations must be set realistically, because their scars Treatment is best commenced when the scar is immature but with
may take a longer time to heal, and may require close monitoring.2,3 the overlying epithelium already intact. This can be achieved via a
Moreover, because of the unique features of the Asian skin, specific multimodal approach to scar therapy. For new scars, silicone gels or
guidelines are needed to optimize scar treatment outcomes. sheeting may be used, together with sun avoidance. An enhanced
silicone gel formulation Dermatix Ultra has vitamin C that not
The recent publication of the paper, Update on Scar Management: only stimulates collagen repair for healing, but also blocks melanin
Guidelines for Treating Asian Patients, makes specific formation that helps lighten scars. Meanwhile, steroid injections,
recommendations for treating Asian scars, and emphasizes the surgery and radiotherapy should be reserved for more problematic
importance of initiating scar prevention in all Asian patients (Table).2 scars.
The guidelines also recognize the significant efficacy of a silicone-
based gel therapy in Asian patients, highlighting its ease of use
and improved patient compliance when compared with silicone Dominic Fuk-Him Li, MD
gel sheeting.2-5 Silicone gels were also assessed to be as effective Honorary Clinical Assistant Professor
as silicone gel sheeting in preventing hypertrophic scars, and that Department of Obstetrics and Gynecology
in select patients, silicone gel therapy is recommended as first-line University of Hong Kong
treatment.2,4 Aside from decreasing scar height and erythema and Hong Kong
improving pliability, silicone gels have also been shown to improve
the subjective symptoms of pain, itching and tension associated
with scars.5 The guidelines will hopefully help practitioners make
Scar management and prevention in
optimal and evidence-based treatment decisions for their patients Obstetrics-Gynecology
to prevent excessive scarring and improve treatment outcomes.
Hypertrophic scars are common problems encountered in post-
cesarean section patients.6 The risk for scarring is influenced by
Table. Recommendations for scar management in Asian patients2 certain factors including age, skin color, family history, location and
size of the scar and duration of inflammation. It affects patients
Scar type Recommendations both physically and psychosocially, and should not be trivialized.
All scars In select patients, silicone gel therapy is recommended
as first-line treatment for the management of both
As with any surgery, a proactive preventive approach on scar
hypertrophic and keloid scars management should always be employed in obstetric and
gynecologic procedures. Silicone-based therapy is considered as
Hypertrophic Silicone-based gel is as effective as silicone gel sheeting a gold standard in treatment. Based on experience, the use of the
scars Multiple sessions of lower fluences of pulsed-dye lasers non-invasive silicone gel Dermatix Ultra has been superior in its
are recommended for prevention of hyperpigmentation ease of use and patient acceptability in obstetric and gynecologic
in Asian patients with hypertrophic scars procedures.
Keloids Steroid monotherapy is effective for symptom
management
Combined excision plus steroid injections or other
adjuvant therapies is effective and safe References
1. Bayat A, et al. BMJ 2003;326:88-92. 2. Kim S, et al. Plast Reconstr Surg 2013;132:1-10. 3. Mustoe TA, et al. Plast Reconstr
Keloid sites with a high risk of recurrence should be Surg 2002;110:560-71. 4. Mustoe TA. Equivalent efficacy of silicone gel (Dermatix Ultra) & silicone gel sheeting in scar
treated with escalated doses of radiation and post- management: Clinical results & MOA. Presented at the 21st World Congress of Dermatology 2007;Buenos Aires, Argentina.
5. Chernoff WG, et al. Aesth Plast Surg 2007;31:495-500. 6. Atkinson JM. Plast Reconstr Surg 2005;116:1648-56.
treatment self-management
Sponsored as a service to the medical profession by A. Menarini
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those of the editor, publisher or sponsor. Any liability or obligation for loss or damage howsoever
arising is hereby disclaimed. 2014 MIMS. All rights reserved. No part of this publication may
be reproduced by any process in any language without the written permission of the publisher.
MIMS Pte Ltd c/o MediMarketing, Inc

