Early onset sepsis

DOI: 10.1542/neo.9-12-e571
2008;9;e571-e579NeoReviews
Karen M. Puopolo
Epidemiology of Neonatal Early-onset Sepsis
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Epidemiology of Neonatal
Early-onset SepsisKaren M. Puopolo, MD,
PhD*
Author Disclosure
Dr Puopolo has
disclosed no financial
relationships relevant
to this article. This
commentary does not
contain a discussion
of an unapproved/
investigative use of a
commercial product/
device.
Objectives After completing this article, readers should be able to:
1. Describe the incidence and microbiology of neonatal early-onset sepsis (EOS).
2. Identify clinical risk factors for neonatal EOS.
3. Review the impact of group B streptococcal prophylaxis policies on the epidemiology
of neonatal EOS.
4. Delineate the differences in incidence, risk, and microbiology of neonatal EOS between
term and very low-birthweight infants.
Abstract
Neonatal early-onset sepsis (EOS) continues to be a significant source of morbidity
and mortality among newborns, especially among very-low birthweight infants.
Epidemiologic risk factors for EOS have been defined, and considerable resources are
devoted to the identification and evaluation of infants at risk for EOS. The widespread
implementation of intrapartum antibiotic prophylaxis for the prevention of early-
onset neonatal group B Streptococcus (GBS) disease has reduced the overall incidence
of neonatal EOS and influenced the microbiology of persistent early-onset infection.
Most early-onset neonatal GBS disease now occurs in preterm infants or in term
infants born to mothers who have negative GBS screening cultures. Ongoing clinical
challenges include reassessment of clinical risk factors for EOS in the era of GBS
prophylaxis; more accurate identification of GBS-colonized women; and continued
surveillance of the impact of GBS prophylaxis practices on the microbiology of EOS,
particularly among very low-birthweight infants.
Introduction
Bacterial sepsis and meningitis continue to be major causes of morbidity and mortality in
newborns, particularly in very-low birthweight (VLBW) infants (birthweight Ͻ1,500 g).
Neonatal early-onset sepsis (EOS) is defined by the Centers for Disease Control and
Prevention (CDC) as blood or cerebrospinal fluid culture-
proven infection occurring in the newborn who is younger
than 7 days of age. (1) For the continuously hospitalized
VLBW infant, EOS is defined as culture-proven infection
occurring at fewer than 72 hours of age. (2) The alternative
definition in VLBW infants is justified by two findings:
1) the risks for infection in VLBW infants after 72 hours of
age primarily derive from the specifics of ongoing neonatal
intensive care rather than from perinatal risk factors, and
2) the organisms causing infection after 72 hours of age
among VLBW infants reflect the nosocomial flora of the
neonatal intensive care unit (NICU) more than perinatally
acquired maternal flora. (2)
The overall incidence of EOS in the United States in the
past 10 years is 1 to 2 cases per 1,000 live births; the
incidence is 10-fold higher in VLBW infants. (3)(4) Since
*Assistant Professor of Pediatrics, Harvard Medical School; Attending Physician, Channing Laboratory and Department of
Newborn Medicine, Brigham and Women’s Hospital and Division of Newborn Medicine, Children’s Hospital, Boston.
Abbreviations
BWH: Brigham and Women’s Hospital
CDC: Centers for Disease Control and Prevention
EOS: early-onset sepsis
GBS: group B Streptococcus
IAP: intrapartum antibiotic prophylaxis
MRSA: methicillin-resistant Staphylococcus aureus
NICHD: National Institute of Child Health and
Development
NICU: neonatal intensive care unit
PCR: polymerase chain reaction
VLBW: very low birthweight
Article infectious disease
NeoReviews Vol.9 No.12 December 2008 e571

the 1970s, the primary pathogen causing EOS in the
United States has been group B Streptococcus (GBS). The
incidence of EOS has fallen with the widespread imple-
mentation of intrapartum antibiotic prophylaxis (IAP)
for the prevention of early-onset GBS disease. The na-
tional incidence of GBS EOS has declined 80% from 1.7
cases per 1,000 live births in 1993 to 0.34 cases per
1,000 live births in 2003 to 2005. (1) Multiple studies
assessing the impact of GBS IAP policies demonstrate
that the incidence of non-GBS EOS is unchanged or
decreasing among term births. (4) Concern remains
about the impact of these policies on the incidence and
microbiology of EOS among VLBW infants.
