11
ARTICLE PEDIATRICS Volume 138, number 6, December 2016:e20162013 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, MD f abstract BACKGROUND: 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. a National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; b Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia; c Atlanta Veterans Affairs Medical Center, Atlanta, Georgia; d Connecticut Department of Public Health, Hartford, Connecticut; e Division of Epidemiolgy, School of Public Health, University of California, Berkley, Berkley, California; and f Minnesota 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 Lynfield 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 final 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] 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 WHAT’S KNOWN ON THIS SUBJECT: Widespread intrapartum prophylaxis for perinatal group B streptococcal disease provoked concerns about potential increases in Escherichia coli sepsis in the first week of life, particularly among preterm infants. Approximately 30% of US deliveries are exposed to intrapartum antibiotics. WHAT THIS STUDY ADDS: Using active, population- based surveillance from 2005 to 2014, we documented stable rates of all-cause and E coli sepsis in the first week of life and characterized current epidemiology. Notably, rates were stable among preterm infants and for those with a birth weight <1500 g. by guest on June 29, 2020 www.aappublications.org/news Downloaded from

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Page 1: Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 ... · PEDIATRICS Volume 138 , number 6 , December 2016 :e 20162013 ARTICLE Epidemiology of Invasive Early-Onset Neonatal

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]

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

WHAT’S KNOWN ON THIS SUBJECT: Widespread

intrapartum prophylaxis for perinatal group B

streptococcal disease provoked concerns about

potential increases in Escherichia coli sepsis in

the fi rst week of life, particularly among preterm

infants. Approximately 30% of US deliveries are

exposed to intrapartum antibiotics.

WHAT THIS STUDY ADDS: Using active, population-

based surveillance from 2005 to 2014, we

documented stable rates of all-cause and E coli

sepsis in the fi rst week of life and characterized

current epidemiology. Notably, rates were stable

among preterm infants and for those with a birth

weight <1500 g.

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SCHRAG et al

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

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

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PEDIATRICS Volume 138 , number 6 , December 2016

(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)

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%;

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SCHRAG et al

95% CI: 6.5%–9.0%), and suspected

maternal chorioamnionitis (cases:

29.9%; 95% CI: 25.4%–34.5% versus

population: 3.4%; 95% CI: 2.5%–

4.5%). Maternal chorioamnionitis

( Table 1) was more common among

infants with E coli (51.6%) than

among those with GBS (23.8%) or

viridans streptococci (17.4%).

Compared with infants with GBS

disease, infants with invasive E coli were more likely to be of younger

gestational age (60.6% vs 20.9%; P

< .0001) and very low birth weight

(43.6% vs 15.6%; P < .001) ( Table

1). Infants with E coli infections

were also more likely than infants

with GBS infections to be delivered

by cesarean section, to have older

mothers, to have mothers with a

range of intrapartum risk factors,

to be exposed to intrapartum

antibiotics, and to have longer

hospitalizations and poorer

outcomes ( Table 1). When limited

to infants <34 weeks of gestation

(n = 334), the only characteristics

differing significantly between

infants with E coli (n = 223) and GBS

(n = 111) infections included black

race (E coli: 39.4%; GBS: 52.7%;

P = .02), membrane rupture of ≥18

hours (E coli: 73.1%; GBS: 35.1%; P <

.0001), and exposure to intrapartum

antibiotics (E coli: 90.1%; GBS:

64.0%; P < .001).

The vast majority of infants exposed

to intrapartum antibiotics were

exposed to a β-lactam or cefazolin

( Table 1). Among GBS cases, 63.3%

(88/139) of cases with an indication

for prophylaxis according to national

guidelines received intrapartum

prophylaxis, 4 although median

durations were shorter than the

recommended 4 hours ( Table 1); a

majority of cases (73% or 377/516

with complete information) did not

have a prophylaxis indication. Among

E coli cases with susceptibility

interpretations documented in

the medical record (255/293 or

87% of E coli cases from 2007 to

2014), ampicillin resistance was

4

TABLE 1 Characteristics of Newborns With Invasive Sepsis in the First 3 Days of Life, Active Bacterial

Core Surveillance Neonatal Sepsis Activity, 2005 to 2014

Characteristic Overall (%, n =

1484)