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JPOG MAy/JUN 2014 125
CONTINUING MEDICAL EDUCATION
Intrauterine Fetal Growth 5 SKP
Restriction
May Li Lim, MBBS, MRCOG, FRANZCOG; Kenneth Kwek, MBBS, MMed, MRCOG, MRANZCOG; Kok Hian Tan, MBBS, FRCOG, MMed, FAMS; George SH Yeo, MBBS, FRCOG, FAMS
INTRODUCTION
Placental insufficiency leading to in-
trauterine growth restriction (IUGR) in
the fetus affects up to 15% of pregnan-
cies.1 IUGR can present diagnostic and
management challenges. The suspi-
cion of IUGR arises when fetal biome-
try indicates small for gestational age
(SGA), variously defined as abdominal
circumference below 2 standard de-
viations, abdominal circumference at
the 5th or 10th percentile, or estimated
fetal weight less than the 10th percen-
tile.2 SGA fetuses represent a heteroge-
neous group comprising constitutional
smallness and pathological smallness.
When pathologies, such as chromo-
somal aberration and genetic syndrome,
are excluded, placental insufficiency is
implied. Intrauterine fetal growth restriction due to placental insufficiency affects up to 15% of
Management challenge lies in time- pregnancies.
ly intervention especially when IUGR
complicates a preterm pregnancy. On evaluated for their predictive strength REGULATION OF FETAL
the one hand, the obstetrician wants of adverse perinatal outcomes which GROWTH
to avoid unnecessary preterm delivery, may guide decision regarding timing of The placenta acts as a conduit for transfer
which puts the neonate at risk for com- delivery. of nutrients and oxygen from mother to fe-
plications of prematurity such as cere- A synopsis of fetal growth regula- tus. Adequate substrate delivery depends
bral palsy, neonatal death, respiratory tion and fetal responses to placental in- on normal uterine perfusion, normal fe-
distress, necrotizing enterocolitis, and sufficiency will first be presented. This toplacental exchange area, and normal
intraventricular haemorrhage. On the is followed by a discussion on Doppler umbilicalplacental perfusion. The pla-
other hand, there is the burden of pos- surveillance, with attention to clinical centa, being a metabolically active com-
sible in utero fetal demise from delay- significance of the various arterial and partment, utilizes approximately 70% of
ing delivering. Surveillance tools, such venous waveforms. Finally, a suggest- the glucose and 45% of the oxygen being
as electronic fetal heart monitoring 3
ed approach to management of IUGR transferred.6 Placental growth follows a
and Doppler velocimetry,4,5 have been is presented. sigmoid-shaped curve, while fetal growth
JPOG_MayJun_2014_CME_Intrauterine Fetal Growth Restriction.indd 125 5/16/14 8:54 AM

