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Educational Gap
There is a need for increased understanding of methods of risk assessment for neonatal
early-onset sepsis.
Abstract
Neonatal early-onset sepsis (EOS) continues to be a signicant source of morbidity
and mortality among newborns, especially among very low-birth-weight infants. Epidemiologic risk factors for EOS have been dened, and considerable resources are devoted to the identication and evaluation of infants at risk for EOS. The widespread
implementation of intrapartum antibiotic prophylaxis for the prevention of early-onset
neonatal group B streptococcal disease has reduced the overall incidence of neonatal
EOS and inuenced the microbiology of persistent early-onset infection. Recommendations for perinatal risk factorbased evaluation and empiric antibiotics treatment of
neonates result in a large proportion of uninfected infants undergoing medical intervention, including antibiotic therapy. Objective risk assessment tools have been developed that may allow safe restriction of medical intervention in uninfected newborns,
promote antibiotic stewardship, and optimize resource use.
device.
Objectives
Introduction
Bacterial sepsis and meningitis continue to be major causes of morbidity and mortality in
newborns, particularly in very low-birth-weight (VLBW) infants (birth weight <1,500 g).
(1)(2) Neonatal early-onset sepsis (EOS) is dened by the Centers for Disease Control and
Prevention (CDC) as blood and/or cerebrospinal uid cultureproven infection occurring
in the newborn at less than 7 days of age. (3) For the continuously hospitalized VLBW
infant, EOS is dened as culture-proven infection occurring at less than 72 hours of
age. (2) The alternative denition in VLBW infants is justied by 2 ndings: (1) the risks
of infection in VLBW infants after age 72 hours primarily derive from the specics of ongoing neonatal intensive care rather than from perinatal risk factors, and (2) the organisms
that cause infection after age 72 hours among VLBW infants reect the nosocomial ora of
the neonatal intensive care unit (NICU) more than perinatally acquired maternal ora.
Table 1.
Organism
NICHD (n [ 370)
BWH (n[335)
GBS
Escherichia coli
Other streptococcia
Enterococcus
Staphylococcus aureus
Coagulase-negative Staphylococcus
Listeria
Bacteroides species
Klebsiella
Hemophili
Other gram-negative organismsb
Otherc
Fungi
Total gram positive
Total gram negative
159
107
39
10
9
3
2
3
1
11
15
9
2
231
137
139
71
39
13
13
14
2
15
4
6
8
8
3
228
104
(43.0)
(28.9)
(10.5)
(2.7)
(2.4)
(0.8)
(0.5)
(0.8)
(0.3)
(3.0)
(4.1)
(2.4)
(0.5)
(62.4)
(37.0)
(41.5)
(20.2)
(11.6)
(3.9)
(3.8)
(4.2)
(0.6)
(4.5)
(1.2)
(1.9)
(2.6)
(2.4)
(0.9)
(68.1)
(31.0)
The BWH data are from all early-onset sepsis cases among infants born in a single center for the period 1990 to 2007. The NICHD data are from all earlyonset sepsis cases among multiple centers from 2006 to 2009.
BWHBrigham and Womens Hospital; GBSgroup B Streptococcus; NICHDEunice Kennedy Shriver National Institute of Child Health and Human
Development.
a
Other streptococci include Streptococcus pneumoniae, Streptococcus bovis, Streptococcus mitis, Peptostreptococcus, group D Streptococcus, a-hemolytic
streptococcus, Streptococcus morbillorum, Streptococcus mutans, Streptococcus oralis, Streptococcus pneumoniae, Streptococcus salivarius, Streptococcus sanguinis,
and viridans streptococci.
b
Other gram-negative organisms include Enterobacter, Citrobacter, Acinetobacter, Pseudomonas, Proteus, Brevundimonas vesicularis, Moraxella species,
Capnocytophaga species, Morganella species, and Yersinia.
c
Other organisms include Bacillus, Actinomyces odontolyticus, gram positive not specied, and Clostridium.
