Identification of Extremely Premature Infants at Low Risk For Early-Onset Sepsis

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Identification of Extremely

Premature Infants at Low Risk


for Early-Onset Sepsis
Karen M. Puopolo, MD, PhD,​a,​b Sagori Mukhopadhyay, MD, MMSc,​a,​b Nellie I. Hansen, MPH,​c C. Michael Cotten, MD, MHS,​d
Barbara J. Stoll, MD,​e Pablo J. Sanchez, MD,​f Edward F. Bell, MD,​g Abhik Das, PhD,​h Angelita M. Hensman, MS, RNC-NIC,​i
Krisa P. Van Meurs, MD,​j,​k Myra H. Wyckoff, MD,​l on behalf of the NICHD Neonatal Research Network

BACKGROUND: Premature infants are at high risk of early-onset sepsis (EOS) relative to term abstract
infants, and most are administered empirical antibiotics after birth. We aimed to determine
if factors evident at birth could be used to identify premature infants at lower risk of EOS.
METHODS: Study infants were born at 22 to 28 weeks’ gestation in Neonatal Research Network
centers from 2006 to 2014. EOS was defined by isolation of pathogenic species from blood
or cerebrospinal fluid culture at ≤72 hours age. Infants were hypothesized as “low risk” for
EOS when delivered via cesarean delivery, with membrane rupture at delivery, and absence
of clinical chorioamnionitis. Frequency of prolonged antibiotics (≥5 days) was compared
between low-risk infants and all others. Risks of mortality, EOS, and other morbidities
were assessed by using regression models adjusted for center, race, antenatal steroid use,
multiple birth, sex, gestation, and birth weight.
RESULTS: Of 15 433 infants, 5759 (37%) met low-risk criteria. EOS incidence among infants
surviving >12 hours was 29 out of 5640 (0.5%) in the low-risk group versus 209 out of 8422
(2.5%) in the comparison group (adjusted relative risk = 0.24 [95% confidence interval,
0.16–0.36]). Low-risk infants also had significantly lower combined risk of EOS or death
≤12 hours. Prolonged antibiotics were administered to 34% of low-risk infants versus 47%
of comparison infants without EOS.
CONCLUSIONS: Delivery characteristics of extremely preterm infants can be used to identify
those with significantly lower incidence of EOS. Recognition of differential risk may help
guide decisions to limit early antibiotic use among approximately one-third of these infants.
NIH

aDivision of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; bDepartment of What’s Known on This Subject: Characteristics
Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; cBiostatistics known at birth including gestational age identify
and Epidemiology Division, RTI International, Research Triangle Park, North Carolina; dDivision of Neonatology,
infants at highest risk of early-onset sepsis (EOS). It
Duke University Medical Center, Duke University, Durham, North Carolina; eMcGovern Medical School, University
of Texas Health Science Center at Houston, Houston, Texas; fSection of Neonatology, Nationwide Children’s is unknown if delivery characteristics can be used
Hospital, The Ohio State University, Columbus, Ohio; gDepartment of Pediatrics, University of Iowa, Iowa City, to identify premature infants at lowest risk of EOS to
Iowa; hBiostatistics and Epidemiology Division, RTI International, Rockville, Maryland; iWarren Alpert Medical guide empirical antibiotic therapy.
School, Brown University and Women & Infants Hospital of Rhode Island, Providence, Rhode Island; jDepartment
of Pediatrics, School of Medicine, Stanford University, Stanford, California; kLucile Packard Children’s Hospital, What This Study Adds: Specific criteria can
Palo Alto, California; and lDepartment of Pediatrics, University of Texas Southwestern Medical Center at Dallas, identify premature infants with a 76% lower
Parkland Health & Hospital System, and Children’s Medical Center Dallas, Dallas, Texas adjusted risk for EOS. A substantial proportion
Dr Puopolo conceptualized and designed the study and reviewed and revised the manuscript; of these infants received prolonged antibiotics
Dr Mukhopadhyay designed the study and drafted the initial manuscript; Ms Hansen conducted despite their lower a priori risk. Recognition of
the statistical analyses and critically reviewed the manuscript; Drs Stoll, Cotten, and Sanchez this differential risk may reduce early antibiotic
contributed to the study concept and reviewed and revised the manuscript; Ms Hensman and exposures.
Drs Bell, Das, Van Meurs, and Wyckoff reviewed and revised the manuscript; and all authors
approved the final manuscript as submitted.
To cite: Puopolo KM, Mukhopadhyay S, Hansen NI, et al.
Identification of Extremely Premature Infants at Low Risk
for Early-Onset Sepsis. Pediatrics. 2017;140(5):e20170925

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November 2017:e20170925
from http://pediatrics.aappublications.org/ by guest on January 29, 2018 Article
Accurately estimating individual infants we hypothesized would be analysis, the low-risk group was
risk of early-onset sepsis (EOS) at lower risk for EOS. Our objectives further defined to also exclude
among very premature infants is were to compare the incidence of infants of mothers with histologic
challenging because of the relatively culture-confirmed EOS and the diagnosis of chorioamnionitis on
high incidence of clinical instability prevalence of prolonged early the basis of placental pathologic
among these infants and the antibiotic treatment among infants examination.
associated concern for sepsis as a with and without low EOS risk
treatable cause of such instability.‍1,​2‍ criteria. Hospital Outcomes and Clinical
Antibiotics are initiated in the Interventions
majority of extremely preterm Hospital morbidities and clinical
infants and are frequently continued Methods interventions were recorded for
despite sterile blood cultures.‍3–5 ‍ Of infants who survived >12 hours. EOS
Study Population
concern, prolonged early antibiotic (≤72 hours of age) and LOS (>72
exposure has been associated with Infants were born at NRN centers hours of age) were defined by blood
increased subsequent risk of late- between January 1, 2006, and or cerebrospinal fluid (CSF) cultures
onset sepsis (LOS), necrotizing December 31, 2014, and enrolled in positive for pathogenic bacteria or
enterocolitis (NEC), severe a registry maintained by the NRN. fungi and antibiotic therapy ≥5 days
retinopathy of prematurity, and Inclusion criteria for the cohort or intent to treat and death within 5
death.‍3,​6‍ –9
‍‍ Identification of premature studied were: gestational age (GA) days. Micrococcus, Propionibacterium,
infants at low risk of EOS may help 22 weeks, 0 days to 28 weeks, 6 Corynebacterium, Bacillus, and
guide decisions for initiating and/ days; birth weight (BW) 401 to 1500 coagulase-negative staphylococci
or discontinuing empirical antibiotic g; inborn; and no major congenital (CONS) grown on cultures of blood
treatments in the first days of life anomaly. Registry data included or CSF ≤72 hours of age were
and would be a critical first step in prospectively collected maternal considered contaminants for the
promoting antibiotic stewardship pregnancy and delivery information; primary outcome of EOS incidence.
among these infants. infant data from birth until death, Cultures growing ≥1 species of
hospital discharge or transfer, or 120 which at least 1 was considered a
The pathogenesis of EOS is days of age; and if hospitalized at true pathogen were counted as EOS
predominantly that of ascending 120 days, final discharge or transfer cases. For a secondary analysis,
colonization of the uterine and date or death up to 1 year of age.‍15 infants with CONS were included
fetal compartments with maternal Participation in the registry was as EOS cases. CONS grown from
recto-vaginal flora, progressing to approved at most sites by the local LOS cultures were included as
inflammation and infection.‍10,​11
‍ institutional review board under a true pathogens. Other morbidities
Preterm onset of labor and preterm waiver of consent; 3 sites required included respiratory distress
rupture of amniotic membranes parental consent. syndrome defined by clinical features
are both significantly associated in the first 24 hours, pneumothorax,
with risk of EOS.‍12,​13
‍ However, a Delivery Criteria for Categorizing pulmonary hemorrhage, pulmonary
proportion of preterm deliveries Infants as Hypothetically “Low Risk” interstitial emphysema, patent
for EOS
occur because of maternal medical ductus arteriosus, NEC stage 2
indications (such as preeclampsia) or Preterm labor was not recorded to 3,​‍16,​17
‍ spontaneous intestinal
for chronic fetal conditions (such as in the registry during the study perforation (SIP), severe intracranial
growth restriction).14 In the absence period. Delivery characteristics hemorrhage (ICH) grade 3 or 4‍18
of labor or rupture of membranes likely to capture infants delivered for based on a cranial sonogram
(ROM), the risk of EOS in preterm maternal health indications without taken within 28 days of birth,
infants delivered via cesarean preterm onset of labor were used periventricular leukomalacia
delivery (CD) should be substantially to define a hypothesized low-risk (PVL), and bronchopulmonary
lower compared with preterm infants group for EOS. Low-risk infants had dysplasia (BPD) defined as need for
delivered because of preterm labor all of the following characteristics: supplemental oxygen at 36 weeks
or premature ROM. We accessed delivery by CD, ROM at delivery, postmenstrual age (PMA). Surviving
data collected by the Eunice Kennedy and no documentation of maternal infants discharged or transferred
Shriver National Institute of Child clinical chorioamnionitis in the before 36 weeks PMA were classified
Health and Human Development obstetrical record. Infants without on the basis of their status at 36
Neonatal Research Network (NRN) low-risk criteria were denoted as the weeks, if known, or on the basis of
and used delivery characteristics to “comparison” group for description oxygen use at discharge or transfer.
define a group of extremely preterm of study results. In a secondary Small for gestational age (SGA) was

