Journal of Perinatology (2017) 00, 1–6

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved 0743-8346/17
www.nature.com/jp

ORIGINAL ARTICLE
Anti-microbial stewardship: antibiotic use in well-appearing
term neonates born to mothers with chorioamnionitis
N Money1, J Newman1, S Demissie2, P Roth1,3 and J Blau1,3

OBJECTIVE: To determine if implementation of a protocol based on a neonatal early-onset sepsis (EOS) calculator developed by
Kaiser Permanente would safely reduce antibiotic use in well-appearing term infants born to mothers with chorioamnionitis in the
unique setting of an Observation Nursery.
STUDY DESIGN: Data obtained from a retrospective chart review of well-appearing term infants born between 2009 and 2016 were
entered into the EOS calculator to obtain management recommendations.
RESULTS: Three hundred and sixty-two infants met the study criteria. Management according to the EOS calculator would reduce
antibiotic use from 99% to 2.5% (P o0.0001) of patients. Average length of therapy would also decrease from 2.08 to 0.05 days
(P o 0.0001). One infant, who remained asymptomatic, had Enterococcus bacteremia and received a 7-day course of broad-
spectrum antibiotics.
CONCLUSIONS: Culture-positive sepsis in asymptomatic neonates born to mothers with chorioamnionitis is rare. Management
according to the EOS calculator would markedly reduce the potential complications of antibiotic use. These data should initiate
re-examination of existing protocols for management of this cohort of patients.
Journal of Perinatology advance online publication, 5 October 2017; doi:10.1038/jp.2017.137

INTRODUCTION despite having a lower incidence of EOS.1,2 Several sources report

Early-onset sepsis (EOS) management remains a controversial
issue. The American Academy of Pediatrics (AAP) and Centers for
Disease Control (CDC) recommendations include empiric broad-
spectrum antibiotic therapy for all infants born to mothers with
chorioamnionitis (CAM) regardless of clinical status.1,2 Despite
these recommendations, antibiotic practice varies greatly between
institutions with similar infection burdens, suggesting the need for
continued research and understanding.3–6 One study of infants
born at ⩾ 35 weeks gestation born to mothers with CAM at 13
medical centers found that the rate for initiating empiric therapy
was between 7 and 76%.7 Another recent survey among 79
nurseries reports that ~ 60% of nurseries follow AAP/CDC guide-
lines, while the rest follow different protocols based on a
published online calculator (14%), local guidelines (13%) or
individual providers (13%), some of whom relied on physical
examination alone.8
CAM is an unreliable predictor of EOS,9–12 in part due to
variability in its clinical diagnosis among obstetricians. The rate of
EOS in infants born to mothers with CAM is lower than previously
thought, likely due to advances in intrapartum antibiotic
management.7,11 Three studies of late preterm and term infants
born to mothers with CAM report EOS rates of 4/554 (0.7%),13
1/698 (0.14%)14 and 5/1243 (0.4%),7 respectively. A recent
workshop including neonatal and obstetric experts highlighted
the need for alternative approaches to the management of
mothers and infants affected by CAM.15
It is no surprise that asymptomatic term newborns are
especially susceptible to unnecessary antibiotic exposure since
according to the CDC and AAP guidelines, they receive the same
empiric treatment as infants who are premature or symptomatic
rates of proven EOS ranging from 0.02 to 0.19% in asymptomatic
newborns with risk factors for EOS.9,16,17 With a shifting emphasis
to serial physical examination and vital sign monitoring in
diagnosing EOS, many reports suggest that this approach is
safe and more effective in predicting EOS than risk-based
strategies.17–20
When evaluating recommendations for this cohort, careful
consideration of the untoward effects of antibiotic treatment have
long been overlooked. Studies have linked early antibiotic
exposure to recurrent wheezing disorders in childhood,21
obesity22–24 and inflammatory bowel disease,25,26 possibly due
to changes in the neonatal intestinal microbiome, the broader
implications of which are still being examined, and to the
emergence of resistant bacteria.27 Antibiotic use is also associated
with increased rates of necrotizing enterocolitis, infections and
increased mortality in premature infants.28,29 In addition to being
costly,30,31 EOS evaluations are also associated with infant–mother
separation, decreased breastfeeding rates and increased rates of
formula supplementation.5 Anti-microbial stewardship initiatives
are therefore critical to identifying non-infected patients, who can
be protected from unnecessary antibiotic exposure and to ensure
the continued efficacy of anti-microbial agents in this
population.9,32,33
One approach to more judicious initiation of antibiotics makes
use of a risk-based protocol using the EOS calculator developed by
Kaiser Permanente.34 The calculator is derived from a multivariate
risk model based on the work of Escobar et al.35 and Puopolo and
Escobar36 that combines intrapartum risk factors as continuous
rather than dichotomous risk factors. While the diagnosis of CAM
is not considered, intrapartum risk factors and infant physical