Bacterial sepsis was the eighth leading cause of death
among newborns in the United States in 2000 to 2001.
(5) Mortality from EOS decreased significantly in term
infants with improvements in NICU care over the past
20 years, primarily due to advances in respiratory support
(including surfactant replacement, high-frequency venti-
lation, inhaled nitric oxide, and extracorporeal mem-
brane oxygenation). Mortality rates from EOS are higher
in preterm infants. The most recent CDC active surveil-
lance data on infants who have early-onset GBS disease
revealed that 2.6% of term infants died of the infection
compared with 19.9% of infants born before 37 weeks’
gestation, an eightfold increase in the risk of infection-
attributable mortality. (1) Among
VLBW infants, mortality is greater:
35% of VLBW infants who had EOS
died in a 2002 to 2003 National In-
stitute of Child Health and Develop-
ment (NICHD) Neonatal Network
cohort study compared with an over-
all 11% mortality among uninfected
VLBW infants. (3) Finally, neonatal
survivors of EOS may have severe
neurologic sequelae, attributable to
concomitant meningitis or from
hypoxemia resulting from septic
shock, persistent pulmonary hyper-
tension, and hypoxic respiratory
failure. Hypotension and increased
concentrations of inflammatory cy-
tokines during sepsis also may in-
jure the developing neonatal cen-
tral nervous system.
Microbiology of EOS
Since the 1980s, GBS has been the
leading cause of neonatal EOS in
the United States. Despite the
widespread implementation of IAP, early-onset GBS dis-
ease remains the leading cause of EOS in term infants
(Table 1). However, coincident with the increased use of
IAP for GBS, gram-negative enteric bacteria have be-
come the leading cause of EOS in preterm infants (Table
2). (3)(4)(6) In Table 1, data from the CDC Active
Bacterial Core Surveillance program are compared with
data from our single center (the Brigham and Women’s
Hospital [BWH]in Boston). The CDC data were ob-
tained from the Atlanta and San Francisco metropolitan
areas in 1998 to 2000. The BWH is a large maternity
hospital that has an average 9,000 deliveries per year. The
BWH data encompass all cases of EOS occurring in
infants cared for in the 50-bed Level III BWH NICU for
the period 1990 to 2007. Both data sets reveal a similar
spectrum of organisms, with a predominance of gram-
positive organisms, primarily GBS and other streptococ-
cal species. Table 2 compares data from the NICHD
Neonatal Network and our single center. The NICHD
data are from 16 centers over the period 2002 to 2003.
Our single-center data include cases of EOS occurring in
infants cared for in the BWH NICU from 1990 to 2007
whose birthweights were less than 1,500 g. Again, the
data sets are strikingly similar, with a predominance of
enteric bacilli, primarily Escherichia coli but including a
spectrum of other Enterobacteriaceae (Klebsiella,
Table 1. Organisms Causing Neonatal Early-onset
Sepsis
Organism
Centers for
Disease Control
and Prevention
(n‫)804؍‬ %
Brigham and
Women’s Hospital
(n‫)703؍‬ %
GBS 166 40.7 130 42.3
Escherichia coli 70 17.2 64 20.8
Other streptococci* 93 22.7 37 12.1
Enterococcus 16 3.9 13 4.2
Staphylococcus aureus 15 3.7 12 3.9
CONS - - 14 4.6
Listeria 6 1.5 2 0.7
Bacteroides 5 1.2 14 4.6
Klebsiella 9 2.2 4 1.3
Haemophilus influenzae 9 2.2 6 2.0
Other gram-negative†
16 3.9 5 1.6
Other§
3 0.7 6 2.0
Total gram-positive 299 73.3 211 68.7
Total gram-negative 109 26.7 96 31.3
CONSϭcoagulase-negative Staphylococcus, GBSϭgroup B Streptococcus.
*Other streptococci include S pneumoniae, S bovis, S mitis, Peptostreptococcus, and viridans streptococci.
†
Other gram-negative organisms include Pseudomonas, Proteus, Morganella, and Yersinia.
§
Other organisms include Bacillus and Clostridium.
Adapted from Hyde et al. Pediatrics. 2002;110:690–695.
infectious disease sepsis
e572 NeoReviews Vol.9 No.12 December 2008

Pseudomonas, Haemophilus, and Enterobacter sp) and the
anaerobic species Bacteroides.