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defined as BW <10th percentile for TABLE 1 Maternal, Delivery, and Neonatal Characteristics
sex and GA.‍19 N (Column %) or as Showna Low Risk of EOS Comparison Group Pb
(N = 5759) (N = 9674)
Prolonged early antibiotic therapy
Study Criteria for Infants With Low Risk of EOS
was defined as receipt of antibiotics
  CD 5759 (100.0) 3899 (40.3) ≤.001
for ≥5 days starting <72 hours of age   ROM before delivery 0 (0.0) 7330 (76.2) <.001
(or intent to treat for ≥5 days in an   Maternal clinical chorioamnionitis 0 (0.0) 2538 (26.2) <.001
infant who died within 5 days and   Placental pathology performed 4898 (85.3) 8258 (85.6) .58
was receiving antibiotics). Those who   Histologic chorioamnionitis reported 1042/4884 (21.3) 5457/8221 (66.4) <.001
Maternal and delivery characteristics
did not receive prolonged antibiotics
  Maternal age in y, median (IQR) 28 (23–32) 27 (22–32) <.001
were either not started on antibiotics   Gravida .003
<72 hours, or had antibiotics   1 1876 (32.6) 3001 (31.0)
initiated but discontinued before 5   2 1378 (23.9) 2279 (23.6)
days. Other interventions recorded   3 992 (17.2) 1589 (16.4)
  4+ 1512 (26.3) 2802 (29.0)
included receipt of surfactant, nitric
  Maternal race and/or ethnicityc <.001
oxide, treatment of hypotension,   African American, non-Hispanic 2141 (37.3) 3846 (39.9)
and duration and type of respiratory   White, non-Hispanic 2415 (42.1) 3648 (37.9)
support.   Hispanic 878 (15.3) 1620 (16.8)
  Other 304 (5.3) 523 (5.4)
  At least 1 prenatal visit 5536 (96.2) 9141 (94.5) <.001
Statistical Analysis
  Maternal insulin-dependent diabetes 332 (5.8) 428 (4.4) <.001
Characteristics and outcomes were   Maternal hypertension 2677 (46.5) 1204 (12.4) <.001
  Antepartum hemorrhage 917 (15.9) 2038 (21.1) <.001
compared between infants in the
  Maternal antibiotics during delivery 3105 (54.1) 7767 (80.6) <.001
low-risk and comparison groups. admission
Additionally, we compared outcomes   Antenatal steroids 5062 (88.1) 7995 (82.8) <.001
for low-risk infants with and without   Magnesium sulfate during delivery 1858/2473 (75.1) 2977/4124 (72.2) .009
early prolonged antibiotics, excluding admissiond
  Multiple birth 1928 (33.5) 2175 (22.5) <.001
infants with any of the following at
Infant characteristics
<7 days of age: positive blood or CSF   GA, weeks, median (IQR) 27 (25–28) 26 (24–27) <.001
culture results (including isolates   By GA week <.001
considered contaminants in this   22 16 (0.3) 601 (6.2)
study) and/or a diagnosis of NEC   23 181 (3.1) 1207 (12.5)
  24 662 (11.5) 1445 (14.9)
or SIP. Statistical significance for
  25 916 (15.9) 1488 (15.4)
unadjusted comparisons between   26 1089 (18.9) 1504 (15.5)
groups was determined by χ2 test for   27 1353 (23.5) 1661 (17.2)
categorical variables and Wilcoxon   28 1542 (26.8) 1768 (18.3)
test for continuous variables. Poisson   BW, g, median (IQR) 820 (660–1000) 820 (640–1028) .64
  SGA 844 (14.7) 299 (3.1) <.001
regression models with robust
  Male 2836 (49.3) 5171 (53.5) <.001
variance estimators‍20 were used to   Apgar <5 at 5 min 1030 (17.9) 2487 (26.0) <.001
assess risk of mortality, the primary Infants surviving >12 h 5640 8422 —
outcome EOS, and other binary   Surfactant 4883 (86.6) 6549 (77.8) <.001
outcomes in comparison groups while   Nitric oxide 371 (6.6) 777 (9.2) <.001
  Median (IQR) highest base deficit in first 6 (4–9) 5 (3–8) <.001
adjusting for study center, maternal
24 hb
race and/or ethnicity, antenatal steroid   Treated for hypotension in first 24 he 684/2429 (28.2) 948/3683 (25.7) .04
use, multiple birth, sex, GA (categorical   Median (IQR) DOL first enteral feed 4 (3–6) 4 (2–5) <.001
by week), and BW (continuous). Infants who survived >24 h 5608 8321 —
Adjusted relative risks (aRRs), 95%   Respiratory support at 24 hf 5297 (94.7) 7606 (91.6) <.001
  Mechanical ventilation at 24 h 3562 (63.7) 4773 (57.5) <.001
confidence intervals (CIs), and P
Infants who survived >3 d 5499 8131 —
values by the score or Wald χ2 test   Any respiratory support day 1–3f 5440 (99.0) 7932 (97.6) <.001
from these models were reported.   Any mechanical ventilation day 1–3 4698 (85.5) 6371 (78.4) <.001
Morbidity outcomes were compared DOL, day of life; IQR, interquartile range; —, not applicable.
between low-risk and comparison a Information was missing as follows: CD, 3; ROM before delivery, 60; placental pathology performed, 49; histologic

chorioamnionitis, 51; maternal age, 1 infant; gravida, 4; maternal race and/or ethnicity, 58; prenatal care, 7; maternal
infants surviving >12 hours, accounting
insulin dependent diabetes, 6; maternal hypertension, 7; antepartum hemorrhage, 4; maternal antibiotics, 54; antenatal
for the age at which assessment took steroids, 29; SGA, 4; infant sex, 4; Apgar score, 116; first temperature within 60 min, 125; temperature if within 60 min,
place. Combined death or morbidity 10; surfactant, 1 infant; nitric oxide, 17 infants; timing of enteral feeds, 3 infants; respiratory support at 24 h, 30 infants;
respiratory support day 1–3, 12 infants.
outcomes were also examined to