1
Division of Neonatology, Department of Pediatrics, Staten Island University Hospital, Northwell Health, Staten Island, NY, USA; 2Biostatistics Unit, Feinstein Institute for Medical
Research, Northwell Health, Staten Island, NY, USA and 3Department of Pediatrics, Hofstra Northwell School of Medicine, Staten Island, NY, USA. Correspondence: Dr J Blau,
Division of Neonatology, Department of Pediatrics, Staten Island University Hospital, Northwell Health, 475 Seaview Avenue, Staten Island, NY 10305, USA.
E-mail: jblau@northwell.edu
Received 22 May 2017; revised 5 July 2017; accepted 18 July 2017
 Antibiotic use in infants with maternal chorioamnionitis
N Money et al
2
exam are used to stratify risk and suggest management strategies.
This tool is used throughout the Kaiser Permanente Northern
California (KPNC) health system and has been accessed by users in
all 50 US states and at least 124 other countries.37 A recent
prospective study done in the KPNC hospital network found that
using a protocol based on the EOS calculator among infants
⩾ 35 weeks gestation decreased antibiotic use from 14.5 to 4.9%
in a cohort of 204 485 infants with no difference in rates of EOS,
severity of illness, readmissions or timing of case identification.38
Retrospective studies also suggest using the EOS calculator to
guide management may safely reduce unnecessary antibiotic use
in infants born to mothers with CAM.14,39
At our institution, asymptomatic, term newborns born to
mothers with CAM are admitted to an Observation Nursery,
where serial vital signs and physical exams are monitored along
with continuous pulse oximetry. CDC and AAP recommendations
are followed with sepsis evaluations and antibiotic therapy
prescribed for all patients. Examination of management recom-
mendations based on the EOS calculator may shed light on the
risk–benefit ratio of widespread uniform use in this cohort. In this
study, we will compare the treatment protocol using the EOS
calculator for a retrospective cohort of well-appearing, term
neonates born to mothers with CAM with antibiotic use under our
current protocol and assess its safety in predicting EOS. We
hypothesize that a protocol based on the EOS calculator would
significantly reduce antibiotic use in well-appearing, term infants
born to mothers with CAM without failing to identify cases of EOS
in a timely manner.
METHODS
All newborns born to mothers with CAM at our institution from January
2009 to April 2016 were identified according to infant and maternal ICD-9
codes. Clinical and demographic data on both newborns and mothers
were gathered via retrospective chart review. Key infant data included
gestational age at birth, physical examination, vital signs, duration of
antibiotics received, total days in hospital and initial complete blood count,
C-reactive protein (CRP) and blood culture results. Initial white blood cell
(WBC) counts of ⩽ 5000 or ⩾ 25 000 per mm, I:T ratio ⩾ 0.2 and CRP
⩾ 1.0 mg dl − 1 were considered abnormal.3 Since the calculator is intended
to be a tool to guide initial EOS management, only ancillary labs drawn at 6
to 12 h of life and all infant physical examinations performed upon
admission to the Observation Nursery were reviewed. The CDC national
incidence of EOS of 0.5/1000 was selected in the calculator as the baseline
EOS rate.
The EOS calculator separates infant physical examinations into three
categories: well-appearing, equivocal and clinically ill.35 We limited our
study population to well-appearing infants in the Observation Nursery
excluding the symptomatic patients who required admission to the
Neonatal Intensive Care Unit (NICU) due to equivocal presentation or
clinical illness.
Maternal data gathered included maternal temperature, duration of
rupture of membranes (ROM) before delivery, group B streptococcus
carriage status and type and timing of intrapartum antibiotics received. All
antenatal maternal temperatures were reviewed and the highest was
entered in the calculator, while postnatal maternal temperatures were not
included. Data on type and timing of antibiotic administration was
obtained by reviewing medication administration flowcharts for each
mother. For ease of data entry into the EOS calculator, ampicillin and
gentamicin given together were considered broad-spectrum antibiotics
and penicillin-class antibiotics given alone were considered group B
streptococcus-specific. Duration of ROM was rounded to the nearest hour.
Study approval was obtained from the Northwell Hofstra School of
Medicine institutional review board. Data were stored in REDCap (Research
Electronic Data Capture), a HIPAA-compliant data storage system
developed specifically for research purposes.40 Data for each infant–
