Epidemiology of Invasive Early-Onset

Neonatal Sepsis, 2005 to 2014

Stephanie J. Schrag, DPhil,a Monica M. Farley, MD,b,c Susan Petit, MPH,d Arthur Reingold, MD,e
Emily J. Weston, MPH,a Tracy Pondo, MSPH,a Jennifer Hudson Jain, MPH,a Ruth Lynfield, MDf

BACKGROUND: Group B Streptococcus (GBS) and Escherichia coli have historically dominated as abstract
causes of early-onset neonatal sepsis. Widespread use of intrapartum prophylaxis for GBS
disease led to concerns about the potential adverse impact on E coli incidence.
METHODS: Active, laboratory, and population-based surveillance for culture-positive (blood
or cerebrospinal fluid) bacterial infections among infants 0 to 2 days of age was conducted
statewide in Minnesota and Connecticut and in selected counties of California and Georgia
during 2005 to 2014. Demographic and clinical information were collected and hospital live
birth denominators were used to calculate incidence rates (per 1000 live births). We used
the Cochran–Amitage test to assess trends.
RESULTS: Surveillance identified 1484 cases. GBS was most common (532) followed by E coli
(368) and viridans streptococci (280). Eleven percent of cases died and 6.3% of survivors
had sequelae at discharge. All-cause (2005: 0.79; 2014: 0.77; P = .05) and E coli (2005: 0.21;
2014: 0.18; P = .25) sepsis incidence were stable. GBS incidence decreased (2005: 0.27;
2014: 0.22; P = .02). Among infants <1500 g, incidence was an order of magnitude higher for
both pathogens and stable. The odds of death among infants <1500 g were similar for both
pathogens but among infants ≥1500 g, the odds of death were greater for E coli cases (odds
ratio: 7.0; 95% confidence interval: 2.7–18.2).
CONCLUSIONS: GBS prevention efforts have not led to an increasing burden of early-onset E coli
infections. However, the stable burden of E coli sepsis and associated mortality underscore
the need for interventions.

aNational Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, WHAT’S KNOWN ON THIS SUBJECT: Widespread
Atlanta, Georgia; bDepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta, intrapartum prophylaxis for perinatal group B
Georgia; cAtlanta Veterans Affairs Medical Center, Atlanta, Georgia; dConnecticut Department of Public Health, streptococcal disease provoked concerns about
Hartford, Connecticut; eDivision of Epidemiolgy, School of Public Health, University of California, Berkley, Berkley,
California; and fMinnesota Department of Health, St. Paul, Minnesota
potential increases in Escherichia coli sepsis in
the first week of life, particularly among preterm
Dr Schrag conceptualized and designed the study, carried out the analyses, and drafted the initial infants. Approximately 30% of US deliveries are
manuscript; Drs Farley, Petit, Reingold, and Lynfield supervised data collection at each of their exposed to intrapartum antibiotics.
respective sites and provided critical input on the manuscript; Ms Weston, Ms Pondo, and
Ms Hudson Jain coordinated design of the data collection instruments, performed quality checks, WHAT THIS STUDY ADDS: Using active, population-
cleaning, and management of the data from all sites, and critically reviewed the manuscript; and based surveillance from 2005 to 2014, we
all authors approved the final manuscript as submitted. documented stable rates of all-cause and E coli
DOI: 10.1542/peds.2016-2013 sepsis in the first week of life and characterized
current epidemiology. Notably, rates were stable
Accepted for publication Sep 12, 2016
among preterm infants and for those with a birth
Address correspondence to Stephanie Schrag, DPhil, MS C25, Centers for Disease Control and weight <1500 g.
Prevention, 1600 Clifton Rd, Atlanta, GA 30329. E-mail: sjschrag@cdc.gov
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2016 by the American Academy of Pediatrics To cite: Schrag SJ, Farley MM, Petit S, et al. Epidemiology
of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014.
Pediatrics. 2016;138(6):e20162013