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TABLE 1  Continued A P value < .05 was considered
b P value by the χ2 test (categorical variables) or the Wilcoxon test (continuous variables).
c Maternal white or African American race with missing ethnicity information (4.6% of African Americans, 0.8% of whites)
significant; no adjustment was made
were classified as non-Hispanic. Other races included Asian American and/or Pacific Islander, American Indian and/or for multiple comparisons. Analyses
Alaskan native, >1 race, other not specified, with non-Hispanic ethnicity.
d Maternal magnesium sulfate use was collected beginning April 1, 2011.
were performed by using SAS version
e Infant hypotension treatment and highest base deficit were collected beginning April 1, 2011. In this group, hypotension 9.4 (SAS Institute, Cary, NC).
treatment was missing for 2 infants and highest base deficit was missing for 263 infants.
f Respiratory support was defined as any one of mechanical ventilation (high frequency or conventional), nasal

synchronized intermittent mandatory ventilation, or continuous positive airway pressure received at 24 h or during any
Results
of the first 3 d of life.
Study Population
Between January 1, 2006, and
TABLE 2 Mortality and EOS December 31, 2014, 16 185 infants
N (Column %) Low Risk of EOS Comparison Adjusted RR for with GA 22 to 28 weeks and BW 401 to
Group Outcome (95% CI): Low 1500 g were born at NRN centers. Of
Risk of EOS Versus the
Comparison Groupa
these, 640 (4%) infants with a major
congenital anomaly, 111 (0.7%) infants
All infants 5759 9674 —
  Died before discharge 938 (16.3) 2629 (27.2) 0.88 (0.82–0.94)
with insufficient information (maternal
  Died ≤12 h 119 (2.1) 1252 (12.9) 0.42 (0.35–0.52) clinical chorioamnionitis, 54; ROM,
  EOS or death ≤12 hb 148 (2.6) 1461 (15.1) 0.36 (0.30–0.43) 43; EOS or antibiotic information, 10;
  By GA, wk delivery type, 4), and 1 infant with
  22 7/16 (43.8) 497/601 (82.7) 0.61 (0.35–1.05) congenital syphilis were excluded.
  23 31/181 (17.1) 480/1207 (39.8) 0.50 (0.36–0.68)
  24 44/662 (6.6) 200/1445 (13.8) 0.46 (0.34–0.63)
Thus, 15 433 infants were studied, of
  25 21/916 (2.3) 107/1488 (7.2) 0.28 (0.18–0.45) whom 5759 (37.3%) were classified
  26 19/1089 (1.7) 73/1504 (4.9) 0.29 (0.18–0.48) into the low-risk group and 9674
  27 16/1353 (1.2) 50/1661 (3.0) 0.31 (0.17–0.53) (62.7%) into the comparison group.
  28 10/1542 (0.6) 54/1768 (3.1) 0.17 (0.08–0.33)
  EOS (incl. CONS) or death ≤12 h 165 (2.9) 1484 (15.3) 0.39 (0.33–0.46) Maternal and Infant Characteristics
Infants who survived >12 h 5640 8422 —
  EOSc 29 (0.5) 209 (2.5) 0.24 (0.16–0.36) By definition, all infants in the low-risk
  EOS (incl. CONS) 46 (0.8) 232 (2.8) 0.33 (0.24–0.46) group were delivered by CD, without
RR, relative risk; —, not applicable. ROM before delivery, and none had
a RRs of each outcome for infants in the low risk of EOS group versus the comparison group were adjusted for center,

maternal race and/or ethnicity, antenatal steroids, multiple birth, GA, BW, and sex.
maternal clinical chorioamnionitis
b The RRs for EOS or death within 12 h of delivery varied by GA (group GA interaction, P = .015). (‍Table 1). Maternal histologic
c The RRs for EOS did not vary significantly by GA (group GA interaction, P = .94). In the model assessing the interaction,
chorioamnionitis was reported for a
GA 22 and 23 wk were combined.
smaller proportion of infants in the
low-risk group versus the comparison
TABLE 3 Distribution of EOS Cases Among 5640 Infants in the Low Risk of EOS Group and 8422 group (21% vs 66%). Mothers in
Infants in the Comparison Group Who Survived >12 Hours Based on Maternal Clinical and the low-risk group were more likely
Histopathology Diagnosis of Chorioamnionitis to suffer complications such as
Clinical Chorioamnionitis No Clinical Chorioamnionitis hypertension, more likely to receive
HCa No HC No HC No HC No Pathology antenatal corticosteroids, and less
Pathology likely to receive antenatal antibiotics.
Low risk, N 0 0 0 1018 3771 851 Median gestation was higher in the
  EOS cases, N (%) 0 0 0 16 (1.6) 10 (0.3) 3 low-risk group, as was the proportion
Comparison, N 1632 289 252 3081 2166 1002 of female infants, multiple births, and
  EOS cases, N (%) 83 (5.1) 4 (1.4) 15 70 (2.3) 20 (0.9) 17
SGA infants. In all measures except 1
HC, histological chorioamnionitis.
a In the low-risk group, placental pathology was not performed for 820 infants; pathology was performed but results were
(nitric oxide therapy), a significantly
missing for 13 infants; and information about whether pathology was done was missing for 18 infants. In the comparison greater proportion of infants in the
group, placental pathology was not performed for 1192 infants; pathology was performed but results were missing for 34 low-risk group had markers of illness
infants; and information about whether pathology was done was missing for 28 infants.
and clinical intervention (‍Table 1).
account for the competing risk of death to prolonged antibiotics to have
Mortality and Early-Onset Infection
before evaluation. For analyses of low- occurred. For these analyses, combined
risk infants with and without early death or morbidity outcomes included The proportion of infants who died
prolonged antibiotics, morbidities all deaths after 7 days and before in the first 12 hours after birth was
were examined among infants who discharge to examine risk of death in smaller in the low-risk group than in
survived >7 days to allow for exposure addition to morbidity before discharge. the comparison group (‍Table 2). Risk