mother pair were entered into the EOS calculator and the derived EOS risk
scores and infant management recommendations were recorded. These
recommendations were then compared with each infant’s actual manage-
ment determined by CDC and AAP guidelines in our Observation Nursery.
Journal of Perinatology (2017), 1 – 6
Statistical analysis
Categorical data were summarized using frequency counts and percen-
tages. Continuous variables were summarized by descriptive statistics,
including mean and standard deviation. Associations between discrete
variables were evaluated using χ2 test or Fisher’s exact test. Within-group
comparisons were made using paired t-test for continuous variables and
McNemar χ2 test for dichotomous variables. All statistical tests were two
sided, and there was no adjustment for multiple testing. A P-value of 0.05
was considered statistically significant. Data analyses were conducted using
SAS (Statistical Analysis System) Software, Version 9.3 (Cary, NC, USA).
RESULTS
A total of 21 758 live infants were born at SIUH from January 2009
through April 2016. Of these, 19 525 (89.7%) were term infants, of
which 441 (2.5%) were born to mothers diagnosed with CAM.
Forty-one (9.3%) infants were symptomatic at birth requiring
admission to the NICU and therefore excluded from study analysis.
An additional 38 (8.6%) infants were initially well but later
developed symptoms and were also excluded, leaving 362 total
subjects for our study (Figure 1). Table 1 contains maternal and
neonatal demographics for our cohort. 37.9% of infants were
delivered via cesarean section, which is higher than the overall
cesarean rate at our institution of 23.7% over the study period of
2009 to 2016. Prolonged ROM (418 h) was identified (data not
shown) in 111 (25.2%) term infants born to mothers with CAM.
Table 2 contains information regarding type and duration of
maternal antibiotics administered.
Management according to the EOS calculator would signifi-
cantly reduce antibiotic use among this population from 99.7% to
2.5% (P o0.0001). Average length of therapy would also decrease
from 2.09 to 0.05 days (Table 3) (P o0.0001) per infant, if we
assume a 48 h course of antibiotics for each infant recommended
to have empiric therapy based on the EOS calculator. Three
hundred and sixty-two (99.7%) infants were empirically treated
with antibiotics for 1 to 7 days, with 29 (8.0%) and 7 (1.9%) of the
infants receiving antibiotic treatment for more than 48 h and for a
7-day course, respectively (Table 3). Therapy was significantly
more likely to be continued beyond 48 h if CRP (P o 0.05) rather
than the WBC count or I:T ratio were abnormal (Table 4). In fact, of
the 16 (4.4%) infants who received antibiotic therapy 472 h, 14
(87.5%) had abnormal CRP values (data not shown).
21 758 Total live infants
2 398 Premature infants
19 525 Term infants
19 084 No diagnosis of CAM
made
441 Term infants born to
mothers with CAM
41 Infants symptomatic at birth
38 Infants later developed
symptoms
362 Well-appearing, term
infants born to mothers with
CAM
Figure 1. Study population.
© 2017 Nature America, Inc., part of Springer Nature.
 Antibiotic use in infants with maternal chorioamnionitis
N Money et al
3
received a 7-day course of broad-spectrum antibiotics. Manage-
Table 1. Maternal and neonatal demographics
ment recommendations via the EOS calculator for this one infant
Mean ± s.d. Range Number (%) with a true-positive blood culture, who remained asymptomatic
throughout the NICU course, would have been restricted to vital
Maternal sign monitoring every four hours.
Age (years) 26.8 ± 6.0 15–43
ROM (hours) 14.5 ± 8.8 0–76
Highest temperature (°F) 101.2 ± 0.8 99.2–103.6 DISCUSSION
GBS Application of a protocol based on the EOS calculator would
Positive 47 (13.0%)
Negative 308 (85.1%) significantly decrease antibiotic use among well-appearing, term
Unknown 7 (1.9%) neonates born to mothers with CAM. Decreasing empiric therapy
Birth in this population has many benefits including reducing adverse
Vaginal 225 (62.1%) medical effects of broad-spectrum therapy, rates of invasive blood
C section 137 (37.9%) testing and mother–infant separation, as well as increased rates of
breastfeeding. Although our study did not evaluate health-care
Infant costs, we assume a financial benefit would have been derived
Birth weight (g) 3431 ± 438 2430–4590 from lower rates of phlebotomy, antibiotic therapy and in some
Gestational age (weeks) 39.5 ± 1.2 37–42.7 cases length of stay.
Gender
Male 183 (50.5%) Many studies have affirmed the importance of serial physical
Female 179 (49.5%) exams in the management of newborns at-risk for EOS.9,12,18 One