EOS Caused by GBS
GBS frequently colonizes the human genital and gastro-
intestinal tracts and the upper respiratory tract in young
infants. GBS are facultative diplococci that are primarily
identified by the Lancefield group B carbohydrate anti-
gen. They are subtyped further into nine distinct capsular
polysaccharide serotypes (types Ia, Ib, II, III, IV, V, VI,
VII, VIII). A potential tenth polysaccharide type recently
has been identified. (7) Most GBS EOS in the United
States currently is caused by types Ia, Ib, II, III, and V
GBS. (1) Type III GBS more commonly are associated
with late-onset sepsis and meningitis.
Early-onset GBS infection is acquired in utero or
during passage through the birth canal. Approximately
20% to 30% of American women are colonized with GBS
at any given time. A longitudinal study of GBS coloniza-
tion in a cohort of primarily young, sexually active
women demonstrated that nearly 60% were colonized
with GBS at some time over a 12-month period. (8) In
the absence of IAP, approximately 50% of infants born to
mothers colonized with GBS are colonized at birth, and
1% to 2% of colonized infants develop invasive GBS
disease. Lack of maternally derived
protective capsular polysaccharide-
specific antibody is associated with
the development of invasive GBS
disease. Other factors predisposing
the newborn to GBS disease are less
well understood, but relative defi-
ciencies in complement, neutrophil
function, and innate immunity may
be important.
A number of studies helped de-
fine maternal and neonatal risk fac-
tors for GBS EOS. Benitz and asso-
ciates (9) performed a literature
review and data reanalysis of studies
of risk factors for GBS EOS from
the 1970s to the 1990s to generate
odds ratio estimates for several clin-
ical factors (Table 3). Maternal
GBS colonization alone was far
more predictive than any other ma-
ternal or neonatal clinical character-
istic, a finding that is the evidence
base for the current recommenda-
tion for use of IAP according to
maternal GBS colonization status.
Additional maternal clinical factors predictive of early-
onset GBS disease include maternal intrapartum fever
(temperature Ͼ99.5°F [37.5°C]), the clinical diagnosis
of chorioamnionitis, and prolonged rupture of mem-
branes (Ͼ18 h). Neonatal risk factors include prematu-
rity (Ͻ37 weeks’ gestation) and low birthweight
(Ͻ2,500 g), especially birthweight less than 1,000 g.
Although once considered a risk factor for GBS disease,
Table 2. Organisms Causing Early-onset Sepsis in
Very Low-birthweight Infants
Organism
National Institute
of Child Health
and Development
(n‫)201؍‬ %
Brigham and
Women’s Hospital
(n‫)59؍‬ %
GBS 12 11.8 20 21.1
Escherichia coli 42 41.2 31 32.6
Other streptococci* 9 8.8 12 12.6
CONS 15 14.7 5 5.3
Listeria 2 2.0 1 1.1
Other gram-positive†
8 7.8 5 5.3
Bacteroides N/A - 9 9.5
Haemophilus influenzae 2 2.0 3 3.2
Enterobacter 4 3.9 1 1.1
Citrobacter 3 2.9 2 2.1
Other gram-negative§
3 2.9 4 4.2
Fungal 2 2.0 2 2.1
Total gram-positive 46 45.1 43 45.3
Total gram-negative 54 52.9 50 52.6
CONSϭcoagulase-negative Staphylococcus, GBSϭgroup B Streptococcus.
*Other streptococci include S pneumoniae, S mitis, viridans streptococci, and group A Streptococcus.
†
Other gram-positive organisms include Bacillus, Corynebacterium, Staphylococcus aureus.
§
Other gram-negative organisms include Klebsiella, Pseudomonas, Acinetobacter, Proteus, Morganella,
and Fusobacterium.
Adapted from Stoll et al. Pediatr Infect Dis J. 2005;24:635–639.
Table 3. Risk Factors for Early-onset
GBS Sepsis in the Absence of IAP
Risk Factor
Odds Ratio (95%
Confidence Interval)
Maternal GBS colonization 204 (100 to 419)
Birthweight <1,000 g 24.8 (12.2 to 50.2)
Birthweight <2,500 g 7.37 (4.48 to 12.1)
Rupture of membranes
>18 h
7.28 (4.42 to 12.0)
Chorioamnionitis 6.42 (2.32 to 17.8)
Intrapartum temperature
>99.5°F (37.5°C)
4.05 (2.17 to 7.56)
GBSϭgroup B Streptococcus, IAPϭintrapartum antibiotic prophylaxis.