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TABLE 4 Morbidities Among Infants Surviving >12 Hours cases) (Supplemental Tables 8 and
N (Column %)a Low Risk of EOS Comparison Adjusted RR for 9). The predictive performance of
Group Outcome (95% CI): Low risk categorization by study criteria is
Risk of EOS Versus shown in Supplemental Table 10. The
Comparison Groupb
likelihood of not having EOS was 3
Infants who survived >12 h 5640 8422 — times greater for low-risk infants than
  RDS 5575 (98.8) 8219 (97.6) 1.01 (1.00–1.01) for infants in the comparison group.
  Pneumothorax 319 (5.7) 483 (5.7) 1.00 (0.87–1.16)
  Pulmonary hemorrhage 418 (7.4) 445 (5.3) 1.50 (1.31–1.72) Placental pathology was available
  PIEc 191/2430 (7.9) 352/3684 (9.6) 0.97 (0.81–1.15)
for 4802 out of 5622 (85.4%) low-
  PDA 2648 (47.0) 3612 (42.9) 1.15 (1.11–1.20)
  NEC in the first 7 d 54 (1.0) 65 (0.8) 1.12 (0.75–1.68) risk infants and 7202 out of 8394
  NEC before discharge 561 (9.9) 864 (10.3) 0.97 (0.87–1.08) (85.7%) comparison infants surviving
  SIP in the first 7 d 93 (1.6) 139 (1.7) 1.06 (0.81–1.40) >12 hours (excluding those with
  SIP before discharge 195 (3.5) 321 (3.8) 1.04 (0.87–1.25) no information). The proportion of
Infants who survived >3 d 5499 8131 —
infants with EOS was similar for those
  LOS on DOL 4–7 135 (2.5) 270 (3.3) 0.95 (0.76–1.19)
  LOS before discharge 1363 (24.8) 2130 (26.2) 1.00 (0.94–1.06) with and without placental pathology
Infants evaluated with cranial 5517 8233 — (with versus without pathology, low-
imaging risk group: 0.5% vs 0.4%; comparison
  Severe ICH or PVL 784/5502 (14.2) 1456/8199 (17.8) 0.97 (0.89–1.05) group: 2.5% vs 2.5%; P = .86 for
Infants who survived to 36 wk PMA 4938 7190 —
overall difference). Among low-risk
  BPD 2286/4900 3115/7128 (43.7) 1.02 (0.98–1.06)
(46.7) infants surviving >12 hours and
DOL, day of life; ICH, intracranial hemorrhage; PDA, patent ductus arteriosus; PIE, pulmonary interstitial emphysema; RDS,
born to mothers without a histologic
respiratory distress syndrome; RR, relative risk; —, not applicable. diagnosis of chorioamnionitis on
a Information was missing as follows: RDS, 1 infant; pulmonary hemorrhage, 1 infant; PDA, 11 infants; NEC in the first 7 d, 4
placental pathology, 10 out of 3771
infants; NEC before discharge, 2 infants; SIP in the first 7 d, 12 infants; SIP before discharge, 6 infants; LOS on days 4–7, 13
infants; LOS before discharge, 5 infants; ICH and/or PVL, 49 infants; BPD, 100 infants.
(0.3%) infants had EOS (‍Table 3).
b RRs of each outcome for infants in the low risk of EOS group versus the comparison group were adjusted for center,

maternal race and/or ethnicity, antenatal steroids, multiple birth, GA (categorical), BW (continuous), and sex, except as
noted below. Because of the small number of infants with the outcome, center was not included in the model assessing Other Morbidities Before Discharge
risk of NEC in the first 7 d of life. Only 1 infant born at GA 22 wk had NEC or SIP in the first 7 d of life; GAs 22 and 23 wk were
combined for the purpose of assessing these outcomes. All infants born at GA 22 wk had RDS; therefore, GA 22 and 23 wk Among infants who survived >12
were combined for the purpose of assessing the outcome RDS. hours, the adjusted risks of respiratory
c PIE was collected beginning April 1, 2011.
distress syndrome, pulmonary
hemorrhage, and patent ductus
of the composite outcome of death [0.16–0.36]). The risk of EOS in the arteriosus were higher in the low-risk
within 12 hours or EOS was also low-risk group was consistently group compared with the comparison
reduced for infants in the low-risk lower than in the comparison group group (‍Table 4). The composite risks
group (2.6% vs 15.1%; aRR [95% for infants born at each GA, as well of death within 12 hours and each of
CI]: 0.36 [0.30–0.43]). Among infants as when CONS cases were included. pneumothorax, pulmonary interstitial
surviving >12 hours, 29 out of 5640 Escherichia coli was the most frequent emphysema, NEC, and SIP, were lower
(0.5%) in the low-risk group and 209 pathogen isolated in both the low- in the low-risk group, as was the risk
out of 8422 (2.5%) in the comparison risk group (9 out of 29 cases) and the of LOS or death within 3 days, and the
group had EOS (aRR [95% CI]: 0.24 comparison group (103 out of 209 risk of intraventricular hemorrhage

TABLE 5 Antibiotic Use in Low-Risk and Comparison Infants Surviving >12 Hours
N (Column %) or as Shown Low Risk of EOS, N = 5640 Comparison Group, N = 8422 Pa
Antibiotics for ≥5 d starting within 72 h 1940 (34.4) 4106 (48.8) <.001
  Antibiotics in the absence of EOS 1911/5611 (34.1) 3897/8213 (47.4) <.001
  Antibiotics in the absence of positive EOS culture (cases and contaminants)b 1890/5590 (33.8) 3862/8177 (47.2) <.001
  Antibiotics in the absence of a positive blood or CSF culture result, NEC, or SIP 1771/5334 (33.2) 3649/7752 (47.1) <.001
≤7 dc
  No. infants given prolonged early antibiotics per EOS case 66 19 <.001
a P value by the χ2 test.
b Of the 5640 infants in the low-risk group who survived >12 h, 50 infants with a positive blood or CSF culture result within 72 h of age were excluded (29 counted as EOS cases and 21 with

an organism considered a contaminant: 17 CONS, 3 Bacillus sp., 1 Micrococcus sp.). Of the 8422 infants in the other group, 245 were excluded (209 counted as EOS cases and 36 with an
organism considered a contaminant: 23 CONS, 3 Bacillus sp., 5 Micrococcus sp., 4 Corynebacterium sp., 1 Lactobacillus sp.).
c In the low-risk group, 256 infants with NEC, SIP, or LOS within the first 7 d of life were excluded in addition to the 50 infants previously noted (44 infants with NEC, 79 with SIP, 113 with LOS,

and 20 with ≥2 of NEC, SIP, or LOS). In the comparison group, 425 infants with NEC, SIP, or LOS within 7 d were excluded in addition to the 245 previously noted (49 infants with NEC, 110 with
SIP, 232 with LOS, and 34 with 2 or more of NEC, SIP, or LOS).

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varied by center (‍Fig 1). In comparison
with the incidence of EOS cases, the
proportion of infants treated with
prolonged antibiotics was many times
higher at all centers in both groups.