study found using physical examination alone to dictate EOS
Calculated EOS 1.6 ± 1.9 management led to decreased antibiotic administration and
risk/1000 at birth shorter hospitalizations without increased risk of severe complica-
Calculated EOS risk/1000 0.6 ± 0.8 tions or of becoming ill following hospital discharge.19 In addition,
after well exam infants managed solely by physical exam monitoring who became
Days in hospital 2.8 ± 1.1 1–7 symptomatic did not experience treatment delay.20
Abbreviations: EOS, early-onset sepsis; GBS, group B streptococcus; ROM, At our institution, infants born to mothers with CAM are
rupture of membranes. admitted to an Observation Nursery, a unique setting inside the
NICU where at-risk infants can be observed while avoiding NICU
admission. These infants are cared for by SCN nursing (1:5 nurse:
patient ratio) and undergo continuous pulse oximetry, allowing for
Table 2. Maternal antibiotics receiveda timely identification of symptoms. Observation nursery patients
are managed by pediatric hospitalists, with the NICU service aware
Type and timing of antibiotics received Frequency (%) of these at-risk newborns. Mothers are encouraged to take these
children to designated private breastfeeding rooms, promoting
Broad-spectrum antibiotics 44 h before birth 94 (26.0%) increased breastfeeding rates and better maternal–infant bond-
Broad-spectrum 2–3.9 h before birth 79 (21.8%) ing, which can suffer in the NICU setting. If patients become
GBS-specific only, 42 h before birth 10 (2.8%) symptomatic, they are promptly transferred to the NICU for further
No antibiotics or any antibiotics given o2 h before 179 (49.4%)
management.
birth
Our study also demonstrates the potential pitfall of relying solely
Abbreviations: EOS, early-onset sepsis; GBS, group B streptococcus. aFour on physical examination in determining when to empirically treat
types and durations of antibiotics as classified by EOS calculator. for EOS as evidenced by the one case of a true-positive blood
culture in an asymptomatic infant. Although this represents an
incidence of ~ 0.3% (1/362), it is important to consider the
potentially serious consequences if this asymptomatic case were
Table 3. Antibiotic utilization in this cohort missed. Similar to our study, which confirmed that culture-positive
sepsis in this population is rare,7,13 Shakib et al.14 reviewed charts
Antibiotic use Number of infants 434 weeks gestation born to mothers with CAM and
found one instance of culture-positive sepsis out of 698 (0.2%).14
Days on antibiotics (avg. ± s.d.) 2.09 ± 0.97 However, the infant with a positive blood culture in that study was
Calculator-determined days on antibiotics (avg. ± s.d.) 0.05 ± 0.31 a symptomatic patient infant with a risk score of 7.85/1000 and
Treated for 448 h, N (%) 29 (8.0%)
would have received empiric antibiotics, whereas the infant in our
Treated for 7 days, N (%) 7 (1.9%)
study was asymptomatic throughout his hospital course and
would not have received empiric therapy. Furthermore, it is
EOS risk score as obtained from the Neonatal EOS calculator possible—although unlikely given the organism—that the positive
ranged from 0.13 to 17.48 per 1000 at birth and 0.05 to 7.24 per blood culture represented contamination and not true EOS. This
1000 after considering each infant’s physical exam. Table 5 infant with a positive culture that grew E. faecalis was born at
42 weeks and 1 day gestation to a 20-year-old mother whose
contains management recommendations from the Neonatal EOS
maximum antepartum temperature was 100.6 with ROM of 20 h
calculator for the entire cohort, including routine care (49.5%),
and heavy meconium-stained amniotic fluid. EOS risk score was
serial vital signs (34.3%), surveillance blood culture (13.8%) and 0.77/1000 (0.08%) for this infant, who had an abnormally high WBC
empiric antibiotics (2.5%). Contrary to these recommendations, all count of 38 000 with a normal CRP and I:T ratio. E. faecalis is an
infants had a blood culture drawn, and three resulted positive opportunistic, nosocomial pathogen typically with high mortality
(0.8%). Two of the pathogens isolated were Actinomyces and antibiotic resistance associated with late-onset neonatal
odontolyticus and coagulase-negative Staphyloccus and were sepsis.41,42 It is also associated with EOS,16 with two studies
considered contaminants with therapy discontinued at 48 h of finding it in 8/125 (6.4%)43 and 2/51 (3.9%)38 episodes of newborn
life. One infant (0.3%), who remained asymptomatic throughout, culture-positive EOS, respectively, and another reporting it in 2/21
albeit on antibiotics, grew Enterococcus faecalis bacteremia and (9.5%) infants with EOS who remained asymptomatic at 72 h.44

