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ARTICLEPEDIATRICS Volume 138 , number 6 , December 2016 :e 20162013
Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014Stephanie 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 Lynfi eld, MDf
abstractBACKGROUND: Group B Streptococcus (GBS) and Escherichia coli have historically dominated as
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,
Atlanta, Georgia; bDepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta,
Georgia; cAtlanta Veterans Affairs Medical Center, Atlanta, Georgia; dConnecticut Department of Public Health,
Hartford, Connecticut; eDivision of Epidemiolgy, School of Public Health, University of California, Berkley, Berkley,
California; and fMinnesota Department of Health, St. Paul, Minnesota
Dr Schrag conceptualized and designed the study, carried out the analyses, and drafted the initial
manuscript; Drs Farley, Petit, Reingold, and Lynfi eld supervised data collection at each of their
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,
cleaning, and management of the data from all sites, and critically reviewed the manuscript; and
all authors approved the fi nal manuscript as submitted.
DOI: 10.1542/peds.2016-2013
Accepted for publication Sep 12, 2016
Address correspondence to Stephanie Schrag, DPhil, MS C25, Centers for Disease Control and
Prevention, 1600 Clifton Rd, Atlanta, GA 30329. E-mail: [email protected]
a Comparison of GBS and E coli by χ2; 4 cases were recorded as growing both GBS and E coli and were excluded from
comparisons.b Continuous variables were compared by Kruskall–Wallace test.c Documented physician-suspected chorioamnionitis; this variable was available for 2011–2014 (n = 545 cases for
evaluation including 181 GBS cases and 128 E coli cases).
TABLE 1 Continued
FIGURE 1All-cause E coli and GBS early-onset invasive disease, 2005 to 2014, Active Bacterial Core surveillance.
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SCHRAG et al
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
leading pathogen across surveillance
years, the CIs around the incidence
rates for GBS and E coli overlapped.
In the most recently reported years
of multisite surveillance from the
National Institute of Child Health and
Development’s Neonatal Research
Network (2009), 14 and the large
Pediatrix network (2010), 13 GBS
early-onset incidence also remained
higher than that of E coli. Nationwide
surveillance in the Netherlands 15
and population-based surveillance
in Italy 16 also continue to show
GBS as more common than E coli in
their most recent reporting years
(2011 and 2009–2012, respectively).
Notably, some single institutions now
report E coli as the most common
cause of invasive early-onset sepsis12;
moreover, in one of the surveillance
areas (California), E coli was more
common than GBS for all surveillance
years. Additionally, a study from
2005 to 2012 of bacteremia among
febrile young infants admitted to
general care units (rather than the
ICU) found E coli as the lead cause. 17
Thus, regionally and globally, the
relative pathogen prevalence likely
varies and should be considered
in the context of management and
prevention strategies.
Early-onset sepsis incidence was
significantly higher among black
term infants with less evident
differences for infants 34 to 36
weeks of gestation and <34 weeks
of gestation. This may in part reflect
the preponderance of GBS cases
among term infants, given that GBS
disease risk is higher among black
infants. 3 Case fatality rates were
highest among preterm and very low
6
FIGURE 2A, Invasive early-onset GBS disease incidence by gestational age categories, 2005 to 2014, Active Bacterial Core surveillance. B, Invasive early-onset E coli disease incidence by gestational age categories, 2005 to 2014, Active Bacterial Core surveillance.
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PEDIATRICS Volume 138 , number 6 , December 2016
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
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
FIGURE 3A, 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.
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SCHRAG et al
Additionally, a predetermined
contaminant definition was applied
to all cases, which in some instances
may have resulted in inclusion
as cases of some instances of
contamination (eg, a portion of
the cases attributed to viridans
streptococci) and may in other
instances have excluded true
cases (eg, all coagulase negative
staphylococci were excluded, and
a portion may have represented
true sepsis). The case-only data
allowed for evaluation of sepsis
risk factors only in instances where
population-level data were available.
Finally, during this surveillance
period, information on antimicrobial
susceptibility was limited to the
drug susceptibility interpretation
for GBS and E coli, when recorded
in the medical chart. More detail
on multidrug resistance for all
pathogens would be of interest in the
future, ideally using a standard panel
of drugs and comparable laboratory
methods.
CONCLUSIONS
Observations from our multisite
surveillance allay persistent
concerns that GBS prevention
efforts might have resulted in an
increased burden of early-onset E coli infections. However, the stable
burden of E coli early-onset sepsis
we observed underscores the need
for a prevention strategy. Although
our surveillance identifies that many
of the risk factors identified for GBS
are similar for E coli, intrapartum
prophylaxis has not resulted in
declines, consistent with previous
observations. 20 Efforts to identify
interventions targeting early-onset
E coli infections specifically, and
very preterm delivery more broadly,
should remain a priority, as well as
ongoing efforts to pursue maternal
GBS vaccine development to protect
newborns in the first days of life.
ACKNOWLEDGMENTS
We thank Mia Apostol, Wendy
Baughman, Pam Daily, Corinne
Holtzman, Brenda Jewell, Gayle
Langley, Melissa Lewis, Carmen
Marquez, Patricia Martell-Cleary,
Londell McGlone, Craig Morin,
Stephanie Thomas, Amy Tunali,
Michelle Wilson, and Carolyn Wright
for their contributions to data
collection and management.
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ABBREVIATIONS
CI: confidence interval
CSF: cerebrospinal fluid
GBS: group B StreptococcusIQR: interquartile range
OR: odds ratio
FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial 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 confl icts 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.
TABLE 2 Univariate Factors Associated With Mortality Among Infants With Invasive Early-Onset
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Multivariable analyses were stratifi ed by birth weight because birth weight and pathogen had a signifi cant interaction. The
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DOI: 10.1542/peds.2016-2013 originally published online November 29, 2016; 2016;138;Pediatrics
Weston, Tracy Pondo, Jennifer Hudson Jain and Ruth LynfieldStephanie J. Schrag, Monica M. Farley, Susan Petit, Arthur Reingold, Emily J.
Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014
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