Comparing Low-Risk Group Infants


With and Without Prolonged Early
Antibiotic Therapy
Maternal and delivery characteristics
did not differ significantly between
the 1771 infants in the low-risk
group who received prolonged early
antibiotics without a positive culture
result and/or a diagnosis of NEC or
SIP ≤7 days of life and the 3563 who
did not (Supplemental Table 11).
However, the low-risk infants who
received prolonged early antibiotics
were significantly younger and smaller
at birth, more likely to be boys, SGA,
and have 5 minute Apgar score <5, and
more likely to have received surfactant
and other interventions (‍Table 6).
After adjustment for GA and other
covariates, the adjusted risk of death
after 7 days and before discharge
and the composite outcomes of death
and/or either NEC, SIP, or LOS were
increased for low-risk infants who
received prolonged early antibiotics
compared with low-risk infants who
did not (‍Table 7). Risks of pulmonary
outcomes were also higher among low-
risk infants who received prolonged
early antibiotics, including the risk of
BPD among survivors to 36 weeks PMA
FIGURE 1 (aRR [95% CI]: 1.28 [1.20–1.36]).
Center variation in proportion of infants treated with prolonged antibiotics. Shown are the
proportion of infants treated with prolonged antibiotics (gray bars) and EOS incidence (black bars)
by NRN center, expressed as percent of total infants at each center. Centers are sorted by increasing Discussion
incidence of EOS. A, Low-risk infant cohort. The rate of EOS was 0% at centers 1, 2, 11, 14, 18, and 22
and 0.2% at centers 6 and 7. B, Comparison infant cohort. The rate of EOS was 0% at center 14. Two
In this NRN cohort of extremely low
centers were excluded from the Figure: 1 center that left the NRN in 2006 and had no low-risk infants
and another center that left the NRN in 2011 and had only 2 low-risk infants. gestation infants, characteristics
evident at birth were able to be
and/or PVL or death within 28 days (‍Table 5). This difference persisted used to identify a group of infants
without evaluation (data not shown). when infants with standard indications with significantly lower risk of EOS.
for antibiotic use (positive culture A third of the infants in the study
Prolonged Early Antibiotic Therapy results, NEC, and/or SIP ≤7 days of life) cohort fulfilled the defined low-
in the Absence of Positive Culture were excluded. For each EOS case, 66 risk delivery criteria. The lower
Results low-risk infants received prolonged incidence of EOS in this group was,
Among infants surviving >12 hours early antibiotics compared with 19 however, not associated with a
without EOS, 34.1% of infants in the infants in the comparison group, P < proportional reduction in prolonged
low-risk group received prolonged .001. Among low-risk and comparison early antibiotic therapy, presenting
early antibiotics compared with 47.4% infants, the proportion of infants who an opportunity to revisit current
in the comparison group, P < .001 received prolonged early antibiotics antibiotic prescribing practices.

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TABLE 6 Neonatal Characteristics and Early Clinical Interventions for Low-Risk Infants Who Survived and subsequently the precision of
>12 Hours, Excluding Infants With a Positive Blood or CSF Culture Result and/or NEC or SIP identifying infants at low risk for EOS.
≤7 Days Hematogenous spread of infection
N (Column %) or as Shown Prolonged Early No Prolonged Pa across the placenta and infection after
Antibiotics (N = Early Antibiotics invasive intrauterine procedures can
1771) (N = 3563)
also rarely cause fetal infection.‍21
Infant characteristicsb Emerging evidence also points
  GA, wk, median (IQR) 26 (25–27) 27 (26–28) <.001
to a placental and amniotic fluid
  By GA week <.001
  22 5 (0.3) 4 (0.1) microbiome whose disturbance may
  23 67 (3.8) 67 (1.9) be associated with preterm labor.‍22
  24 251 (14.2) 311 (8.7)
  25 327 (18.5) 492 (13.8) Despite these limitations, the 76%
  26 350 (19.8) 670 (18.8)
lower risk of EOS among low-risk
  27 394 (22.2) 904 (25.4)
  28 377 (21.3) 1115 (31.3) infants compared with the comparison
  BW, g, median (IQR) 754 (620–930) 865 (710–1040) <.001 group is substantial and warrants
  SGA 353 (19.9) 411 (11.5) <.001 consideration in making management
  Male 947 (53.5) 1683 (47.2) <.001 decisions. We recently reported
  Apgar <5 at 5 min 340 (19.2) 527 (14.8) <.001
a similar single-center study that
  First temperature ≤60 min of birth 1644 (93.5) 3314 (93.5) .92
  Temperature (°F) if ≤60 min, median (IQR) 97.5 (96.5–98.2) 97.7 (96.8–98.3) <.001 included detailed maternal chart
Clinical interventionsc review of EOS cases among very low
  Surfactant 1653 (93.3) 2941 (82.6) <.001 birth weight (VLBW) infants (BW
  Nitric oxide 184 (10.4) 153 (4.3) <.001 <1500 g). In that study, we found a
  Treated for hypotension in first 24 hd 296/689 (43.0) 357/1621 (22.0) <.001
92% lower unadjusted risk for EOS
  Highest median (IQR) base deficit in 24 hd 7 (5–9) 6 (4–8) <.001
  Enteral feeds 1648 (93.1) 3393 (95.2) .001 among VLBW infants delivered by
  If yes, median (IQR) DOL first enteral feed 5 (3–8) 4 (2–5) <.001 CD to mothers with a diagnosis of
Infants who survived >24 h 1764 3538 — preeclampsia and without diagnoses
  Respiratory support at 24 he 1695 (96.1) 3306 (93.8) <.001 of preterm ROM or chorioamnionitis,
  Mechanical ventilation at 24 h 1325 (75.2) 2014 (57.1) <.001
compared with VLBW infants born
Infants who survived >3 d 1742 3454 —
  Any respiratory support day 1–3e 1736 (99.7) 3401 (98.6) <.001 without these characteristics (1 out of
  Any mechanical ventilation day 1–3 1621 (93.1) 2795 (81.0) <.001 605 [0.17%] vs 45 out of 2143 [2.1%],
Of the 5640 infants in the low risk of EOS group who survived >12 h, the following 306 infants were excluded: 50 with a P = .001).‍23 The incidence of EOS in the
positive blood or CSF culture result within 72 h of age (29 counted as EOS cases and 21 with an organism considered a current study was even lower (0.3%
contaminant: 17 CONS, 3 Bacillus sp., 1 Micrococcus sp.), 44 with NEC ≤7 d, 79 with SIP ≤7 d, 113 with LOS on days 4–7, and
vs 0.5%) among low-risk infants when
20 with 2 or more of NEC, SIP, or LOS ≤7 d. DOL, day of life; IQR, interquartile range; —, not applicable.
a P value by the χ2 test (categorical variables) or the Wilcoxon test (continuous variables). the definition was refined to exclude
b Information was missing as follows: SGA, 2 infants; infant sex, 2; Apgar score, 4; first temperature within 60 min, 32;
infants born in the setting of histologic
temperature if within 60 min, 2.
c Information was missing as follows: surfactant, 1 infant; nitric oxide, 3; timing of enteral feeds, 2; respiratory support at
as well as clinical chorioamnionitis.
24 h, 13 infants; respiratory support day 1–3, 4 infants. Placental histopathology results
d Infant hypotension treatment and highest base deficit were collected beginning April 1, 2011. In this group, hypotension
obtained shortly after delivery may
treatment was missing for 1 infant and highest base deficit was missing for 92 infants.
e Respiratory support was defined as any one of mechanical ventilation (high frequency or conventional), nasal
further aid in decisions to continue
synchronized intermittent mandatory ventilation, or continuous positive airway pressure received at 24 h or during any early empirical antibiotic therapy
of the first 3 d of life. beyond the first few days of age.