© 2017 Nature America, Inc., part of Springer Nature. Journal of Perinatology (2017), 1 – 6
 Antibiotic use in infants with maternal chorioamnionitis
N Money et al
4
Table 4. Infant laboratory data

Normala Abnormala Normal vs abnormal rx448 h

antibiotic

Total Rx448 h Not rx448 h Total Rx448 h Not rx448 h P-value

antibiotics antibiotics antibiotics antibiotics

WBC 254 24 (9.4) 230 (90.6) 108 5 (4.6) 103 (95.4) NS

I:T 323 (89.2) 25 (7.7) 298 (92.3) 25 3 (12.0) 22 (88.0) NS
CRP 166 (45.9) 4 (2.4) 162 (97.6) 36 17 (47.2) 19 (52.8) o 0.001
Blood 359 (99.2) 20 (5.6) 339 (94.4) 3 1 (33.3) 2 (66.7) o 0.001
culture
Abbreviations: CRP, C-reactive protein; EOS, early-onset sepsis; I/T, immature/total neutrophils ratio; NS, nonsignificant; WBC, white blood cell. aOf the total
cohort, I:T ratio and CRP were not performed on 14(3.9%) and 160 (44.2%) of the cohort, respectively.

Table 5. Recommendation based on EOS score after examination
Recommendation Risk of EOS Frequency (%)
Routine management 0.0–0.42 per 1000 179 (49.4%)
Vitals Q4 hours 0.43–0.99 124 (34.3%)
per 1000
Blood culture and vitals Q4 hours 1–2.99 per 1000 50 (13.8%)
Empiric antibiotics ⩾3.0 per 1000 9 (2.5%)
Abbreviation: EOS, early-onset sepsis.
Asymptomatic culture-positive sepsis in neonates is well
documented with reports of culture-positive infants born to
mothers with CAM44 and ⩾ 35 weeks gestation38 to be without
symptoms in 22.2% and 23.5%, respectively. It is difficult to predict
if and when these infants, like the infant in our cohort, would have
become symptomatic had they not been receiving early empiric
treatment. More studies are needed to determine whether these
infants had true EOS or transient bacteremia.
Other than a single infant in our cohort who did not receive
antibiotics despite the diagnosis of CAM with fever the only
reported sign, all others had a blood culture drawn at birth
followed by antibiotic therapy. Complete blood count and CRP, in
contrast, were drawn at 6 to 12 h of life in most cases. While
ancillary lab data are limited in their ability to predict EOS, acute-
phase reactants such as CRP and procalcitonin have been studied
extensively45 and are better predictors of EOS than other common
lab values.2,46,47 Efforts are being made to identify a more
sensitive and specific marker. Some indicators that have been
recently studied are cord blood acute-phase reactants such as
CRP,48 serum amyloid A,49 serum apelin,50 immature/total
neutrophils ratio (I/T)2,51 and interleukin-27.52 Combinations of
these may be more sensitive and specific than any single
measure.53,54 Table 4 shows that providers at our institution were
significantly more likely to continue empiric treatment beyond
48 h with an abnormal CRP than with other abnormal lab values.
However, as CRP was not obtained in 44% of cases, we cannot rule
out selection bias in cases where it was obtained.
As the EOS calculator does not include ancillary lab data in
making management recommendations, the impact of abnormal
lab data on EOS risk and resultant management recommendations
is unknown. Kuzniewicz et al.37 suggest possibly creating a
composite likelihood ratio by multiplying likelihood ratios of EOS
based on parameters like abnormal WBC count as discussed by
Newman et al.55 by an infant’s EOS calculator-derived likelihood
ratio. Institutions implementing a protocol based on this calculator
would need to decide how abnormal laboratory values will affect
EOS management. Similarly, institutions would need to set
parameters of when to continue or discontinue antibiotics, as
this calculator is a tool for initial management only. Although the
AAP, the United Kingdom’s National Institute for Health Care and
Excellence and others have published recommendations for
initiating and continuing empiric antibiotic therapy,2,56,57 larger
prospective studies using the calculator to guide EOS manage-
ment are needed.38
Although there are no randomized controlled trials that specify
at what risk level the benefits of starting antibiotics exceed the risk
of delaying treatment,37 the authors of the EOS calculator have set
the risk cutoffs shown in Table 5 for when to initiate treatment
based on conservative number needed to treat values.37 Empiric
antibiotics were recommended for asymptomatic patients with
EOS risk scores 43/1000 (0.3%). In the setting of symptoms, the
calculator recommends antibiotic therapy for a higher percentage
of patients, regardless of risk factors. To enable providers to
choose a more conservative approach, the EOS calculator gives
the option of choosing a baseline incidence of sepsis between 0.3
and 0.6/1000 based on the EOS rate that is most consistent with
their institutional experience.
Limitations of our study include its retrospective nature and the
inherent subjectivity among obstetric providers—an observation
made in many studies—in diagnosing CAM. In addition, as fevers
are not frequently detected in the delivery room, many maternal
febrile episodes that would have led to a diagnosis of CAM may
have been missed and the actual highest maternal temperature
may have been higher than that which was recorded. Similarly, as
physical exams were only documented a few times per day, the
designation of infants as either symptomatic or not may have
differed if they had they been examined at a different time of the
day. Nonetheless, infants with true sepsis, if untreated usually
show clinical progression and persistence of symptoms.
Future investigations will require larger prospective, rando-
mized controlled trials evaluating the safety and efficacy of using
the Neonatal EOS calculator with or without addition of laboratory
data to guide initial EOS management for infants born to mothers
with CAM. Comparing infants managed according to the EOS
calculator and those managed by physical exam monitoring alone
would also be informative, especially when comparing infants
managed in the well-born nursery with those in a setting
optimized to monitor physical findings similar to our Observation
Nursery.
In conclusion, culture-positive EOS in well-appearing term
neonates born to mothers with CAM is a rare event. Application
of a protocol based on the EOS calculator would significantly
decrease antibiotic use in this population, which in the right
setting could be closely followed for timely identification of
symptomatic patients requiring more aggressive care.
CONFLICT OF INTEREST
The authors declare no conflict of interest.