Adapted from Benitz et al. Pediatrics. 1999;103:e77.

multiple gestation now is not considered an independent
risk factor for EOS. (10) GBS bacteriuria during preg-
nancy is associated with heavy colonization of the recto-
vaginal tract and is considered a significant risk factor for
EOS. Black race is associated with higher rates of GBS
EOS, although it is not entirely clear whether this simply
reflects the higher rate of GBS colonization in this pop-
ulation. The most recent CDC surveillance data demon-
strate a fourfold increased incidence of neonatal GBS
EOS among black infants compared with white infants.
(1)
IAP for the Prevention of Early-onset
GBS infection
After recognizing that maternal colonization with GBS
was the greatest risk factor for neonatal GBS disease,
multiple trials demonstrated that the use of intrapartum
penicillin or ampicillin significantly reduced the rate of
neonatal colonization with GBS and the incidence of
early-onset GBS disease. The ability to prevent neonatal
GBS colonization and neonatal EOS was demonstrated
most dramatically in a trial of only 160 women in 1986.
(11) IAP for the prevention of GBS EOS can be admin-
istered to pregnant women during labor based on specific
clinical risk factors for early-onset GBS infection or the
results of antepartum screening of pregnant women for
GBS colonization. In 1996, the CDC published consen-
sus guidelines for the prevention of neonatal GBS disease
that endorsed the use of either a risk factor-based or
screening-based approach. (10) The CDC later con-
ducted a large retrospective cohort study of more than
600,000 births that demonstrated the superiority of the
screening-based approach for the prevention of neonatal
GBS disease. (12) Based on these results, the CDC issued
revised guidelines for the prevention of early-onset GBS
disease in 2002, recommending universal screening of
pregnant women for GBS by rectovaginal culture at
35 to 37 weeks’ gestation and management of IAP based
on screening results. (13) The revised guidelines can be
accessed at http://www.cdc.gov/mmwr/preview/
mmwrhtml/rr5111a1.htm or in PDF form at http://
www.cdc.gov/mmwr/PDF/rr/rr5111.pdf.
The CDC guideline includes specific recommenda-
tions for pregnant women who have documented GBS
bacteriuria or who previously delivered infants who had
GBS disease and for the use of IAP in women experienc-
ing threatened preterm labor. The revised guidelines also
address concerns over the documented emergence of
GBS resistance to erythromycin and clindamycin, antibi-
otics frequently used for IAP in women allergic to peni-
cillin. The CDC continues to recommend penicillin or
ampicillin for IAP. In those who have penicillin allergy,
testing of GBS screening isolates for antibiotic suscepti-
bility is recommended to guide the choice of antibiotic
(erythromycin, clindamycin, cefazolin, or vancomycin)
for IAP. “Adequate IAP” is defined as the administration
of one of the endorsed antibiotics 4 or more hours prior
to delivery. The revised CDC guideline also includes a
recommended algorithm for the evaluation of infants
born to mothers exposed to IAP.
Current Status of GBS EOS
CDC active surveillance data for the United States from
1999 to 2005 demonstrate that the incidence of GBS
EOS has fallen to 0.34 cases per 1,000 live births in
2003 to 2005 (compared with 1.7 cases per 1,000 live
births in 1993). (1) We recently evaluated the reasons for
persistent GBS EOS despite the use of a screening-based
approach to IAP at the BWH. (14)(15) We found that
most GBS EOS in term infants now occurs in infants
born to women who have negative antepartum screening
results for GBS colonization. Many of the mothers in this
study had other intrapartum risk factors for sepsis, un-
derscoring the importance of continued evaluation of
infants at risk for EOS in the era of GBS prophylaxis.
There is a low incidence (approximately 4%) of noncon-
cordance between results of maternal GBS screening
performed at 35 to 37 weeks’ gestation and repeat
screening on presentation for delivery at term, (16)
which may account for many cases of persistent GBS
EOS.
Bacterial culture remains the CDC-recommended
standard for detection of maternal GBS colonization. In
2002, the United States Food and Drug Administration
approved the first polymerase chain reaction (PCR)-
based rapid diagnostic test for use in detection of mater-
nal GBS colonization. The test can be completed in
1 hour and potentially allows for screening of pregnant
women on presentation for delivery. (17) Although this
type of testing could address the risk of antenatal false-
negative GBS screens, the costs and technicalities of
providing continuous support for a real-time PCR-based
diagnostic are considerable, and most obstetric services
continue to rely on antenatal screening culture alone.