The lower incidence of EOS in the low- labor, unexplained fetal distress, Our findings suggest that clinicians
risk cohort confirmed our hypothesis or criteria leading to a diagnosis of did not recognize the differential
that the absence of factors that clinical chorioamnionitis. Therefore, incidence of EOS among low-risk
might reflect (eg, preterm labor) or we used CD with ROM at delivery and infants or failed to account for it
promote (eg, membrane rupture) the absence of clinical chorioamnionitis in their antibiotic management
pathogenesis of ascending infection as indirect estimators. It is likely decisions. Although prolonged
would be associated with a reduced that we included some mothers who empirical antibiotic use was lower
occurrence of infection. However, 29 labored before being taken for a among low-risk infants than among
cases of EOS were identified in the CD delivery before ROM, providing the comparison infants, the ratio
low-risk group. These cases may be opportunity for ascending infection. of prolonged antibiotics to number
due to imprecision in our definition of Prospective collection of delivery of EOS cases was 3 times higher in
these risk factors. The NRN database criteria in real-time practice could the low-risk group. Fewer low-risk
does not record presence of preterm improve capture of EOS risk factors infants died at ≤12 hours, but those

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TABLE 7 Mortality for Low-Risk Infants Who Survived >12 Hours and Morbidities in Survivors >7 Days, infants who received prolonged early
Excluding Infants With a Positive Blood or CSF Culture Result and/or With NEC or SIP ≤7 Days antibiotics despite negative blood
N (Column %)a Prolonged Early No Prolonged Adjusted RR for culture results and/or NEC or SIP in
Antibiotics (N = Early Antibiotics Outcome (95% CI): the first week of life. After adjusting
1771) (N = 3563) Prolonged Early for baseline characteristics associated
Antibiotics Versus
with increased risk of morbidity
No Antibioticsb
and mortality, we still found higher
Died >12 h and before discharge 315 (17.8) 429 (12.0) 1.16 (1.01–1.32)
subsequent mortality and increased
Died >7 d 236 (13.3) 258 (7.2) 1.52 (1.28–1.80)
Infants who survived >7 d 1692 3392 — incidence of BPD and other pulmonary
  RDS 1683 (99.5) 3339 (98.4) 1.01 (1.00–1.01) outcomes among the low-risk infants
  Pneumothorax 117 (6.9) 123 (3.6) 1.83 (1.38–2.43) who received prolonged early
  Pulmonary hemorrhage 148 (8.7) 127 (3.7) 1.96 (1.52–2.52) antibiotics. The decision to extend
  PIEc 83/664 (12.5) 76/1547 (4.9) 1.80 (1.31–2.45)
early empirical therapy may reflect a
  PDA 951 (56.2) 1477 (43.6) 1.15 (1.08–1.22)
  NEC >7 d 173 (10.2) 315 (9.3) 0.97 (0.80–1.17) severity of initial illness that strongly
  NEC >7 d or death before discharge 346 (20.4) 469 (13.8) 1.22 (1.07–1.40) influences subsequent morbidity
  SIP >7 d 55 (3.3) 40 (1.2) 1.86 (1.23–2.82) and mortality in a manner for which
  SIP >7 d or death before discharge 263 (15.5) 286 (8.4) 1.46 (1.24–1.71) we could not adequately account in
  LOS >7 d 436 (25.8) 746 (22.0) 1.00 (0.89–1.11)
our risk-adjusted analyses. However,
  LOS >7 d or death before discharge 583 (34.5) 878 (25.9) 1.12 (1.03–1.23)
Infants evaluated with cranial imaging 1692 3365 — there is evidence for the critical role
  Severe ICH or PVL 316/1687 (18.7) 321/3357 (9.6) 1.65 (1.40–1.94) of the early life microbiome in the
Infants who survived to 36 wk PMA 1500 3194 — development of neonatal immune
  BPD 919/1491 (61.6) 1220/3167 (38.5) 1.28 (1.20–1.36) responses and for the significant
Of the 5640 infants in the low risk of EOS group who survived >12 h, the following 306 infants were excluded: 50 with a disruption of that microbiome
positive blood or CSF culture result within 72 h of age (29 counted as EOS cases and 21 with an organism considered a
contaminant: 17 CONS, 3 Bacillus sp., 1 Micrococcus sp.), 44 with NEC ≤7 d, 79 with SIP ≤7 d, 113 with LOS on days 4–7, and
induced by antibiotic exposure.‍29–33‍‍‍
20 with ≥2 of NEC, SIP, or LOS ≤7 d. ICH, intracranial hemorrhage; PDA, patent ductus arteriosus; PIE, pulmonary interstitial Although with this study we cannot
emphysema; RDS, respiratory distress syndrome; RR, relative risk; —, not applicable. determine why it may be, our findings
a Information was missing for survivors >7 d as follows: PDA, 2 infants; SIP, 2 infants; LOS, 2 infants; ICH and/or PVL, 13

infants; BPD, 36 infants.


reveal that among infants with a low
b RRs of each outcome for infants who received antibiotics for ≥5 days started within 72 h of birth versus those who previous probability of EOS, extended
either did not receive antibiotics within 72 h or received antibiotics for <5 d were adjusted for center, maternal race and/ empirical administration of early
or ethnicity, antenatal steroids, multiple birth, GA (categorical), BW (continuous), and sex except as noted below. Because
of the number of centers with no infants who had the outcome (or, for RDS, centers with no infants without the outcome),
antibiotics for critical illness may not
center was not included in models assessing risk of RDS and SIP. All infants born at GA 22–24 wk had RDS; therefore, GA be beneficial and could potentially be
22–25 wk were combined for the purpose of assessing RDS. GAs 22 and 23 wk were combined in the models assessing harmful.
SIP and BPD (only 1 of the 9 infants included who were born at GA 22 wk and survived >7 d had SIP before discharge; all 5
infants born at GA 22 wk who survived to 36 wk PMA had BPD).
c PIE was collected beginning April 1, 2011. Our study is limited by its
retrospective design. During the
who survived were as sick as or sicker reluctance to stop antibiotic treatment. study period, the registry lacked
than comparison infants. Maternal These decisions are likely driven by information on the indication for
morbidity, SGA status, and a stressed clinical uncertainties and provider preterm delivery. We have no
in utero environment in infants preference more than biology because information on the presence of
delivered for maternal indications are we observed marked variation around preterm labor, attempts to induce
associated with greater respiratory prolonged antibiotic administration labor, or unexplained fetal distress.
morbidity and may explain the greater across study centers that did not Information about antibiotic therapy
initial morbidity observed in the correlate with variation in the was limited to whether antibiotics
low-risk infants.‍24–‍ 26
‍ Administration incidence of EOS at these centers. were started in the first 72 hours
of antibiotics for increasing clinical after birth and continued for ≥5 days.
instability and attribution of such Clinicians make antibiotic and other Types of antibiotics, total duration of
instability to culture negative sepsis is treatment decisions to protect sick antibiotic administration during the
well-documented in neonatal care.‍4,​27,​28
‍ newborns, yet multiple reports NICU admission, and indication for
A previous study revealed that >90% now suggest harm from early and therapy were not recorded.
of all infants in an earlier NRN cohort prolonged empirical antibiotics.‍3,​6‍ –9
‍‍
were treated with antibiotics at birth.‍3 We addressed this issue with an
Conclusions
We speculate that the greater need analysis restricted to the low-risk
for intensive care interventions in group. To focus on potentially Delivery characteristics of infants
the low-risk cohort and persistence modifiable use of antibiotics, we born at 22 to 28 weeks GA were useful
of illness beyond 48 hours led to a limited this analysis to low-risk in identifying those with significantly