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PEDIATRICS Volume 138, number 6, December 2016:e20162013 ARTICLE
Infections in the first 3 days of
life (early onset) remain among
the leading causes of infant death
in the United States and can
result in lifelong sequelae among
survivors.1 The widespread uptake
of intrapartum antibiotic prophylaxis
for the prevention of perinatal
group B Streptococcus (GBS) disease,
the leading cause of early-onset
infections, has resulted in an 80%
decline in early-onset GBS disease
incidence.2 However, this decline
has been accompanied by a more
than doubling (30% vs 12%) in the
proportion of deliveries exposed to
intrapartum antibiotics compared
with the preprevention era.3
Intrapartum prophylaxis has always
been viewed as an interim perinatal
GBS disease prevention strategy,
in part because of concerns for the
potential emergence of resistance
among GBS to the first line, highly
effective β lactam therapies, and
in part because of concerns that
intrapartum antibiotic exposures
may increase the risk of sepsis due to
non-GBS pathogens.4 Several years
after the first national perinatal GBS
disease prevention guidelines in
1996,5 a 1 multicenter and a series
of single hospital studies reported
increases in early-onset sepsis due
to Escherichia coli, accompanied by
high case fatality.6–10 Evidence of
an increase was strongest among
preterm and very low birth weight
infants, populations that account
for the majority of early-onset E coli
infections.8,11
Although the incidence of early-onset
invasive sepsis is high compared
with most invasive infections in older
age groups, the number of cases at
individual facilities remains low
because the age group (first 3 days
of life) is so narrow. Single hospital
studies are thus challenging for
trend ascertainment, particularly
if pathogen-specific trends and
trends among subgroups, such as
preterm or low birth weight infants,
are of interest. In 2005, the Active
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2 SCHRAG et al
Bacterial Core surveillance/Emerging
Infections Program network
established active, population-based
surveillance for early-onset invasive
bacterial infections. Here we describe
overall, GBS, and E coli-specific
early-onset incidence trends from
2005–2014 and compare the clinical
and epidemiologic characteristics of
GBS and E coli infections.
METHODS
Active laboratory surveillance for
invasive (culture positive from
blood or cerebrospinal fluid [CSF])
bacterial infections among infants
0–2 days of age was conducted by
the Centers for Disease Control and
Prevention Active Bacterial Core
surveillance/Emerging Infections
Program network from 2005 to 2014
in the following catchment areas: 20
hospitals capturing 95% of births
in the San Francisco Bay area in
California; 18 hospitals representing
98% of births in 8 metropolitan
Atlanta counties in Georgia; 30
hospitals representing 99% of births
in Connecticut; and 140 hospitals
representing 97% of births in
Minnesota. Surveillance officers in
each area reviewed microbiology
records at clinical laboratories
serving the catchment populations
on a regular basis and collected
demographic, intrapartum, and
clinical information from the labor
and delivery record and case medical
records by using a standardized
form. Antimicrobial susceptibility
interpretations were abstracted
from the medical record starting in
2007; diagnosis of chorioamnionitis
was abstracted starting in 2011. The
surveillance catchments combined
included ∼200 000 live births
annually. Live birth denominators
for the hospitals in the surveillance
catchment were obtained from state
vital records files; the 2013 live
birth denominator was used for both
2013 and 2014, and in California,
live births from 2007 were used to
estimate those in 2008. Among the
live birth denominator data, missing
values for race (8%), gestational age
(1%), and birth weight (<0.5%) were
distributed based on the distribution
of those with known values within
surveillance sites.
Stillborn infants, infants <23 weeks
of gestation, infants born at home,
and infants with a first positive
culture collected >12 hours after
death were excluded. Additionally,
cultures yielding ≥3 organisms were
considered contaminants, as well as
cultures yielding single organisms
belonging to the following groups:
Aerococcus, Bacillus, Burkholderia,
Capnocytophago, Corynebacterium,
Cupriavidus, Flavimonas, Gemella,
Granulicatella, Haemophilus other
than H influenzae, Lactobacillus,
Micrococcus, Morganella,
Mycobacteria other than M
tuberculosis, Neisseria other than
N meningitides, Ochrobacterum,
Paenibacillus, Previotella,
Propionibacterium, Roseomonas,
Staphylococcus other than S aureus,
Stetrophomonas, Stomatococcus, and
Tatumella.
When race, gestational age, or
outcome were missing from
the medical record they were