126 JPOG MAY/JUN 2014
Fetal growth is exponential at 1.5% per day to term whereas placental growth follows a sigmoid-shaped curve.
is exponential at 1.5% per day to term.7 modify blood flow to meet the oxygen onary circulation and brain, there is an
The development of the matched fetopla- and nutrient demands. 6,8
increase in peripheral vascular and pla-
cental unit from early pregnancy is critical cental blood flow resistance (increased
in ensuring optimal fetal growth and de- FETAL RESPONSES TO right ventricular afterload) and a decline
velopment throughout pregnancy. PLACENTAL INSUFFICIENCY in cerebral flow resistance (decreased
Following fertilization, cytotroph- In placental insufficiency, fetal responses left ventricular afterload). Reduced liver
oblast migration occurs, leading to the are seen in various systems. Metabolical- perfusion from the increased shunting
establishment of placental adherence ly, fetal hypoglycaemia leads to blunting through the DV to the heart leads to the
through anchoring the villi to the decid- of pancreatic insulin responses, which in accumulation of blood lactate, thus aci-
ua and uterus. The process is complete turn allows hepatic gluconeogenesis. As daemia. As hypoxaemia and acidaemia
when a low-resistance, high-capacitance the situation worsens, there is inability worsen, the metabolic demands of the
placental compartment is achieved. Nu- to maintain oxidative metabolism. The heart can no longer be maintained and
trient-rich blood entering the fetal circula- ensuing anaerobic metabolism leads to myocardial dysfunction supervenes.
tion is delivered via the umbilical vein to the production of lactate, which is me- With declining cardiac function, there
the heart and liver. The ductus venosus tabolized by the liver and used as alter- is failure to accommodate the venous
(DV) acts as a shunt to direct a larger native substrate by fetal heart and brain. return and so the central venous pres-
proportion of that blood to the liver and Acid-base balance will be maintained sure rises. Progressively, forward cardi-
the remaining to the heart. Differential as long as fetal haemoglobin buffering ac function fails. As cardiac dysfunction
directionality of blood entering the right capacity is sufficient with a matching re- reaches a critical state, there is cardiac
atrium ensures that well-oxygenated moval rate by the liver, heart and brain. 6
dilatation, indicative of loss of cardiovas-
blood is distributed to the left ventricle, To maintain oxygenation of the vital or- cular homeostasis.9 Typically, this starts
myocardium and brain. Low-nutrient ve- gans such as the heart and brain, there in the right heart, manifesting as dilated
nous return is forwarded to the placenta is preferential shunting of blood from the tricuspid annulus, tricuspid regurgita-
for re-oxygenation and nutrient-waste umbilical vein through the DV. To facil- tion and reversed a wave in the DV flow.
exchange via the umbilical arteries. itate preferential distribution of cardiac Characteristic responses are seen in the
Through autoregulation, various organs output to the left ventricle and thus cor- fetal behaviour when there is hypoxae-

Doppler ultrasound is the mainstay of fetal surveillance in pregnancies with IUGR.
mia. There is delayed central nervous cies.10 Doppler ultrasound, which pro- poxia, and to predict adverse perinatal
system maturation and delayed central vides information about placental vas- outcomes. Cardiotocography of the fetal
integration with the fetal heart, resulting cular resistance,11,12 preferential cerebral heart also plays an important role in as-
in reduced short- and long-term fetal blood flow 13
and filling capacity of fetal sessing the fetal condition in IUGR preg-
heart variation. As the hypoxaemia wors- heart,14,15 allows the tracking of progres- nancies, although it is considered a late-
ens, fetal activity slows down and fetal sion of placental insufficiency. The evi- stage disease when there is abnormality
heart decelerations are observed.8 dence for Doppler velocimetry in clinical such as deceleration in the tracing.16
management has been evaluated more UA velocimetry gives information
FETAL SURVEILLANCE thoroughly and more systematically about placental function. There is abun-
There are multiple methods of fetal as- than evidence for any other techniques dant data linking abnormal UA Doppler
sessment in IUGR. The biophysical pro- in modern obstetrics. Doppler has been and adverse outcomes in IUGR preg-
file score, which incorporates fetal tone, applied to various vessels including nancies5,17,18 This is hardly surprising
fetal movement, fetal breathing, amniot- umbilical artery (UA), middle cerebral because histological analysis has con-
ic fluid volume and non-stress test, has artery (MCA), uterine artery, DV, aorta firmed placental vascular pathology in
been shown to predict fetal status and (isthmus) and umbilical vein to predict the presence of abnormal UA velocime-
to produce improvement in outcomes placental dysfunction, to assess fetal try, such as reduction in volume of the
when employed in high-risk pregnan- cardiovascular status in response to hy- intervillous space, reduction in the elab-