EOS Caused by E coli
E coli is the second most common organism isolated in
EOS in all neonates and the single most common EOS
organism in VLBW infants. (3)(6) E coli are facultative
anaerobic gram-negative rods found universally in the
human intestinal tract and commonly in the human
vagina and urinary tract. There are hundreds of different

antigenic types of E coli, but EOS E coli infections,
particularly those complicated by meningitis, are primar-
ily due to strains that have the K1-type polysaccharide
capsule. With the implementation of IAP against GBS,
an increasing proportion of EOS cases are caused by
gram-negative organisms. (4) Whether GBS IAP policies
are contributing to an absolute increase in the incidence
of EOS caused by gram-negative organisms, particularly
ampicillin-resistant gram-negative organisms, is contro-
versial.
In 2003, the CDC published a review of 23 reports of
EOS in the era of GBS prophylaxis, (4) which concluded
that there is no evidence of an increase in non-GBS EOS
among term infants. A case-control study of 132 cases of
neonatal EOS caused by E coli occurring from 1997 to
2001 recently published by the CDC concluded that
exposure to intrapartum antibiotic therapy did not in-
crease the odds of invasive early-onset E coli infection.
(18) In fact, this study demonstrated a protective effect
of intrapartum antibiotic exposure on the risk of E coli
EOS among term infants. However, worrisome increases
in non-GBS EOS and ampicillin-resistant EOS in VLBW
infants have been reported by single centers (19) and by
the NICHD Neonatal Research Network. (20) The mul-
ticenter NICHD Network documented an increase in E
coli EOS in VLBW infants from 3.2 cases per 1,000 live
births in 1991 to 1993 to 7.0 cases per 1,000 live births
in 2002 to 2003.
Trends in the microbiology of EOS likely vary to some
extent by institution and may be influenced by local
obstetric practices as well as by local variation in indige-
nous bacterial flora. To address this important issue, the
CDC Active Bacterial Core Surveillance Program and the
NICHD Neonatal Research Network are conducting
active surveillance for early-onset neonatal sepsis from
2007 to 2009 that will include data on intrapartum
antibiotic exposure and collection of specific infecting
bacterial isolates for microbiologic study. (21) Informa-
tion from studies of this type may help guide clinical
decisions regarding empiric antibiotic choice for EOS,
particularly in VLBW infants. Currently, when there is
strong clinical suspicion for sepsis in a critically ill infant,
the possibility of ampicillin-resistant gram-negative in-
fection suggests the consideration of empiric use of a
third-generation cephalosporin such as cefotaxime or
ceftazidime.
Other Organisms Responsible for EOS
In addition to GBS and E coli, a number of other patho-
gens that cause EOS in the United States deserve special
note. Listeria monocytogenes are gram-positive, beta-
hemolytic, motile bacteria that most commonly infect
humans via the ingestion of contaminated food. An
association with prepared foods held at moderate tem-
perature (particularly cheeses and deli meats) has been
documented, occasionally in epidemic outbreaks. These
bacteria do not cause significant disease in immunocom-
petent adults but can cause severe illness in the immuno-
compromised (ie, renal transplant patients), in pregnant
women and their fetuses, and in newborns. The true
incidence of listeriosis in pregnancy is difficult to deter-
mine 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
both methicillin-sensitive and methicillin-resistant S au-
reus (MRSA) cause a large proportion of hospital-
acquired infection in VLBW infants and represent an
increasing issue in community-acquired pediatric infec-
tions, they remain a rare cause of neonatal EOS. A recent
study of 5,732 pregnant women documented a 3.5%
incidence of MRSA in GBS rectovaginal screening cul-
tures but found no cases of MRSA neonatal EOS in
delivered infants. (22) Finally, fungal organisms (primar-
ily Candida sp) rarely cause neonatal EOS. Fungal EOS
is found largely in preterm and VLBW infants and in our
center is associated with very prolonged antibiotic (Ͼ24
h) exposure of pregnant mothers prior to delivery.