supplemented with values from vital
records; remaining unknowns were
distributed based on the distribution
of those with known values within
surveillance sites. Because of the
limited number of cases with Asian,
American Indian, or Pactific Islander
race, race in multivariable analyses
was categorized as black versus
all others (“nonblack”). Clinical
syndrome refers to the clinical
presentation abstracted from the
medical record and was categorized
as meningitis, primary bacteremia,
pneumonia, or other. Preterm was
defined as <37 weeks of gestation,
and was additionally categorized
into early (<34 weeks of gestation)
and late preterm (34–36 weeks of
gestation). Similarly, standard birth
weight categories were considered
(very low birth weight: <1500 g;
low birth weight: 1500–2499 g;
2500–3999 g; ≥4000 g). Incidence
rates were calculated as cases per
1000 live births. We calculated
95% confidence intervals (CIs) for
the incidence rates based on the
assumption that the annual case
count followed a Poisson distribution.
We tested for linear trends in
incidence by using the Cochran–
Armitage test. Univariate differences
were assessed by χ2 for categorical
variables and by the Kruskal–Wallis
test for continuous variables.
Multivariable analysis was conducted
by using manual backward,
stepwise logistic regression, starting
with all univariate factors that
were significant at P < .15. Final
multivariable models included all
factors significant at P < .05 and
were assessed for interaction and
collinearity.
RESULTS
Surveillance identified 1484 invasive
early-onset sepsis cases from 2005
to 2014. GBS was the leading cause
(n = 532) followed by E coli (n =
368). Remaining organisms with
a frequency of at least 10 cases
included: viridans streptococci
(n = 280); H influenzae (n = 67), S
aureus (n = 52), Enterococcus
(n = 46), group D Streptococcus
(n = 21), Listeria monocytogenes
(n = 19), Klebsiella pneumoniae (n
= 14), and S pneumoniae (n = 14).
Overall, primary bacteremia was
the leading syndrome documented
(82.9%), followed by pneumonia
(5.0%) and meningitis (4.2%); 97.8%
of cases were diagnosed by blood
culture with the remaining from
CSF. Preterm birth was common
(42.2% of cases). Polymicrobial
infections were rare (1.6%, n = 23).
The median length of hospitalization
was 10 days (interquartile range
[IQR]: 6–22 days). Eleven percent
of newborns died; among survivors
at hospital discharge, 6.3% (n = 94)
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PEDIATRICS Volume 138, number 6, December 2016
had documented sequelae (Table 1);
the most common sequelae included
oxygen requirement on discharge
(51%), hearing loss (35%), and
seizures (21%).
During the 10-year period, the
overall incidence of invasive early-
onset sepsis was stable (2005: 0.79
cases per 1000 live births; 2014: 0.77
cases per 1000 live births; P = .052);
similarly, the incidence trend for E
coli was stable (2005: 0.21 cases per
1000 live births; 2014: 0.18 cases per
1000 live births; P = .25) whereas the
incidence of GBS decreased (2005:
0.27 cases per 1000 live births; 2014:
0.22 cases per 1000 live births; P =
.02; Fig 1). Additionally, although the
observed incidence of E coli early-
onset sepsis remained lower than
that of GBS early-onset sepsis for
each of the years under surveillance,
the 95% CIs around GBS and E coli
incidence estimates overlapped with
the degree of overlap more marked
in the second half of the surveillance
period. The relative incidence of
E coli to GBS invasive early-onset
infections also varied by state. In
California, E coli cases were more
common than GBS cases in each of
the 10 surveillance years; the other
3 surveillance areas had at least
1 year with more E coli than GBS
cases. Incidence trends for viridans
streptococci, the most common group
among the non-GBS and E coli sepsis
cases, were stable overall with a low
of 0.12 cases per 1000 live births in
2007, 2012, and 2013 and a high of
0.16 cases per 1000 live births in
2008 and 2014.
For both GBS and E coli sepsis,
incidence was at least an order of
magnitude higher among infants <34
weeks of gestational age compared
with infants born at term (Fig 2 A and
B). Similarly, early-onset GBS and
E coli sepsis incidence was notably
higher among very low birth weight
infants compared with infants with
birth weights of 2500 grams or more
(Fig 3 A and B). However, there
was no evidence of a trend toward
increasing incidence among either
the low gestational age (GBS: P =
.11; E coli: P = .49) or very low birth
weight subpopulations (GBS: P = .09;
E coli: P = .15) for either pathogen. In
fact, the point estimates for both GBS
and E coli incidence among very low
birth weight infants declined (Fig 2 A
and B).
When all-cause early-onset sepsis
was stratified by both race and
gestational age, the incidence among