The risks associated with IUGR extend into adulthood.
oration of distal villi, smaller exchange tion of UA PI for predicting adverse peri- Perinatal mortality rates of up to 28% are
surface area, and thicker trophoblastic natal outcome has been widely practised reported in such cases.20 It is generally
epithelium. 12
The categories of abnor- for many years. The sensitivity and speci- accepted that the finding of these wave-
mal UA waveformsincreased pulsatil- ficity for any adverse outcome have been forms indicates that the condition is se-
ity index (PI), absent end-diastolic flow reported to be 44.7% and 86.6%, respec- vere and indeed should prompt the ob-
(AEDF) or reversed end-diastolic flow tively.18 Comparing pregnancies with stetrician to re-assess management, in
(REDF)represent progressively wors- positive end-diastolic flow, those with particular, to make a decision regarding
ening placental dysfunction. Hence, fe- AEDF or REDF have been shown to be delivery.
tuses can be assigned varying degrees associated with lower birthweight, earlier Decision on the timing of delivery
of risk according to these waveforms. gestation at birth, and higher frequency should be considered with gestational
The risk stratification can help inform the of severe respiratory distress syndrome, age in mind. Baschat et al investigated
obstetrician on the level of fetal monitor- cerebral haemorrhage, hypoglycaemia the outcomes of fetuses with abnormal
ing required. and anaemia.20 The temporal changes Doppler velocimetry in arterial and ve-
Although fetuses with abnormal venous circulation generally fared the worst,
gestational age at delivery was the most significant contributor to short-term
outcomes after multivariate analysis
McCowan et al found raised UA PI on Doppler ultrasound in IUGR are well nous circulations.16 The outcome pa-
to be associated with fetuses of smaller documented. Pregnancies with raised rameters evaluated were perinatal mor-
proportions in terms of birthweight, head UA PI have been seen to sequentially tality, respiratory distress syndrome,
circumference, and length. 19
The utiliza- deteriorate to UA AEDF and UA REDF. 21
bronchopulmonary dysplasia, necrotiz-

ing enterocolitis, intraventricular haem-

orrhage, and circulatory insufficiency.
Although fetuses with abnormal venous
circulation generally fared the worst,
gestational age at delivery was the most
significant contributor to short-term out-
comes after multivariate analysis. This
effect was most marked for respiratory
distress syndrome and least for intraven-
tricular haemorrhage and necrotizing en-
terocolitis.16 In following the progression
of fetuses with UA AEDF or UA REDF,
Hartung et al also concluded that while
perinatal mortality was related to ab-
normal UA velocimetry, gestational age
at delivery had a significant impact on
short-term morbidity.22 One recommen-
dation by Hartung et al is that delivery
should be considered if the pregnancy
is greater than 32 weeks gestation as Late-onset IUGR is associated with a lesser degree of placental vascular abnormality and
morbidity is low. 22
In the ascertainment hence the lack of abnormal umbilical artery Doppler findings.
of gestation-specific survival and compli-
cation rates, Baschat et al showed that As well as detecting decreased cerebral significant predictor of perinatal morbid-
the median survival gained per day in blood flow resistance due to brain-spar- ity and mortality.4 Longitudinal studies
utero was 2% between 24 and 27 weeks ing, CPR may be the first sign of elevated have demonstrated abnormal DV to be
gestation. With more advanced gesta- placental blood flow resistance.23 Longi- a sign of advanced stages of fetal com-
tion, major morbidity fell from 56.6% at tudinal studies have shown brain-spar- promise and be indicative of the need for
24 weeks to 10.5% at 32 weeks, leading ing to be an early phenomenon in pla- delivery within the subsequent 7 days.1,24
to significant neonatal survival and intact cental dysfunction. Persistent dilation of Bilardo and colleagues showed that at
survival. 4
MCA was seen in > 50% of fetuses 2 to 27 days before delivery, abnormal DV
Brain-sparing is a compensatory 3 weeks before any fetal heart tracing was present in 79% of fetuses with ad-
fetal response seen in placental insuffi- abnormality. 1,24
The consensus that cer- verse outcome. On the day before deliv-
ciency whereby blood is preferentially ebral redistribution is a marker for early ery, this increased to 93%.5 The signifi-
distributed to cerebral structures by au- hypoxaemia is also supported by find- cance of DV velocimetry is supported by
toregulation to maintain delivery of oxy- ings of Dubiel et al who demonstrated the work of Baschat et al. Having correct-
gen and nutrients. MCA is the vessel of that fetuses with brain-sparing effect still ed for birthweight and gestation at deliv-
choice because it is the most accessible had reserves to cope with the stress of ery, DV velocity was the only statistically
and there is a high degree of observer normal labour. 25
significant predictor of intact survival of
agreement in terms of PI measurement. In IUGR, understanding of the vas- IUGR babies.4
MCA velocimetry is expressed as either cular dynamics is enhanced by the in- Doppler velocimetry at the level
MCA PI or a ratio such as MCA/UA PI corporation of venous Doppler on ves- of aortic isthmus has been evaluated
(cerebroplacental ratio [CPR]). CPR is sels such as umbilical vein, DV, inferior as a monitoring tool in IUGR. The isth-
thought to be a better index because it vena cava, and portal vein. Abnormal DV mus is the area between the origin of
allows detection of blood flow redistri- velocimetry has been shown to correlate the left subclavian artery (perfused by
bution from two potential mechanisms. with acidaemia at cordocentesis and a26
the left ventricle) and aortic end of the