Adapted from Stoll et al (1) and Puopolo and Eichenwald (8).
ampicillin signicantly reduces the rate of neonatal colonization with GBS and the incidence of early-onset GBS disease. The efcacy of IAP was most substantially revealed in
a trial of only 160 women in 1986. (12) IAP for the prevention of GBS EOS can be administered to pregnant
women during labor based on (1) specic clinical risk factors for early-onset GBS infection or (2) the results of
antepartum screening of pregnant women for GBS colonization. The CDC has published consensus guidelines that
endorsed the use of IAP for prevention of neonatal GBS
disease, rst in 1996 and subsequently in revised form
in 2002 and 2010 recommending universal GBS screening
among pregnant women. (5)(13)(14) Risk factors to consider include maternal GBS colonization status determined
at 35 to 37 weeks gestation, documented GBS bacteriuria
during pregnancy, prior delivery of an infant with GBS disease, preterm labor, unknown GBS status combined with
an intrapartum temperature of 100.4F (38C), or duration of rupture of membranes of 18 hours or longer. Adequate IAP was dened as the administration of one of the
endorsed antibiotics 4 or more hours before delivery. The
most current version also endorses intrapartum use of nucleic acid amplication tests (NAATs) as an acceptable
Table 2.
Study
Study Specifics
Pre-IAP era
GBS early-onset sepsis only
All newborns
Post-IAP era
BW of 2,000 g
N[2,785 infants, including
62 cases
Post-IAP
Escherichia coli early-onset
sepsis only
All newborns
N[ 132 cases, 1,212 controls
Post-IAP
34 weeks gestation
N[350 cases, 1,063 controls
Risk Factors
Intrapartum fever
PROM
GA 33 weeks
GA 3436 weeks
GA (per day)
GBS status
Positive
Unknown
Duration of ROM (per hour)
Highest intrapartum temperature
(per degrees Celsius)
GBS IAP given on time or any
antibiotic given <4 hours
Broad-spectrum antibiotic
given >4 hours
24.8
7.37
7.28
6.42
4.05
(12.250.2)
(4.4812.1)
(4.4212.0)
(2.3217.8)
(2.177.56)
5.78
2.05
2.82
0.27
2.24
(1.5721.29)
(1.063.96)
(1.505.34)
(0.110.65)
(1.194.22)
3.50
3.60
0.42
6.6
(1.309.42)
(1.458.96)
(0.161.11)
(3.313.2)
3.5
26.5
5.3
0.001
1.78
1.04
3.41
2.38
(2.15.8)
(15.046.8)
(3.09.7)
(0.00010.014)
(1.112.85)
(0.761.44)
(2.235.20)
(2.052.77)
0.35 (0.230.53)
0.31 (0.130.71)
ANCabsolute neutrophil count; BWbody weight; CIcondence interval; GAgestational age; GBSgroup B Streptococcus; IAPintrapartum antibiotic
prophylaxis; PROMpremature rupture of membranes; ROMrupture of membranes.
a
Benitz et al reported unadjusted odds ratios, whereas the other 3 studies reported adjusted odds ratios.
b
Model also included a gestational age squared (adjusted odds ratio, 1.09; 95% CI, 1.051.13).
performed at 35 to 37 weeks gestation and repeat screening on presentation for delivery at term, which may account for many cases of persistent GBS EOS. (18) Use
of NAATs for intrapartum GBS detection where available
may facilitate identication among mothers with onset of
labor before 35 to 37 weeks gestation or with missed
(particularly cheeses and deli meats) has been documented, occasionally in epidemic outbreaks. These bacteria do not cause signicant disease in immunocompetent
adults but can cause severe illness in pregnant women
and their fetuses and in newborns. The true incidence of
listeriosis in pregnancy is difcult to determine because
many cases are undiagnosed when they result in spontaneous abortion of the previable fetus. Obligate anaerobic
bacteria (primarily the encapsulated enteric organism Bacteroides fragilis) can cause neonatal EOS and justify the use
of both aerobic and anaerobic blood culture bottles in the
evaluation of EOS. Although methicillin-sensitive Staphylococcus aureus and methicillin-resistant S aureus cause
a large proportion of hospital-acquired infection in VLBW
infants and are increasing issues in community-acquired
pediatric infections, these remain rare causes of neonatal
EOS. A recent study of 5,732 pregnant women documented a 3.5% incidence of MRSA in GBS rectovaginal
screening cultures but found no cases of MRSA neonatal
EOS in delivered infants. (23) Finally, fungal organisms
(primarily Candida species) rarely cause neonatal EOS.
Fungal EOS is largely found in preterm and VLBW infants,
often associated with very prolonged antibiotic (>24 hours)
exposure of pregnant mothers before delivery.