black infants was significantly higher
than among nonblack infants for
term infants and for some calendar
years among infants <34 weeks
of gestation. Black infants <34
weeks of gestation had the highest
all-cause sepsis incidence (10.2
cases per 1000 live births in 2012;
Supplemental Information). Notably,
however, none of the subpopulations
showed evidence of an increasing
trend during the study period
(Supplemental Information).
Black race (34.9% vs 20.3%;
P < .0001), birth at <34 weeks
of gestation (32.2% vs 3.1%; P <
.0001), and very low birth weight
(23.3% vs 1.5%; P < .0001) were
overrepresented among early-onset
sepsis cases compared with the
surveillance catchment population.
Compared with population-level
estimates based on a representative
sample of live births from the same
Active Bacterial Core surveillance
areas in 2003 to 2004,3 early-onset
cases also differed importantly from
the population of live births in the
following characteristics: cesarean
delivery (cases: 46.1%; 95% CI:
43.5%–48.7% versus population:
26.3%; 95% CI: 24.5%–28.2%),
maternal intrapartum fever (cases:
20.7%; 95% CI: 18.6%–22.7% versus
population: 3.9%; 95% CI: 3.1%–
4.9%), exposure to intrapartum
antibiotics (cases: 50.0%; 95% CI:
47.5%–52.5% versus population:
32.7%; 95% CI: 30.7%–34.7%),
prolonged membrane rupture before
delivery (cases 42.0%; 95% CI:
39.5%–44.5% vs population: 7.7%;
3
TABLE 1 Characteristics of Newborns With Invasive Sepsis in the First 3 Days of Life, Active Bacterial 95% CI: 6.5%–9.0%), and suspected
Core Surveillance Neonatal Sepsis Activity, 2005 to 2014 maternal chorioamnionitis (cases:
Characteristic Overall (%, n = GBS (%, n = 532) E coli (%, n = 368) Pa 29.9%; 95% CI: 25.4%–34.5% versus
1484) population: 3.4%; 95% CI: 2.5%–
Surveillance area <.0001 4.5%). Maternal chorioamnionitis
California 17.5 11.1 24.7 (Table 1) was more common among
Connecticut 16.9 15.6 16.0 infants with E coli (51.6%) than
Georgia 40.5 42.3 38.0
among those with GBS (23.8%) or
Minnesota 25.1 31.0 21.2
Year .92 viridans streptococci (17.4%).
2005 8.2 7.7 8.7
2006 12.4 13.7 11.7
Compared with infants with GBS
2007 11.8 12.8 11.4 disease, infants with invasive E coli
2008 11.9 12.2 12.0 were more likely to be of younger
2009 9.5 9.2 11.4 gestational age (60.6% vs 20.9%; P
2010 9.5 10.3 10.1 < .0001) and very low birth weight
2011 10.4 10.0 9.8
2012 7.8 7.0 5.4
(43.6% vs 15.6%; P < .001) (Table
2013 8.6 9.0 10.3 1). Infants with E coli infections
2014 10.0 8.1 9.2 were also more likely than infants
Boy 53.3 53.4 54.6 .71 with GBS infections to be delivered
Race .01 by cesarean section, to have older
White 49.6 49.3 48.4
Black 34.9 40.4 33.7
mothers, to have mothers with a
Other 8.4 6.0 8.7 range of intrapartum risk factors,
Unknown 7.1 4.3 9.2 to be exposed to intrapartum
Ethnicity .03 antibiotics, and to have longer
Hispanic 19.3 15.4 22.3 hospitalizations and poorer
Unknown 5.4 4.3 4.9
Gestational age, wk <.0001
outcomes (Table 1). When limited
≤33 32.2 20.9 60.6 to infants <34 weeks of gestation
34–36 10.0 7.7 6.8 (n = 334), the only characteristics
37+ 57.8 71.4 32.6 differing significantly between
Birth weight, g <.0001 infants with E coli (n = 223) and GBS
<1500 23.3 15.6 43.6
1500–2499 15.8 11.3 23.4 (n = 111) infections included black
2500–3999 54.2 65.8 29.2 race (E coli: 39.4%; GBS: 52.7%;
≥4000 6.7 7.3 3.8 P = .02), membrane rupture of ≥18
Cesarean delivery 46.1 42.7 57.6 <.0001 hours (E coli: 73.1%; GBS: 35.1%; P <
Maternal characteristics
.0001), and exposure to intrapartum
Age (median, IQR)b 28 (23–33) 26 (22–32) 30 (25–35) <.0001
Intrapartum fever 20.6 19.3 27.1 .006 antibiotics (E coli: 90.1%; GBS:
Suspected 30.5 23.8 51.6 <.0001 64.0%; P < .001).
chorioamnionitisc
Rupture of membranes 42.0 35.0 61.7 <.0001 The vast majority of infants exposed
≥18 hours before to intrapartum antibiotics were
delivery exposed to a β-lactam or cefazolin
Preterm rupture of 23.3 14.3 45.7 <.0001 (Table 1). Among GBS cases, 63.3%
membranes before
(88/139) of cases with an indication
labor onset
Intrapartum exposure to 50.0 34.6 75.8 <.0001 for prophylaxis according to national
antibiotics guidelines received intrapartum
Intrapartum antibiotic 4.6 (1.1–24.3) 1.9 (0.7–6.5) 20.1 (3.1–112) <.0001 prophylaxis,4 although median
exposure duration in durations were shorter than the
hours (median, IQR)
recommended 4 hours (Table 1); a
Intrapartum exposure to β 37.5 22.7 60.9 <.0001
lactam/cefazolin majority of cases (73% or 377/516
Day of onset <.0001 with complete information) did not
Day 0 77.4 80.6 81.5 have a prophylaxis indication. Among
Day 1 16.7 16.7 13.3 E coli cases with susceptibility
Day 2 5.9 2.6 5.2
interpretations documented in
Clinical syndrome .06
Meningitis 4.2 4.9 6.3 the medical record (255/293 or
Primary bacteremia 82.9 83.7 81.3 87% of E coli cases from 2007 to
2014), ampicillin resistance was