Journal of Perinatology (2017), 1 – 6 © 2017 Nature America, Inc., part of Springer Nature.

ACKNOWLEDGEMENTS
This research was presented, in part, at Hot Topics in Neonatology conference in
Washington DC in 2016, the Eastern Society for Pediatric Research, Philadelphia, PA in
2017 and the Pediatric Academic Society Meeting, San Francisco, CA in 2017.
REFERENCES
1 Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases NCfIaRD, Centers for
Disease Control and Prevention (CDC). Prevention of perinatal group B strepto-
coccal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep 2010; 59
(RR-10): 1–36.
2 Polin RA. Newborn CoFa. Management of neonates with suspected or proven
early-onset bacterial sepsis. Pediatrics 2012; 129(5): 1006–1015.
3 Schulman J, Saiman L. Metrics for NICU antibiotic use: which rate is right? J
Perinatol 2011; 31(8): 511–513.
4 Schulman J, Dimand RJ, Lee HC, Duenas GV, Bennett MV, Gould JB. Neonatal
intensive care unit antibiotic use. Pediatrics 2015; 135(5): 826–833.
5 Mukhopadhyay S, Lieberman ES, Puopolo KM, Riley LE, Johnson LC. Effect of early-
onset sepsis evaluations on in-hospital breastfeeding practices among asymp-
tomatic term neonates. Hosp Pediatr 2015; 5(4): 203–210.
6 Soll RF, Edwards WH. Antibiotic use in neonatal intensive care. Pediatrics 2015;
135(5): 928–929.
7 Braun D, Bromberger P, Ho NJ, Getahun D. Low rate of perinatal sepsis in term
infants of mothers with chorioamnionitis. Am J Perinatol 2016; 33(2): 143–150.
8 Mukhopadhyay S, Taylor JA, Von Kohorn I, Flaherman V, Burgos AE, Phillipi CA
et al. Variation in sepsis evaluation across a national network of nurseries.
Pediatrics 2017; 139(3): e20162845.
9 Benitz WE, Wynn JL, Polin RA. Reappraisal of guidelines for management of
neonates with suspected early-onset sepsis. J Pediatr 2015; 166(4): 1070–1074.
10 Cantey JB, Patel SJ. Antimicrobial stewardship in the NICU. Infect Dis Clin N Am
2014; 28(2): 247–261.
11 Taylor JA, Opel DJ. Choriophobia: a 1-act play. Pediatrics 2012; 130(2): 342–346.
12 Polin RA, Watterberg K, Benitz W, Eichenwald E. The conundrum of early-
onset sepsis. Pediatrics 2014; 133(6): 1122–1123.
13 Kiser C, Nawab U, McKenna K, Aghai ZH. Role of guidelines on length of therapy in
chorioamnionitis and neonatal sepsis. Pediatrics 2014; 133(6): 992–998.
14 Shakib J, Buchi K, Smith E, Young PC. Management of newborns born to mothers
with chorioamnionitis: is it time for a kinder, gentler approach? Acad Pediatr 2015;
15(3): 340–344.
15 Higgins RD, Saade G, Polin RA, Grobman WA, Buhimschi IA, Watterberg K et al.
Evaluation and management of women and newborns with a maternal diagnosis
of chorioamnionitis: summary of a workshop. Obstet Gynecol 2016; 127(3):
426–436.
16 Mukhopadhyay S, Eichenwald EC, Puopolo KM. Neonatal early-onset sepsis eva-
luations among well-appearing infants: projected impact of changes in CDC GBS
guidelines. J Perinatol 2013; 33(3): 198–205.
17 Flidel-Rimon O, Galstyan S, Juster-Reicher A, Rozin I, Shinwell ES. Limitations of
the risk factor based approach in early neonatal sepsis evaluations. Acta Paediatr
2012; 101(12): e540–e544.
18 Buckler B, Bell J, Sams R, Cagle W, Bell SA, Allen C et al. Unnecessary workup of
asymptomatic neonates in the era of group B streptococcus prophylaxis. Infect Dis
Obstet Gynecol 2010; 2010: 369654.
19 Berardi A, Fornaciari S, Rossi C, Patianna V, Bacchi Reggiani ML, Ferrari F et al.
Safety of physical examination alone for managing well-appearing neonates
≥ 35 weeks' gestation at risk for early-onset sepsis. J Matern Fetal Neonatal Med
2015; 28(10): 1123–1127.