GBS (%, n = 532) E coli (%, n = 368) Pa

Surveillance area <.0001

California 17.5 11.1 24.7

Connecticut 16.9 15.6 16.0

Georgia 40.5 42.3 38.0

Minnesota 25.1 31.0 21.2

Year .92

2005 8.2 7.7 8.7

2006 12.4 13.7 11.7

2007 11.8 12.8 11.4

2008 11.9 12.2 12.0

2009 9.5 9.2 11.4

2010 9.5 10.3 10.1

2011 10.4 10.0 9.8

2012 7.8 7.0 5.4

2013 8.6 9.0 10.3

2014 10.0 8.1 9.2

Boy 53.3 53.4 54.6 .71

Race .01

White 49.6 49.3 48.4

Black 34.9 40.4 33.7

Other 8.4 6.0 8.7

Unknown 7.1 4.3 9.2

Ethnicity .03

Hispanic 19.3 15.4 22.3

Unknown 5.4 4.3 4.9

Gestational age, wk <.0001

≤33 32.2 20.9 60.6

34–36 10.0 7.7 6.8

37+ 57.8 71.4 32.6

Birth weight, g <.0001

<1500 23.3 15.6 43.6

1500–2499 15.8 11.3 23.4

2500–3999 54.2 65.8 29.2

≥4000 6.7 7.3 3.8

Cesarean delivery 46.1 42.7 57.6 <.0001

Maternal characteristics

Age (median, IQR)b 28 (23–33) 26 (22–32) 30 (25–35) <.0001

Intrapartum fever 20.6 19.3 27.1 .006

Suspected

chorioamnionitisc

30.5 23.8 51.6 <.0001

Rupture of membranes

≥18 hours before

delivery

42.0 35.0 61.7 <.0001

Preterm rupture of

membranes before

labor onset

23.3 14.3 45.7 <.0001

Intrapartum exposure to

antibiotics

50.0 34.6 75.8 <.0001

Intrapartum antibiotic

exposure duration in

hours (median, IQR)

4.6 (1.1–24.3) 1.9 (0.7–6.5) 20.1 (3.1–112) <.0001

Intrapartum exposure to β

lactam/cefazolin

37.5 22.7 60.9 <.0001

Day of onset <.0001

Day 0 77.4 80.6 81.5

Day 1 16.7 16.7 13.3

Day 2 5.9 2.6 5.2

Clinical syndrome .06

Meningitis 4.2 4.9 6.3

Primary bacteremia 82.9 83.7 81.3

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PEDIATRICS Volume 138 , number 6 , December 2016

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

not significantly more likely than

GBS to result in death (odds ratio

[OR]: 1.3; 95% CI: 0.7–2.2). Among

preterm infants with E coli infection,

27% of deaths (21/77) occurred on

day 0 and 31% (24/77) on day 1;

86% of these deaths (66/77) were

exposed to intrapartum antibiotics.

Among infants weighing ≥1500 g

(n = 1139), deaths were much more

rare (n = 40); for this population, the

odds of death among infants with

E coli infection were significantly

greater than among those with GBS

infection (OR: 7.0; 95% CI: 2.7–18.2),

as were the odds of death among

infants with infections due to other

pathogens compared with infants

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

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

5

Characteristic Overall (%, n =

1484)

GBS (%, n = 532) E coli (%, n = 368) Pa

Pneumonia 5.0 7.0 4.6

Other 7.9 4.4 7.8

Sterile site

Blood only 97.8 98.3 97.0

CSF only 0.9 (n = 14) 0.6 (n = 3) 0.3 (n = 1)

Blood and CSF 1.3 (n = 19) 1.1 (n = 6) 2.7 (n = 10)

Length of hospitalization (d,

median, IQR)b

10 (6–22) 10 (9–14) 17 (9–50) <.0001

Outcome <.0001

Survived, no sequelae at

discharge

82.6 87.0 68.5

Survived, sequelae at

discharge

6.3 6.0 8.4

Died 11.1 7.0 23.1

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

Sepsis, Active Bacterial Core Surveillance, 2005 to 2014

Characteristic Died (n = 165), %

Exposed

Survived (n = 1319), %

Exposed

OR (95% CI)

Pathogen

GBS 22.4 37.5 Referent

E coli 51.5 21.5 4.0 (2.7–6.1)

Other 26.1 41.0 1.1 (0.7–1.7)

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)

Boy 61.8 52.2 1.5 (1.1–2.1)

Black race 45.5 36.6 1.4 (1.0–2.0)

Cesarean delivery 59.4 44.4 1.8 (1.3–2.5)

Membrane rupture ≥18 h

before delivery

50.3 40.9 1.5 (1.1–2.0)

Exposure to intrapartum

antibiotics

71.5 47.3 2.8 (2.0–4.0)

Maternal intrapartum fever 14.1 21.5 0.6 (0.4–1.0)

Multivariable analyses were stratifi ed by birth weight because birth weight and pathogen had a signifi cant interaction. The

only variable signifi cant at P < .05 on stratifi ed 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).

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