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4 SCHRAG et al
TABLE 1 Continued not significantly more likely than
Characteristic Overall (%, n = GBS (%, n = 532) E coli (%, n = 368) Pa GBS to result in death (odds ratio
1484) [OR]: 1.3; 95% CI: 0.7–2.2). Among
Pneumonia 5.0 7.0 4.6 preterm infants with E coli infection,
Other 7.9 4.4 7.8 27% of deaths (21/77) occurred on
Sterile site
day 0 and 31% (24/77) on day 1;
Blood only 97.8 98.3 97.0
CSF only 0.9 (n = 14) 0.6 (n = 3) 0.3 (n = 1) 86% of these deaths (66/77) were
Blood and CSF 1.3 (n = 19) 1.1 (n = 6) 2.7 (n = 10) exposed to intrapartum antibiotics.
Length of hospitalization (d, 10 (6–22) 10 (9–14) 17 (9–50) <.0001 Among infants weighing ≥1500 g
median, IQR)b (n = 1139), deaths were much more
Outcome <.0001
rare (n = 40); for this population, the
Survived, no sequelae at 82.6 87.0 68.5
discharge odds of death among infants with
Survived, sequelae at 6.3 6.0 8.4 E coli infection were significantly
discharge greater than among those with GBS
Died 11.1 7.0 23.1 infection (OR: 7.0; 95% CI: 2.7–18.2),
a Comparison of GBS and E coli by χ2; 4 cases were recorded as growing both GBS and E coli and were excluded from as were the odds of death among
comparisons.
b Continuous variables were compared by Kruskall–Wallace test. infants with infections due to other
c Documented physician-suspected chorioamnionitis; this variable was available for 2011–2014 (n = 545 cases for pathogens compared with infants
evaluation including 181 GBS cases and 128 E coli cases). with GBS infection (OR: 2.7; 95% CI:
1.0–6.9). Among survivors, factors
associated with sequelae at discharge
on univariate analysis included:
pathogen class, clinical syndrome as
denoted in the medical record, race,
birth weight category, gestational
age category, prolonged membrane
rupture, and exposure to intrapartum
antibiotics. On multivariable analysis,
only meningitis syndrome (adjusted
OR: 3.53; 95% CI: 1.74–7.16) and
very low birth weight (adjusted
OR: 3.88; 95% CI: 1.47–10.22) had
significant associations.