20 Duvoisin G, Fischer C, Maucort-Boulch D, Giannoni E. Reduction in the use of
diagnostic tests in infants with risk factors for early-onset neonatal sepsis does
not delay antibiotic treatment. Swiss Med Wkly 2014; 144: w13981.
21 Alm B, Erdes L, Möllborg P, Pettersson R, Norvenius SG, Aberg N et al. Neonatal
antibiotic treatment is a risk factor for early wheezing. Pediatrics 2008; 121(4):
697–702.
22 Azad MB, Bridgman SL, Becker AB, Kozyrskyj AL. Infant antibiotic exposure and
the development of childhood overweight and central adiposity. Int J Obes (Lond)
2014; 38(10): 1290–1298.
23 Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, DeRusso PA. Association of
antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014; 168(11):
1063–1069.
24 Murphy R, Stewart AW, Braithwaite I, Beasley R, Hancox RJ, Mitchell EA et al.
Antibiotic treatment during infancy and increased body mass index in boys: an
international cross-sectional study. Int J Obes (Lond) 2014; 38(8): 1115–1119.
25 Kronman MP, Zaoutis TE, Haynes K, Feng R, Coffin SE. Antibiotic exposure and IBD
development among children: a population-based cohort study. Pediatrics 2012;
130(4): e794–e803.
© 2017 Nature America, Inc., part of Springer Nature.
Antibiotic use in infants with maternal chorioamnionitis
N Money et al
5
26 Hviid A, Svanström H, Frisch M. Antibiotic use and inflammatory bowel diseases in
childhood. Gut 2011; 60(1): 49–54.
27 Rutten NB, Rijkers GT, Meijssen CB, Crijns CE, Oudshoorn JH, van der Ent CK et al.
Intestinal microbiota composition after antibiotic treatment in early life: the
INCA study. BMC Pediatr 2015; 15: 204.
28 Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn
intensive care unit and the risk of necrotizing enterocolitis. J Pediatr 2011; 159(3):
392–397.
29 Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical
antibiotic treatment is associated with adverse outcomes in premature infants. J
Pediatr 2011; 159(5): 720–725.
30 Mukhopadhyay S, Dukhovny D, Mao W, Eichenwald EC, Puopolo KM. 2010 peri-
natal GBS prevention guideline and resource utilization. Pediatrics 2014; 133(2):
196–203.
31 Malloy MH. Chorioamnionitis: epidemiology of newborn management and out-
come United States 2008. J Perinatol 2014; 34(8): 611–615.
32 Patel SJ, Saiman L. Principles and strategies of antimicrobial stewardship in the
neonatal intensive care unit. Semin Perinatol 2012; 36(6): 431–436.
33 Falciglia G, Hageman JR, Schreiber M, Alexander K. Antibiotic therapy and early
onset sepsis. NeoReviews 2012; 13(2): e86–e93.
34 Kaiser Permanente. Neonatal Early-Onset Sepsis Calculator, 2015. Available at:
https://neonatalsepsiscalculator.kaiserpermanente.org/ (last accessed 7 February
2017).
35 Escobar GJ, Puopolo KM, Wi S, Turk BJ, Kuzniewicz MW, Walsh EM et al. Stratifi-
cation of risk of early-onset sepsis in newborns ≥ 34 weeks' gestation. Pediatrics
2014; 133(1): 30–36.
36 Puopolo KM, Escobar GJ. Early-onset sepsis: a predictive model based on maternal
risk factors. Curr Opin Pediatr 2013; 25(2): 161–166.
37 Kuzniewicz MW, Walsh EM, Li S, Fischer A, Escobar GJ. Development and imple-
mentation of an early-onset sepsis calculator to guide antibiotic management in
late preterm and term neonates. Jt Comm J Qual Patient Saf 2016; 42(5):
232–239.
38 Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB et al. A
quantitative, risk-based approach to the management of neonatal early-
onset sepsis. JAMA Pediatr 2017; 171(4): 365–371.
39 Kerste M, Corver J, Sonnevelt MC, van Brakel M, van der Linden PD, M Braams-
Lisman BA et al. Application of sepsis calculator in newborns with suspected