Figure. A suggested management approach for intrauterine fetal growth restriction.
Small for gestational age
Confirm dates correct
Exclude aneuploidy,
infection
< 28 weeks > 28 weeks
Yes No
Is maternal status at risk Deliver Is CTG normal? Deliver
No Yes
Yes Is umbilical No
Is umbilical artery 1-weekly Doppler Give steroids
artery
Doppler normal? 2-weekly growth scan then deliver
Doppler normal?
No Yes
Is ductus venosus Yes Repeat every 1

Repeat daily
Doppler normal? week
No
Continual discussion with couple

Neonatal counselling
Consideration to gestational age
Options
-Expectant with risk of IUD
-Steroids and deliver
CTG = cardiotocograph; IUD = intrauterine fetal demise.
ductus arteriosus (perfused by the right flow velocimetry has a low sensitivity al- of fetuses with suspected IUGR diag-
ventricle). Its unique position means though it appears to be highly specific as nosed at a mean gestation of 34.1 weeks
that it is influenced by both downstream a sign of decompensation.27,28 until delivery at 38.7 weeks.29 They found
impedance in the lower body and that There is increasing recognition of no significant difference in UA PI. There
of the upper body especially the brain. the entity of late-onset IUGR. In contrast to was, however, progressive decrease in
Waveform abnormalities are classified early-onset IUGR, late-onset IUGR is as- MCA PI and CPR until delivery.29 The util-
as decreased, absent or reversed flow. sociated with a lesser degree of placental ity of MCA Doppler as a prognostic indi-
Reversed flow through the aortic isthmus vascular abnormality and hence the lack cator in late-gestation IUGR is supported
results in low-oxygen blood from the right of abnormal umbilical artery Doppler find- by findings from studies showing abnor-
heart being directed to the brain. This has ings. The progressive cardiovascular de- mal neurobehavioural performance in the
been shown to be associated with long- terioration observed in early-onset IUGR neonatal period and early childhood in
term neurodevelopmental impairment. is also not seen. Oros et al monitored the fetuses with abnormal MCA Doppler an-
The current thinking is that aortic isthmus longitudinal Doppler changes in a cohort tenatally.30,31,32