DISCUSSION

Between 2005 and 2014, a period of

FIGURE 1
All-cause E coli and GBS early-onset invasive disease, 2005 to 2014, Active Bacterial Core surveillance.
documented for 168 cases (66%)
and gentamicin resistance was
documented for 26 cases (10%; 25
of these 26 also had resistance to
ampicillin). Among infants with E
coli infections with susceptibility
results, 84% (141/168) of those
exposed to intrapartum antibiotics
had ampicillin-resistant infections
compared with 65% (50/77) of
unexposed infants (P < .001).
The proportion of infants with E
coli infections who died was not
significantly higher among those with
ampicillin-resistant infections (20.8%
vs 18.2%).
Factors associated with mortality
in univariate analysis are shown in
Table 2. In multivariable analysis,
birth weight and pathogen (GBS,
E coli, or other) were the only
significant factors; however, they
had a significant interaction. When
we stratified by birth weight,
among infants weighing <1500 g
(n = 345; deaths = 123), E coli was
widespread intrapartum prophylaxis
for prevention of early-onset GBS
disease, we documented stable
incidence rates of all-cause and E
coli invasive early-onset sepsis and
a modest decline in GBS invasive
early-onset sepsis in a population
representing ∼5% of US live births.
Additionally, the observed incidence
of E coli infections among early-
preterm and very low birth weight
infants declined during the 8-year
period, although the declines were
not statistically significant. These
trends suggest that exposure of
approximately one-third of live
births to ampicillin or penicillin for