Clinical Risk Factors for EOS
Maternal and infant characteristics associated with the
development of EOS have been studied most rigorously
with respect to GBS EOS, but much of these data were
obtained prior to the implementation of IAP for GBS
prevention. Perhaps the most challenging clinical issue in
the era of GBS prophylaxis is the identification and
evaluation of the initially asymptomatic term and late
preterm infant at risk for EOS. Escobar and associates
(23) studied a cohort of more than 18,000 infants born
in 1995 to 1996, cared for in a single health-care plan,
whose birthweights were at least 2,000 g, and who had
no major anomalies. Of these, 2,785 infants were evalu-
ated for EOS with a complete blood count and blood
culture. Multivariate analyses of predictors of EOS ac-
counted for intrapartum antibiotic exposure and mod-
eled maternal chorioamnionitis either as a clinical obstet-
ric diagnosis or as an entity defined by prolonged rupture
of membranes and maternal fever. Results of the latter
model are shown in Table 4, but the overall findings were
the same in each model: maternal intrapartum fever, the

clinical diagnosis of chorioamnionitis, low absolute neu-
trophil count, and the presence of meconium-stained
amniotic fluid each were associated with increased risk of
EOS, with some modification of these factors in the
presence of maternal intrapartum antibiotic exposure.
Although this study aids in our understanding the issues
of overall EOS risk in the era of GBS prophylaxis, it also
underscores the challenge of evaluating the initially
asymptomatic infant. Only 1% of the initially asymptom-
atic infants in this study had EOS, and asymptomatic
status predicted against infection. Yet, this incidence is
10-fold higher than the population risk of 1 to 2 cases per
1,000 live births, pointing out the importance of the
clinical factors that prompted the evaluation for infection
and confirming the concept that asymptomatic status
alone cannot rule out infection.
Algorithm for the Evaluation of
Asymptomatic Infants at Risk for EOS
The CDC 2002 guidelines for the use of IAP to prevent
early-onset GBS disease address the evaluation of infants
at risk for GBS-specific EOS. Other microbiologic causes
of EOS also must be considered in evaluating the asymp-
tomatic infant at risk for infection. Many centers develop
protocols to standardize the decision to evaluate an
asymptomatic infant for EOS. We use a protocol for
evaluation of the asymptomatic infant born at 35 or more
weeks’ gestation who is at risk for EOS (Figure). This
protocol takes into account the 2002 CDC guideline for
GBS prophylaxis as well as the existing literature on the
risk of overall EOS. In addition, it accounts for center-
specific factors (including the primary role of pediatric
resident housestaff in conducting
EOS evaluations at our center and
the use of epidural analgesia in most
deliveries). A total white blood cell
count less than 5.0ϫ103
/mcL
(5.0ϫ109
/L) or an immature to
total neutrophil ratio greater than
0.2 is used to guide treatment de-
cisions in the evaluation of the
well-appearing infant at risk for
sepsis. A single white blood cell
determination is used in most cases
to avoid multiple blood collections
from otherwise asymptomatic in-
fants. This particular algorithm may
not be ideal for all centers and only
is included as a model protocol.
A quality improvement study con-
ducted at our institution compared
the rate of compliance with CDC recommendations
for the evaluation of infants at risk for early-onset GBS
disease between hospitals within our health-care system
that did or did not have a mandated protocol and found
significantly greater compliance in the hospitals that used
a specific protocol.
Current Clinical Challenges in EOS
EOS remains an infrequent but potentially devastating
clinical issue for term and preterm infants. The wide-
spread implementation of IAP for the prevention of
GBS early-onset disease has resulted in an overall de-
crease in neonatal EOS in the United States. There
remain, however, a number of research questions that
need to be addressed to optimize neonatal care further
with respect to EOS. Considerable clinical time and
economic resources are expended in the identification
and evaluation of infants at risk for EOS. A multicenter
reassessment of the clinical risk factors for EOS in the
setting of proper implementation of a screening-based
program for IAP should be performed. Such a study may
allow clinicians to identify more accurately the initially
asymptomatic infant who needs to be evaluated for in-
fection in the era of GBS prophylaxis. The utility of
real-time PCR-based GBS diagnostics, used either as a
substitute for third trimester culture-based GBS screen-
ing or as an addition to culture-based screening, needs to
be assessed on a national basis to determine if this test can
lower the national incidence of early-onset GBS disease
further. Finally, the CDC has endorsed the need for
continued surveillance to assess the impact of GBS pro-
phylaxis practices on the microbiology of EOS, particu-
Table 4. Risk Factors for All Causes of Early-onset
Sepsis in Infants Weighing Less than 2,000 g
At Birth in the Era of Intrapartum Antibiotic
Prophylaxis
Multivariate Odds Ratio (95% Confidence
Interval)
Predictor
No Intrapartum
Antibiotics
(n‫)865,1؍‬
Intrapartum
Antibiotics
(n‫)712,1؍‬
Temperature >101.5°F (38.6°C) 5.78 (1.57 to 21.29) 3.50 (1.30 to 9.42)
Rupture of membranes >12 h 2.05 (1.06 to 3.96) Not significant
Low absolute neutrophil count
for age
2.82 (1.50 to 5.34) 3.60 (1.45 to 8.96)
Infant asymptomatic 0.27 (0.11 to 0.65) 0.42 (0.16 to 1.11)
Meconium in amniotic fluid 2.24 (1.19 to 4.22) Not significant
Adapted from Escobar et al. Pediatrics. 2000;106:256–263.