C-reactive protein, and blood cultures. A variety of biomarkers are subject to investigation (eg, CD64 or procalcitonin) but are either not clinically available or not
validated in EOS. The components of the complete
blood cell count and C-reactive protein perform relatively poorly when used as single values to assess EOS
risk; the low incidence of EOS among term infants
means there is little value in their positive and negative
predictive values. A full discussion of the use of laboratory results to predict EOS is beyond the scope of
this review.
Both the CDC and the American Academy of Pediatrics advocate evaluation of infants who are born with
signs of illness, well-appearing infants born in the setting
of maternal chorioamnionitis (with maternal intrapartum
fever often used as a surrogate for that condition), and
infants born to women who received inadequately indicated GBS IAP, with consideration given to gestational
age at birth and duration of rupture of membranes.
(14)(24)(25) Individual care centers often implement
these recommendations with local variation in practice.
We recently surveyed EOS risk assessment practices
among 23 NICUs in Massachusetts. Three-quarters of
the surveyed units had local written protocols for EOS
evaluation of term and late preterm infants. Most were
aligned with the CDC 2010 recommendations, (14) approximately 10% were aligned with the American Academy of Pediatrics recommendations, (24)(25) and one
center still adhered to the CDC 2002 recommendations.
(13) Signicant variation was reported with respect to
chorioamnionitis as a risk factor and in the use of laboratory tests for EOS evaluation.
Figure. Quantitative risk stratification for early-onset sepsis. A quantitative risk stratification scheme is shown for infants born
at 34 weeks gestation or more. Stratification is based on newborn clinical condition during the first 12 hours after birth and the
sepsis risk at birth estimated from maternal/intrapartum risk factors. Infants who have a sepsis risk at birth of 1.54 per 1,000 live
births or more or who have a sepsis risk at birth of 0.65 or more per 1,000 live births and an equivocal presentation fall into the
treat empirically group, which has a number needed to treat (NNT) of 118 and accounts for 4% of all live births. Infants with an
equivocal presentation or who are well-appearing but whose sepsis risk at birth is 0.65 to 1.54 per 1,000 fall into the observe
and evaluate group; these groups together have an NNT of 823 and account for 11% of all live births. The largest group, wellappearing infants with a sepsis risk at birth of less than 0.65 per 1,000, has an NNT of 9,370 and accounts for 85% of all live
births. Adapted from Escobar et al. (24)
References
1. Stoll BJ, Hansen NI, Snchez PJ, et al; Eunice Kennedy Shriver
National Institute of Child Health and Human Development Neonatal
Research Network. Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817826
2. Weston EJ, Pondo T, Lewis MM, et al. The burden of invasive
early-onset neonatal sepsis in the United States, 2005-2008.
Pediatr Infect Dis J. 2011;30(11):937941
3. Phares CR, Lyneld R, Farley MM, et al; Active Bacterial Core
surveillance/Emerging Infections Program Network. Epidemiology of invasive group B streptococcal disease in the United States,
1999-2005. JAMA. 2008;299(17):20562065
4. Puopolo KM, Draper D, Wi S, et al. Estimating the probability
of neonatal early-onset infection on the basis of maternal risk
factors. Pediatrics. 2011;128(5):e1155e1163
5. Centers for Disease Control and Prevention. Prevention of
perinatal group B streptococcal disease: a public health perspective.
MMWR Recomm Rep. 1996;45(RR-7):124
6. Centers for Disease Control and Prevention. Active bacterial core
surveillance report, emerging infections program network, group B streptococcus, 2013 [Internet]. Updated 2013. http://www.cdc.gov/abcs/
reports-ndings/survreports/gbs13.pdf. Accessed September 18, 2014
7. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens
causing early-onset sepsis in very-low-birth-weight infants. N Engl J
Med. 2002;347(4):240247
NeoReviews Vol.16 No.4 April 2015 e227
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1. A 4-day-old infant who was born at 24 weeks gestational age with a birth weight of 600 g is noted to have
a positive blood culture result. The culture was obtained at age 48 hours. Which of the following regarding the
timing of infection and definitions of sepsis in newborns is correct?
A. If this patient is diagnosed as having sepsis, it would be correctly categorized as early-onset sepsis.
B. For infants with birth weight greater than 1,500 g, culture-proven infection occurring before 48 hours is
considered as early-onset sepsis and after 48 hours as late-onset sepsis.