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PEDIATRICS Volume 138, number 6, December 2016 5
GBS prophylaxis has not resulted
in an increase in Gram-negative
sepsis. Moreover, reports from
the early years of GBS prevention
raising concern about increasing E
coli incidence among very low birth
weight or preterm infants are not
borne out by our observations. More
recent observations from single
institutions and hospital networks
are consistent with our results.12,13
GBS remained the most common
invasive early-onset pathogen in
each surveillance year, followed by
E coli, with other pathogens notably
less frequent. An assessment of
implementation of perinatal GBS
disease prevention guidelines in
these surveillance areas among
a representative sample of live
births in 2003 to 2004 already
showed strong implementation
of universal antenatal screening
and administration of intrapartum
prophylaxis to colonized women.3
The case-only data presented in
this study do not reflect population-
level implementation because it is
enriched for implementation failures;
our data do suggest that there may
be potential for small additional
decreases in GBS incidence based on
the observation that 37% of cases
with an indication for prophylaxis did
not receive it.
Although overall GBS remained the
FIGURE 2
leading pathogen across surveillance A, Invasive early-onset GBS disease incidence by gestational age categories, 2005 to 2014, Active
years, the CIs around the incidence Bacterial Core surveillance. B, Invasive early-onset E coli disease incidence by gestational age
rates for GBS and E coli overlapped. categories, 2005 to 2014, Active Bacterial Core surveillance.
In the most recently reported years
of multisite surveillance from the report E coli as the most common in the context of management and
National Institute of Child Health and cause of invasive early-onset sepsis12; prevention strategies.
Development’s Neonatal Research moreover, in one of the surveillance
Network (2009),14 and the large areas (California), E coli was more Early-onset sepsis incidence was
Pediatrix network (2010),13 GBS common than GBS for all surveillance significantly higher among black
early-onset incidence also remained term infants with less evident
years. Additionally, a study from
higher than that of E coli. Nationwide differences for infants 34 to 36
2005 to 2012 of bacteremia among
surveillance in the Netherlands15 weeks of gestation and <34 weeks
febrile young infants admitted to
and population-based surveillance of gestation. This may in part reflect
in Italy16 also continue to show general care units (rather than the the preponderance of GBS cases
GBS as more common than E coli in ICU) found E coli as the lead cause.17 among term infants, given that GBS
their most recent reporting years Thus, regionally and globally, the disease risk is higher among black
(2011 and 2009–2012, respectively). relative pathogen prevalence likely infants.3 Case fatality rates were
Notably, some single institutions now varies and should be considered highest among preterm and very low