infection. J Matern Fetal Neonatal Med 2016; 29(23): 3860–3865.
40 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic
data capture (REDCap)—a metadata-driven methodology and workflow process
for providing translational research informatics support. J Biomed Inform 2009; 42
(2): 377–381.
41 Cordero L, Sananes M, Ayers LW. Bloodstream infections in a neonatal intensive-
care unit: 12 years' experience with an antibiotic control program. Infect Control
Hosp Epidemiol 1999; 20(4): 242–246.
42 Kumar A, Kumar P, Basu S. Enterococcus fecalis sepsis and leukemoid reaction: an
unusual association at birth. J Pediatr Hematol Oncol 2015; 37(7): e419–e420.
43 Resch B, Renoldner B, Hofer N. Comparison between pathogen associated
laboratory and clinical parameters in early-onset sepsis of the newborn. Open
Microbiol J 2016; 10: 133–139.
44 Wortham JM, Hansen NI, Schrag SJ, Hale E, Van Meurs K, Sánchez PJ et al.
Chorioamnionitis and culture-confirmed, early-onset neonatal infections. Pedia-
trics 2016; 137(1): e20152323.
45 Vouloumanou EK, Plessa E, Karageorgopoulos DE, Mantadakis E, Falagas ME.
Serum procalcitonin as a diagnostic marker for neonatal sepsis: a systematic
review and meta-analysis. Intens Care Med 2011; 37(5): 747–762.
46 Christensen RD, Rothstein G, Hill HR, Hall RT. Fatal early onset group B
streptococcal sepsis with normal leukocyte counts. Pediatr Infect Dis 1985; 4(3):
242–245.
47 Benitz WE. Adjunct laboratory tests in the diagnosis of early-onset
neonatal sepsis. Clin Perinatol 2010; 37(2): 421–438.
48 Mithal LB, Palac HL, Yogev R, Ernst LM, Mestan KK. Cord blood acute phase
reactants predict early onset neonatal sepsis in preterm infants. PLoS ONE 2017;
12(1): e0168677.
49 Arnon S, Litmanovitz I, Regev RH, Bauer S, Shainkin-Kestenbaum R, Dolfin T.
Serum amyloid A: an early and accurate marker of neonatal early-onset sepsis. J
Perinatol 2007; 27(5): 297–302.
50 Gad GI, Ismail RI, El-Masry SA, Gouda HR. Serum apelin in early-onset neonatal
sepsis: is it diagnostic? J Neonatal Perinatal Med 2014; 7(3): 207–212.
51 Newman TB, Draper D, Puopolo KM, Wi S, Escobar GJ. Combining immature and
total neutrophil counts to predict early onset sepsis in term and late preterm
newborns: use of the I/T2. Pediatr Infect Dis J 2014; 33(8): 798–802.
52 He Y, Du WX, Jiang HY, Ai Q, Feng J, Liu Z et al. Multiplex cytokine profiling
identifies interleukin-27 as a novel biomarker for neonatal early onset sepsis.
Shock 2017; 47(2): 140–147.
Journal of Perinatology (2017), 1 – 6
 Antibiotic use in infants with maternal chorioamnionitis
N Money et al
6
53 Al-Zahrani AKh, Ghonaim MM, Hussein YM, Eed EM, Khalifa AS, Dorgham LS.
Evaluation of recent methods versus conventional methods for diagnosis of early-
onset neonatal sepsis. J Infect Dev Ctries 2015; 9(4): 388–393.
54 Franz AR, Bauer K, Schalk A, Garland SM, Bowman ED, Rex K et al. Measurement of
interleukin 8 in combination with C-reactive protein reduced unnecessary
antibiotic therapy in newborn infants: a multicenter, randomized, controlled trial.
Pediatrics 2004; 114(1): 1–8.
Journal of Perinatology (2017), 1 – 6
55 Newman TB, Puopolo KM, Wi S, Draper D, Escobar GJ. Interpreting complete
blood counts soon after birth in newborns at risk for sepsis. Pediatrics 2010; 126
(5): 903–909.
56 Antibiotics for Early-Onset Neonatal Infection. NICE Clinical Guideline. National
Institute for Health and Clinical Excellence: Manchester, UK, 2014, 149.
57 Cotten CM, Smith PB. Duration of empirical antibiotic therapy for infants
suspected of early-onset sepsis. Curr Opin Pediatr 2013; 25(2): 167–171.
© 2017 Nature America, Inc., part of Springer Nature.