SUGGESTED APPROACH TO terioration.21 Delivery threshold needs to CONCLUSION

MANAGEMENT be high if gestational age is less than 26 IUGR is associated with significant risk
A suggested management approach is weeks owing to a high chance of mortal- of mortality and morbidity, which ex-
as described in the Figure. It is useful to ity. Up until 28 weeks, each day in utero tends into adult life. Doppler ultrasound
bear in mind the time frame of progres- potentially increases survival by 2% per is the mainstay of fetal surveillance in
sion. In early-onset IUGR, the anticipated day. Abnormal DV is the most significant these pregnancies. There are sequential
progression rate is defined by the rate of predictor of neonatal mortality. changes in Doppler velocimetry, which
progression of UA Doppler. Loss of UA In late-gestation IUGR, there is no can provide clues to worsening of con-
end-diastolic flow within 2 weeks is sug- good evidence to guide the best man- dition and hence guide decision-making
gestive of a rapidly progressive picture agement. The clinician needs to balance regarding delivery.
with venous flow abnormality within the the risk of intrauterine fetal demise from
subsequent 4 weeks. If, however, loss not delivering and the risk of delivery About the Authors
of UA end-diastolic flow is more gradual by either labour induction or caesarean Dr Lim is Consultant, Dr Kwek is Head and Senior Consultant,
Dr Tan is Clinical Associate Professor and Senior Consult-
over 4 weeks, there will be a longer laten- section. The choice of delivery to avoid ant, and Dr Yeo is Chief of Obstetrics, Adjunct Professor and
Senior Consultant, Department of Maternal Fetal Medicine,
cy period of about 6 weeks to venous de- stillbirth is, however, considered rational. KK Womens and Childrens Hospital, Singapore.
Acknowledgement
This paper was made possible through a collaboration between KK Womens and Childrens Hospital (KKH) and the
Journal of Paediatrics, Obstetrics and Gynaecology. KKH is the largest medical facility in Singapore which
provides specialized care for women, babies and children.
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1. Ferrazzi E, Bozzo M, Rigano S, et al. 10. Oyelese Y, Vintzileos AM. The uses and al. Prediction of perinatal outcome in fetus- 1997;47:177184.
Temporal sequence of abnormal Doppler limitations of the fetal biophysical profile. es suspected to have intrauterine growth 26. Pardi G, Cetin I, Marconi AM, et al. Di-
changes in the peripheral and central cir- Clin Perinatol 2011;38:4764. restriction: Doppler US study of fetal cere- agnostic value of blood sampling in fetus-
culatory systems of the severely growth-re- 11. Maulik D, Mundy D, Heitmann E, Maulik bral, renal and umbilical arteries. Radiology es with growth retardation. N Engl J Med
stricted fetus. Ultrasound Obstet Gynecol D. Umbilical artery Doppler in the assess- 1999;213:681689. 1993;328:692696.
2002;19:140146. ment of fetal growth restriction. Clin Perina- 19. McCowan LME, Harding JE, Stewart 27. Fouron JC, Gosselin J, Raboisson MJ, et
2. Miller J, Turan S, Baschat A. Fetal growth tol 2011;38:6582. AW. Umbilical artery Doppler studies in al. The relationship between an aortic isth-
restriction. Semin Perinatol 2008;32:274280. 12. Giles WB, Trudinger BJ, Baird PJ. Fe- small for gestational age babies reflect mus blood flow velocity index and the post-
3. Torrance HL, Bloemen MCT, Mulder tal umbilical artery flow velocity waveforms disease severity. BJOG 2000;107:916925. natal neurodevelopmental status of fetuses
EJH, et al. Predictors of outcome at 2 and placental resistance: pathological cor- 20. Karsdorp VHM, van Vugt JM, van Geijn with placental circulatory insufficiency. Am J
years of age after early intrauterine growth relation. Br J Obstet Gynaecol 1985;92:31 HP, et al. Clinical significance of absent or Obstet Gynecol 2005;192:497503.
restriction. Ultrasound Obstet Gynecol 38. reversed end diastolic velocity waveforms 28. Tideman E, Marsal K, Ley D. Cognitive
2010;36:171177. 13. Mari G, Deter R. Middle cerebral ar- in umbilical artery. Lancet 1994;344:1664 function in young adult following intrauter-
4. Baschat A, Cosmi E, Bilardo CM, et al. tery flow velocity waveforms in normal and 1668. ine growth restriction with abnormal fetal
Predictors of neonatal outcome in early-on- small-for-gestational age fetuses. Am J Ob- 21. Turan OM, Turan S, Gungor S, et al. aortic blood flow. Ultrasound Obstet Gyne-
set placental dysfunction. Obstet Gynecol stet Gynecol 1992;166:12621270. Progression of Doppler abnormalities in col 2007;29:614618.
2007;109:253261. 14. Kiserud T, Kessler J, Ebbing C, Ras- intrauterine growth restriction. Ultrasound 29. Oros D, Figueras F, Cruz-Martinez R,
5. Bilardo CM, Wolf H, Stigter RH, et al. mussen S. Ductus venosus shunting in Obstet Gynecol 2008;32:160167. Meler E, Munmany M, Gratacos E. Longi-
Relationship between monitoring parame- growth-restricted fetuses and the effect of 22. Hartung J, Kalache KD, Heyna C, et al. tudinal changes in uterine, umbilical and
ters and perinatal outcome in severe, early umbilical circulatory compromise. Ultra- Outcome of 60 neonates who had ARED fetal cerebral Doppler indices in late-onset
intrauterine growth restriction. Ultrasound sound Obstet Gynecol 2006;28:143149. flow prenatally compared with a matched small-for-gestational age fetuses. Ultra-
Obstet Gynecol 2004;23:119125. 15. Gudmundsson S, Tulzer G, Huhta JC, control group of appropriate-for-gestational sound Obstet Gynecol 2011;37:191195.
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242. al. Fetal umbilical artery velocity waveforms son G, Marsal K. Middle cerebral artery 32. Figueras F, Oros D, Cruz-Martinez R,
9. Baschat A. Venous Doppler evaluation and subsequent neonatal outcome. Br J velocimetry as a predictor of hypoxemia in et al. Neurobehavior in term, small-for-ges-
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CME QUESTIONS
Program pendidikan kedokteran berkelanjutan ini dipersembahkan oleh MIMS, bekerjasama