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6 SCHRAG et al

FIGURE 3
A, Invasive early-onset GBS disease incidence by birth weight categories, 2005 to 2014, Active Bacterial
Core surveillance. B, Invasive early-onset E coli disease incidence by birth weight categories, 2005 to
2014, Active Bacterial Core surveillance.
birth weight infants. Consistent with
other recent surveillance,9,13,14
E coli was associated with most
early-onset sepsis deaths, primarily
due to its predominance among
very low birth weight infants. For
this subpopulation, E coli was not
significantly more likely to result
in death than GBS. It is likely in
this vulnerable population that
pathogen virulence may not be
strongly associated with risk of
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PEDIATRICS Volume 138, number 6, December 2016
death. However, among infants
≥1500 g at birth, where death was
less frequent, E coli infections were
associated more often with severe
outcomes. The large catchment in
our surveillance may have given
us the power to detect this trend,
which was not noted in other,
smaller studies.14,16 Clonal changes
among E coli associated with early-
onset sepsis and, in particular,
emerging ampicillin resistance, which
was documented in two-thirds of our
cases, may contribute to the severity
of E coli outcomes,18
although on univariate analysis,
death among infants with E coli
was not associated with ampicillin
resistance. Aminoglycoside
resistance remained rare but notably,
gentamicin resistance was strongly
associated with ampicillin resistance,
highlighting the importance of
continued evaluation of regimens
for first-line early-onset sepsis
treatment.19 Our observation that
more than half of preterm E coli
cases died very close to birth, despite
exposure to intrapartum prophylaxis,
further supports this need.
A number of maternal, intrapartum,
and demographic features differed
between invasive GBS and E coli
cases in univariate analysis. Black
race (more common among GBS
cases) and prolonged membrane
rupture and intrapartum antibiotic
exposure (more common among
E coli cases) were the only
factors that remained when
controlling for gestational age. The
overrepresentation of intrapartum
antibiotic exposure among infants
with E coli infection compared
with those with GBS may reflect,
in part, that intrapartum regimens
used for GBS prevention (most
typically penicillin or ampicillin) are
not effective in preventing early-
onset E coli infections. The high
proportion of chorioamnionitis in
this group suggests that intrapartum
intervention may be too late for
prevention but may still hold value
for initiation of early newborn
treatment.
Although our surveillance
benefitted from a large, population-
based catchment population and
detailed labor and delivery record
review to capture intrapartum
histories, it captured only limited
clinical information on disease
management and course. Maternal
chorioamnionitis was also only
collected from 2011 to 2014.
7
TABLE 2 Univariate Factors Associated With Mortality Among Infants With Invasive Early-Onset burden of E coli early-onset sepsis
Sepsis, Active Bacterial Core Surveillance, 2005 to 2014 we observed underscores the need
Characteristic Died (n = 165), % Survived (n = 1319), % OR (95% CI) for a prevention strategy. Although
Exposed Exposed our surveillance identifies that many
Pathogen of the risk factors identified for GBS
GBS 22.4 37.5 Referent are similar for E coli, intrapartum
E coli 51.5 21.5 4.0 (2.7–6.1) prophylaxis has not resulted in
Other 26.1 41.0 1.1 (0.7–1.7)
declines, consistent with previous
Birth weight <1500 g 75.8 16.7 15.6 (10.6–22.9)
Gestational age <34 wk 82.4 26.0 13.3 (8.8–20.3) observations.20 Efforts to identify
Boy 61.8 52.2 1.5 (1.1–2.1) interventions targeting early-onset
Black race 45.5 36.6 1.4 (1.0–2.0) E coli infections specifically, and
Cesarean delivery 59.4 44.4 1.8 (1.3–2.5) very preterm delivery more broadly,
Membrane rupture ≥18 h 50.3 40.9 1.5 (1.1–2.0)
should remain a priority, as well as
before delivery
Exposure to intrapartum 71.5 47.3 2.8 (2.0–4.0) ongoing efforts to pursue maternal
antibiotics GBS vaccine development to protect
Maternal intrapartum fever 14.1 21.5 0.6 (0.4–1.0) newborns in the first days of life.
Multivariable analyses were stratified by birth weight because birth weight and pathogen had a significant interaction. The
only variable significant at P < .05 on stratified multivariable analysis was pathogen type among infants >1500 g (E coli and
“other” pathogens were associated with elevated odds of mortality compared with GBS, see Results section). ACKNOWLEDGMENTS
We thank Mia Apostol, Wendy
Additionally, a predetermined susceptibility was limited to the Baughman, Pam Daily, Corinne
contaminant definition was applied drug susceptibility interpretation Holtzman, Brenda Jewell, Gayle
to all cases, which in some instances for GBS and E coli, when recorded Langley, Melissa Lewis, Carmen
may have resulted in inclusion in the medical chart. More detail Marquez, Patricia Martell-Cleary,
as cases of some instances of on multidrug resistance for all Londell McGlone, Craig Morin,
contamination (eg, a portion of pathogens would be of interest in the Stephanie Thomas, Amy Tunali,
the cases attributed to viridans future, ideally using a standard panel Michelle Wilson, and Carolyn Wright
streptococci) and may in other of drugs and comparable laboratory for their contributions to data
instances have excluded true methods. collection and management.
cases (eg, all coagulase negative
staphylococci were excluded, and
a portion may have represented CONCLUSIONS ABBREVIATIONS
true sepsis). The case-only data Observations from our multisite
CI: confidence interval
allowed for evaluation of sepsis surveillance allay persistent
CSF: cerebrospinal fluid
risk factors only in instances where concerns that GBS prevention
GBS: group B Streptococcus
population-level data were available. efforts might have resulted in an
IQR: interquartile range
Finally, during this surveillance increased burden of early-onset E
OR: odds ratio
period, information on antimicrobial coli infections. However, the stable

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: This work was supported by the Centers for Disease Control and Prevention’s Emerging Infections Program Network/Active Bacterial Core surveillance.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-3038.

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9
 Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014
Stephanie J. Schrag, Monica M. Farley, Susan Petit, Arthur Reingold, Emily J.
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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 Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014
Stephanie J. Schrag, Monica M. Farley, Susan Petit, Arthur Reingold, Emily J.
Weston, Tracy Pondo, Jennifer Hudson Jain and Ruth Lynfield
Pediatrics 2016;138;; originally published online November 29, 2016;
DOI: 10.1542/peds.2016-2013

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/138/6/e20162013.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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