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lower risk of EOS. Prolonged early Hospital of Rhode Island (U10 Diane I. Bottcher, RN, MSN; Colleen
antibiotics were administered to HD27904): Abbott R. Laptook, MD; Mackie, BS, RT.
a large proportion of these infants Martin Keszler, MD; Andrea M. Knoll;
Eunice Kennedy Shriver National
despite their lower a priori risk, Emilee Little, RN, BSN; Elisa Vieira,
Institute of Child Health and Human
and this was associated with higher RN, BSN; Kristin M. Basso, RN, MaT;
Development: Rosemary D. Higgins,
adjusted incidence of death and Jennifer A. Keller, RN, BSN.
MD; Stephanie Wilson Archer, MA.
pulmonary morbidity. Recognition of
Case Western Reserve University, Indiana University, University
differential EOS risk may help guide
Rainbow Babies & Children’s Hospital, Methodist Hospital, Riley
early empirical antibiotic use among
Hospital (U10 HD21364, M01 RR80): Hospital for Children, and Wishard
approximately one-third of extremely
Michele C. Walsh, MD, MS; Anna Health Services (U10 HD27856, M01
preterm infants.
Maria Hibbs, MD; Avroy A. Fanaroff, RR750): Brenda B. Poindexter, MD,
MD; Nancy S. Newman, BA, RN; MS; Gregory M. Sokol, MD; Dianne
Allison H. Payne, MD, MS. E. Herron, RN, CCRC; Lucy Miller,
Acknowledgments
Children’s Mercy Hospital, University BSN, CCRC; Leslie Dawn Wilson, BSN,
The National Institutes of Health, of Missouri Kansas City School of CCRC.
the Eunice Kennedy Shriver National Medicine (U10 HD68284): William E. McGovern Medical School at The
Institute of Child Health and Human Truog, MD; Eugenia K. Pallotto, MD, University of Texas Health Science
Development, the National Center for MSCE; Howard W. Kilbride, MD; Cheri Center at Houston, Children’s
Research Resources, and the National Gauldin, RN, BS, CCRC; Anne Holmes, Memorial Hermann Hospital,
Center for Advancing Translational RN, MSN, MBA-HCM, CCRC; Kathy Memorial Hermann Southwest
Sciences provided grant support for Johnson, RN, CCRC; Allison Knutson, Hospital, and Lyndon Baines Johnson
the NRN Generic Database through BSN, RNC-NIC. General Hospital/Harris County
cooperative agreements. The
Hospital District (U10 HD21373):
content of this article is solely the Cincinnati Children’s Hospital
Kathleen A. Kennedy, MD, MPH;
responsibility of the authors and does Medical Center, University Hospital,
Jon E. Tyson, MD, MPH; Georgia E.
not necessarily represent the official and Good Samaritan Hospital (U10
McDavid, RN; Julie Arldt-McAlister,
views of the National Institutes of HD27853, M01 RR8084): Kurt
RN, BSN; Katrina Burson, RN, BSN;
Health. Data collected at participating Schibler, MD; Edward F. Donovan,
Carmen Garcia, RN, CCRP; Beverly
sites of the Eunice Kennedy Shriver MD; Cathy Grisby, BSN, CCRC; Kate
Foley Harris, RN, BSN; Anna E. Lis,
National Institute of Child Health Bridges, MD; Barbara Alexander, RN;
RN, BSN; Karen Martin, RN; Sara C.
and Human Development NRN were Estelle E. Fischer, MHSA, MBA; Holly
Martin, RN, BSN; Shawna Rodgers,
transmitted to RTI International, the L. Mincey, RN, BSN; Jody Hessling,
RN; Maegan C. Simmons, RN; Patti L.
data coordinating center (DCC) for RN; Lenora Jackson, CRC; Kristin
Pierce Tate, RCP.
the network, which stored, managed, Kirker, CRC; Greg Muthig, BS; Stacey
and analyzed the data for this study. Tepe, BS. Nationwide Children’s Hospital and
On behalf of the NRN, Dr Abhik Das The Ohio State University Wexner
(DCC Principal Investigator) and Ms Duke University School of Medicine,
University Hospital, University of Medical Center (U10 HD68278): Leif
Nellie Hansen (DCC Statistician) had D. Nelin, MD; Sudarshan R. Jadcherla,
full access to all the data in the study North Carolina, and Duke Regional
Hospital (U10 HD40492, UL1 MD; Patricia Luzader, RN; Christine
and take responsibility for the integrity A. Fortney, PhD, RN; Nehal A. Parikh,
of the data and accuracy of the data TR1117, M01 RR30, UL1 TR1111):
Ronald N. Goldberg, MD; Kathy J. MD.
analysis.
Auten, MSHS; Kimberley A. Fisher, RTI International (U10 HD36790):
We are indebted to our medical and PhD, FNP-BC, IBCLC; Joanne Finkle, Dennis Wallace, PhD; Marie G.
nursing colleagues and the infants RN, JD; Matthew M. Laughon, MD, Gantz, PhD; W. Kenneth Poole, PhD
and their parents who agreed to MPH; Carl L. Bose, MD; Janice (deceased); Jeanette O’Donnell
take part in this study. The following Bernhardt, MS, RN; Gennie Bose, RN. Auman, BS; Margaret M. Crawford,
investigators, in addition to those listed BS, CCRP; Carolyn M. Petrie Huitema,
as authors, participated in this study: Emory University, Children’s MS, CCRP; Kristin M. Zaterka-Baxter,
Healthcare of Atlanta, Grady RN, BSN, CCRP.
NRN Steering Committee Chair:
Memorial Hospital, and Emory
Michael S. Caplan, MD, University of Stanford University, Dominican
University Hospital Midtown (U10
Chicago, Pritzker School of Medicine. Hospital, El Camino Hospital, and
HD27851, M01 RR39): David P.
Alpert Medical School of Brown Carlton, MD; Ellen C. Hale, RN, BS, Lucile Packard Children’s Hospital
University and Women & Infants CCRC; Yvonne Loggins, RN, BSN; (U10 HD27880, M01 RR70): David