dengan Ikatan Dokter Indonesia.
Setelah membaca artikel Intrauterine Fetal Growth Restriction, jawab pertanyaan berikut
kemudian kirimkan dengan menggunakan formulir jawaban yang sudah disediakan ke CME
Journal of Paediatrics, Obstetrics & Gynaecology, untuk mendapatkan 5 SKP.
ARTIKEL CME 5 SKP
Intrauterine Fetal Growth Restriction

Jawab pertanyaan di bawah ini dengan Benar atau Salah.
1. The placenta is an inactive compartment.

2. The placental compartment is a low-capacitance, high-resistance system.
3. Progression in fetal response to hypoxaemia can be observed with cardiotocographic monitoring.
4. Umbilical velocimetry is helpful in the assessment of cardiac function of fetus with intrauterine growth
restriction (IUGR).
5. In IUGR pregnancies, adverse outcomes correlate positively with umbilical velocimetry.
6. Gestational age at delivery is the single most important contributor to short-term outcomes in IUGR
pregnancies.
7. In placental insufficiency, brain-sparing effect is a late observation.
8. Late-onset IUGR is considered to be a progressive disease from early-onset IUGR.
9. Abnormal ductus venosus velocimetry significantly predicts intact survival of IUGR fetuses.
10. Survival gained in utero for fetuses between 24 and 27 weeks gestation is 4% per day.

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JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY

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to mobile genes on plasmids that can be easily Key points

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COMMON CHILDHOOD INFECTIONS About the Authors

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Yours Sincerely, Prof. LEUNG Tak Yeung Dr. Tony TAN

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