C. The risk of infection in very low-birth-weight infants after 72 hours up to age 1 week derives primarily
from prenatal and maternal risk factors.
D. The organisms found in blood cultures of very low-birth-weight infants at this age (48 hours) are more
likely to reflect the nosocomial flora of the neonatal intensive care unit (NICU) than positive culture
obtained later in hospitalization.
E. The incidence of early-onset sepsis for very low-birth-weight infants in the United States is 10 per 1,000
live births in recent years.
2. A term newborn infant has respiratory distress soon after birth and is admitted to the NICU. Blood culture is
obtained, and antibiotics are administered in case the patient has sepsis. Which of the following is true
regarding the microorganisms that cause neonatal sepsis?
A. With increasing colonization in the general population, the incidence of early-onset sepsis caused by group
B Streptococcus (GBS) has increased steadily during the past 4 decades.
B. Intrapartum antibiotic prophylaxis has reduced the severity of GBS early-onset sepsis in newborns but has
not had any effect on its incidence.
C. Early-onset sepsis caused by gram-negative enteric bacteria is found in term infants but not in preterm
infants.
D. The pathogenesis of early-onset sepsis involves ascending colonization of the fetal compartment through
ruptured and less frequently intact amniotic membranes.
E. Clostridium difficile is the most common cause of early-onset sepsis in both term and preterm infants.
3. The patients blood culture yields GBS. Which of the following statements concerning GBS is correct?
A. GBS is always a pathogenic organism and is found only in humans during pregnancy complicated by
chorioamnionitis or in newborns after intrapartum infection.
B. Most early-onset sepsis caused by GBS in the United States is currently caused by capsular polysaccharide
serotypes Ia, Ib, II, III, and V.
C. Early-onset sepsis associated with GBS is most often caused by transmission through breastfeeding during
the first 24 hours after birth.
D. Maternal GBS colonization has no effect on the development of GBS sepsis in newborns.
E. Current recommendations from the Centers for Disease Control and Prevention (CDC) do not suggest any
benefit of routine testing for GBS or a benefit of prophylactic intrapartum antibiotics for prevention of
GBS sepsis.
4. A male infant is born at 26 weeks gestational age after spontaneous preterm labor. A blood culture is obtained
in the NICU soon after admission and later yields Escherichia coli. Which of the following is correct regarding
early-onset sepsis in very low-birth-weight infants?
A. E coli is currently the most common organism causing early-onset sepsis in very low-birth-weight infants.
B. All large epidemiologic studies have found that increased use of intrapartum prophylactic antibiotics leads
to an absolute decrease in E colispecific early-onset sepsis and a decreased proportion of sepsis caused by
E coli for very low-birth-weight infants.
C. Methicillin-resistant Staphylococcus aureus is strongly associated with early-onset sepsis in very lowbirth-weight infants when mothers have recently ingested contaminated foods, such as soft cheeses and
deli meats.
D. Because the likelihood of anaerobic bacteria causing neonatal early-onset sepsis is exceedingly low, only
aerobic blood cultures are warranted.
E. Since the introduction of intrapartum antibiotic prophylaxis, more than 50% of neonatal early-onset
sepsis by S aureus is methicillin resistant.
5. Your maternal child unit is developing guidelines for risk assessment and practice surrounding neonatal earlyonset sepsis. Which of the following statements concerning risk assessment for early-onset sepsis is correct?
A. Because of conflicting studies, the CDC and the American Academy of Pediatrics have both declined to
make overarching recommendations surrounding this issue.
B. Because clinical status can often be misleading, infant symptoms should not be included in risk assessment
strategies.
C. Single components of the complete blood cell count or C-reactive protein level can perform very well as
predictors of early-onset sepsis, and it is up to each unit to determine which component to use as its main
test for risk assessment.
D. Use of a multivariable model that takes into account prior probability of sepsis based on multiple variables,
including maternal factors, can help to reduce the number of infants evaluated and empirically treated for
early-onset sepsis.
E. The most pragmatic approach that leads to highest sensitivity and specificity for diagnosis of early-onset
sepsis is to evaluate and treat all infants whose mother had more than 18 hours of ruptured membranes.
References
This article cites 30 articles, 14 of which you can access for free at:
http://neoreviews.aappublications.org/content/16/4/e221#BIBL
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