PEDIATRICS Volume 140, number 5, November 2017from http://pediatrics.aappublications.org/ by guest on January 29, 2018
Downloaded 9
K. Stevenson, MD; Marian M. Adams, University of Pennsylvania, Hospital Jennifer J. Jensen, RN, BSN; Karen
MD; M. Bethany Ball, BS, CCRC; of the University of Pennsylvania, Zanetti, RN.
Magdy Ismail, MD, MPH; Andrew W. Pennsylvania Hospital, and
Wake Forest University, Baptist
Palmquist, RN; Melinda S. Proud, RCP. Children’s Hospital of Philadelphia
Medical Center, Forsyth Medical
Tufts Medical Center, Floating (U10 HD68244): Barbara Schmidt,
Center, and Brenner Children’s
Hospital for Children (U10 HD53119, MD, MSc; Haresh Kirpalani, MB, MSc;
Hospital (U10 HD40498, M01
M01 RR54): Ivan D. Frantz III, MD; Sara B. DeMauro, MD, MSCE; Aasma
RR7122): T. Michael O’Shea, MD,
John M. Fiascone, MD; Brenda L. S. Chaudhary, BS, RRT; Soraya Abbasi,
MPH; Nancy Peters, RN.
MacKinnon, RNC; Anne Furey, MPH; MD; Toni Mancini, RN, BSN, CCRC;
Dara M. Cucinotta, RN. Wayne State University, Hutzel
Ellen Nylen, RN, BSN.
Women’s Hospital, and Children’s
University of Alabama at Birmingham University of Rochester Medical Hospital of Michigan (U10
Health System and Children’s Center, Golisano Children’s Hospital, HD21385): Seetha Shankaran, MD;
Hospital of Alabama (U10 HD34216, and the University of Buffalo Athina Pappas, MD; John Barks,
M01 RR32): Waldemar A. Carlo, MD; Women’s and Children’s Hospital MD; Rebecca Bara, RN, BSN; Girija
Namasivayam Ambalavanan, MD; of Buffalo (U10 HD68263, U10 Natarajan, MD; Mary Christensen,
Monica V. Collins, RN, BSN, MaEd; HD40521, M01 RR44, UL1 TR42): RT; Stephanie A. Wiggins, MS; Diane
Shirley S. Cosby, RN, BSN. Carl T. D’Angio, MD; Dale L. Phelps, White, RT.
University of California Los Angeles, MD; Ronnie Guillet, MD, PhD; Satyan
Yale University, Yale-New Haven
Mattel Children’s Hospital, Santa Lakshminrusimha, MD; Linda J.
Children’s Hospital, and Bridgeport
Monica Hospital, Los Robles Hospital Reubens, RN, CCRC; Cassandra A.
Hospital (U10 HD27871, ULTR142,
and Medical Center, and Olive View Horihan, MS; Mary Rowan, RN;
M01 RR125): Richard A. Ehrenkranz,
Medical Center (U10 HD68270): Uday Holly I.M. Wadkins, MA; Rosemary
MD; Harris Jacobs, MD; Patricia
Devaskar, MD; Meena Garg, MD; Teresa Jensen; Melissa Bowman, MSN;
Cervone, RN; Monica Konstantino,
Chanlaw, MPH; Rachel Geller, RN, BSN. Julianne Hunn, BS; Stephanie
RN, BSN; JoAnn Poulsen, RN; Janet
Guilford, BS; Deanna Maffett, RN;
University of California San Diego Taft, RN, BSN.
Diane Prinzing; Anne Marie
Medical Center and Sharp Mary Birch Reynolds, MD, MPH; Ashley Williams,
Hospital for Women and Newborns MSEd; Karen Wynn, RN; Erica
(U10 HD40461): Neil N. Finer, Burnell, RN; Michael G. Sacilowski,
MD; David Kaegi, MD; Maynard R. MAT, CCRC.
Rasmussen, MD; Kathy Arnell, RNC;
Clarence Demetrio, RN; Wade Rich, University of Texas Southwestern Abbreviations
BSHS, RRT. Medical Center at Dallas, Parkland aRR: adjusted relative risk
Health & Hospital System, and BPD: bronchopulmonary
University of Iowa and Mercy Medical Children’s Medical Center Dallas dysplasia
Center (U10 HD53109, M01 RR59): (U10 HD40689, M01 RR633): Luc BW: birth weight
Tarah T. Colaizy, MD, MPH; Dan L. P. Brion, MD; Walid A. Salhab, MD; CD: cesarean delivery
Ellsbury, MD; John A. Widness, MD; Charles R. Rosenfeld, MD; Diana CONS: coagulase-negative
Karen J. Johnson, RN, BSN; Donia B. M. Vasil, MSN, BSN, RNC-NIC; Lijun staphylococci
Campbell, RNC-NC; Jacky R. Walker, Chen, PhD, RN; Alicia Guzman; CSF: cerebrospinal fluid
RN; Tracy L. Tud, RN. Gaynelle Hensley, RN; Lizette E. Lee, EOS: early-onset sepsis
University of Miami, Holtz Children’s RN; Melissa H. Leps, RN; Nancy A. GA: gestational age
Hospital (U10 HD21397, M01 Miller, RN; Janet S. Morgan, RN; Lara LOS: late-onset sepsis
RR16587): Shahnaz Duara, MD; Pavageau, MD. NEC: necrotizing enterocolitis
Charles R. Bauer, MD; Ruth Everett- NRN: Neonatal Research
University of Utah Medical Center,
Thomas, RN, MSN. Network
Intermountain Medical Center, LDS
PMA: postmenstrual age
University of New Mexico Health Hospital, and Primary Children’s
PVL: periventricular
Sciences Center (U10 HD53089, M01 Medical Center (U10 HD53124,
leukomalacia
RR997): Kristi L. Watterberg, MD; M01 RR64, UL1 RR25764):
ROM: rupture of membranes
Robin K. Ohls, MD; Conra Backstrom Roger G. Faix, MD; Bradley A. Yoder,
SGA: small for gestational age
Lacy, RN; Carol H. Hartenberger, MD; Karen A. Osborne, RN, BSN,
SIP: spontaneous intestinal
MPH, RN; Sandra Sundquist CCRC; Cynthia Spencer, RNC, BSN;
perforation
Beauman, MSN, RNC-NIC, Mary Kimberlee Weaver-Lewis, RN, MS; Karie
VLBW: very low birth weight
Ruffaner Hanson, RN, BSN. Bird, RN, BSN; Jill Burnett, RNC, BSN;

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DOI: https://​doi.​org/​10.​1542/​peds.​2017-​0925
Accepted for publication Jul 31, 2017
Address correspondence to Karen M. Puopolo, MD, PhD, The Children’s Hospital of Philadelphia, Newborn Care at Pennsylvania Hospital, 800 Spruce St,
Philadelphia, PA 19107. E-mail: karen.puopolo@uphs.upenn.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2017 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: The National Institutes of Health: the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Center for
Research Resources, and the National Center for Advancing Translational Sciences. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Identification of Extremely Premature Infants at Low Risk for Early-Onset
Sepsis
Karen M. Puopolo, Sagori Mukhopadhyay, Nellie I. Hansen, C. Michael Cotten,
Barbara J. Stoll, Pablo J. Sanchez, Edward F. Bell, Abhik Das, Angelita M. Hensman,
Krisa P. Van Meurs, Myra H. Wyckoff and on behalf of the NICHD Neonatal
Research Network
Pediatrics 2017;140;
DOI: 10.1542/peds.2017-0925 originally published online October 5, 2017;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
.

Downloaded from http://pediatrics.aappublications.org/ by guest on January 29, 2018


Identification of Extremely Premature Infants at Low Risk for Early-Onset
Sepsis
Karen M. Puopolo, Sagori Mukhopadhyay, Nellie I. Hansen, C. Michael Cotten,
Barbara J. Stoll, Pablo J. Sanchez, Edward F. Bell, Abhik Das, Angelita M. Hensman,
Krisa P. Van Meurs, Myra H. Wyckoff and on behalf of the NICHD Neonatal
Research Network
Pediatrics 2017;140;
DOI: 10.1542/peds.2017-0925 originally published online October 5, 2017;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/140/5/e20170925

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
.

Downloaded from http://pediatrics.aappublications.org/ by guest on January 29, 2018

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