larly among VLBW infants. Research into individual
center obstetric practices as well as national surveillance
may help identify the risks that may be associated with
IAP to allow neonates to continue to beneﬁt from this
important advance in the prevention of EOS.
References
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2. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very
Figure. Guidelines for the management of asymptomatic infants born at 35 or more weeks’ gestation who have risk factors for
early-onset sepsis. CBC‫؍‬complete blood count, Csxn‫؍‬cesarean section delivery, FHR‫؍‬fetal heart rate, GBS‫؍‬group B Streptococcus,
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NeoReviews Quiz
5. Widespread implementation of intrapartum antibiotic prophylaxis has altered the epidemiology of early-
onset sepsis (occurring at less than 72 hours after birth) in the newborn. The incidence of group B
Streptococcus (GBS) early-onset sepsis has decreased; the incidence of non-GBS early-onset sepsis is
unchanged or decreasing. Of the following, the national incidence of GBS early-onset sepsis, as estimated
in 2003 through 2005, is closest to:
A. 0.03 per 1,000 live births.
B. 0.30 per 1,000 live births.
C. 0.60 per 1,000 live births.
D. 0.90 per 1,000 live births.
E. 0.20 per 1,000 live births.
6. The spectrum of microorganisms causing early-onset sepsis in the era of intrapartum antibiotic prophylaxis
is different between term neonates (>2,000 g birthweight) and very low-birthweight neonates (<1,500 g
birthweight). Of the following, the most common microorganism attributable to early-onset sepsis in term
neonates, as reported by the Centers for Disease Control and Prevention, is:
A. Coagulase-negative Staphylococcus.
B. Escherichia coli
C. Group B Streptococcus.
D. Haemophilus inﬂuenzae.
E. Listeria monocytogenes.
7. The spectrum of microorganisms causing early-onset sepsis in the era of intrapartum antibiotic prophylaxis
is different between term neonates (>2,000 g birthweight) and very low-birthweight (VLBW) neonates
(<1,500 g birthweight). Of the following, the most common microorganism attributable to early-onset
sepsis in VLBW neonates, as reported by the National Institute of Health and Human Development Neonatal
Research Network, is:
A. Coagulase-negative Staphylococcus.
B. Escherichia coli.
C. Group B Streptococcus.
D. Haemophilus inﬂuenzae.
E. Listeria monocytogenes.
8. Most cases of early-onset sepsis attributable to GBS in the United States currently are caused by GBS
serotypes Ia, Ib, II, III, and V. Intrapartum antibiotic prophylaxis for prevention of GBS sepsis was advocated
following several studies examining the maternal and neonatal risk factors for early-onset GBS sepsis. Of
the following, the clinical risk factor most predictive of neonatal early-onset GBS sepsis in the absence of
intrapartum antibiotic prophylaxis is:
A. Chorioamnionitis.
B. Extremely low birthweight (<1,000 g).
C. Intrapartum fever (temperature >99.5°F [37.5°C]).
D. Maternal GBS colonization.
E. Prolonged rupture of membranes (>18 hours).

DOI: 10.1542/neo.9-12-e571
2008;9;e571-e579NeoReviews
Karen M. Puopolo
Epidemiology of Neonatal Early-onset Sepsis
& Services
Updated Information
s;9/12/e571
http://neoreviews.aappublications.org/cgi/content/full/neoreview
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