Neonatal Early-Onset Sepsis: Epidemiology and RiskAssessmentSagori Mukhopadhyay,

MD, MMSc, Karen

M. Puopolo, MD, PhD

Author Disclosure

Drs Mukhopadhyay

and Puopolo have

disclosed no financial

relationships relevant

to this article. This

commentary does not

contain a discussion of

an unapproved/

investigative use of

a commercial product/

device.

Educational Gap

There is a need for increased understanding of methods of risk assessment for neonatal

early-onset sepsis.

AbstractNeonatal early-onset sepsis (EOS) continues to be a significant source of morbidityand mortality among newborns, especially among very low-birth-weight infants. Ep-idemiologic risk factors for EOS have been defined, and considerable resources are de-voted to the identification and evaluation of infants at risk for EOS. The widespreadimplementation of intrapartum antibiotic prophylaxis for the prevention of early-onsetneonatal group B streptococcal disease has reduced the overall incidence of neonatalEOS and influenced the microbiology of persistent early-onset infection. Recommen-dations for perinatal risk factor–based evaluation and empiric antibiotics treatment ofneonates result in a large proportion of uninfected infants undergoing medical inter-vention, including antibiotic therapy. Objective risk assessment tools have been devel-oped that may allow safe restriction of medical intervention in uninfected newborns,promote antibiotic stewardship, and optimize resource use.

Objectives After completing this article, readers should be able to:

1. Describe the incidence and pathogenesis of neonatal early-onset sepsis.

2. Understand the host, pathogen, and environmental mediators of neonatal early-onset

sepsis epidemiology.

3. Review the effect of group B Streptococcus prophylaxis policies on the epidemiology

of neonatal early-onset sepsis.

4. Understand the need for and methods of risk assessment in approaching neonatal

early-onset sepsis.

IntroductionBacterial sepsis and meningitis continue to be major causes of morbidity and mortality innewborns, particularly in very low-birth-weight (VLBW) infants (birth weight <1,500 g).(1)(2) Neonatal early-onset sepsis (EOS) is defined by the Centers for Disease Control andPrevention (CDC) as blood and/or cerebrospinal fluid culture–proven infection occurringin the newborn at less than 7 days of age. (3) For the continuously hospitalized VLBWinfant, EOS is defined as culture-proven infection occurring at less than 72 hours ofage. (2) The alternative definition in VLBW infants is justified by 2 findings: (1) the risksof infection in VLBW infants after age 72 hours primarily derive from the specifics of on-going neonatal intensive care rather than from perinatal risk factors, and (2) the organismsthat cause infection after age 72 hours among VLBW infants reflect the nosocomial flora ofthe neonatal intensive care unit (NICU) more than perinatally acquired maternal flora.

Epidemiology of Neonatal EOSThe overall incidence of EOS in the United States is estimated to be 0.77 case per 1,000live births (95% confidence interval, 0.72–0.84) by Weston et al (2) in a population-basedstudy using data from 2005 to 2008. A slightly higher rate of 0.98 per 1,000 live births

Children’s Hospital of Philadelphia Newborn Care at Pennsylvania Hospital, Philadelphia, PA.

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(range, 0.33–2.44 across centers) was reported by Stollet al (1) in a study of more than 390,000 live birth de-liveries between 2006 and 2009 at 16 university-basedneonatal centers in the United States that constitutedthe Neonatal Research Network (NRN). Incidence isstrongly influenced by gestational age at birth. Among in-fants born at 37 weeks’ gestation or more in 16 centers inCalifornia and Massachusetts, the incidence was only0.53 per 1,000 live births. (4) In contrast, among the pre-term population (<37 weeks’ gestation at birth), the in-cidence of EOS is approximately 7 times higher at 3.71per 1,000 live births and 20 times higher among theVLBW infants at 10.96 per 1,000 live births. (1)(2) Casefatality rates range from 11% to 16%, with more than 90%of the deaths occurring among the preterm population.These findings translate to approximately 3,300 new-borns affected and more than 340 deaths annually inthe United States. (1)(2)

Group B Streptococcus (GBS) emerged as the leadingcause of EOS in the 1970s and continues to remain soamong the term population, accounting for approximately40% of EOS cases. Its absolute national incidence, how-ever, has decreased substantially by 87% (1.8 cases per1,000 live births in 1990 to 0.24 case per 1,000 live birthsin 2013) with the widespread implementation of intrapar-tum antibiotic prophylaxis (IAP) for the prevention ofearly-onset GBS disease. (5)(6) Coincident with the in-creased use of IAP for GBS, gram-negative enteric bacteria(primarily Escherichia coli) have become the leading causeof EOS in preterm infants. (2)(7)(8) E coli accounts formore than 38% of EOS cases affecting preterm infants(Table 1). The remaining organisms causing EOS arelisted in Table 1; similar results are observed both withinNRN centers and at a single large maternity center. Mostof the organisms in Table 1 normally colonize thematernalgastrointestinal and genitourinary tract. The pathogenesisof EOS is that of ascending colonization of the fetalcompartment through ruptured and less frequently intactamniotic membranes. This can result in intra-amniotic in-fection or colonization of the infant during the process ofdelivery, leading to invasive infection soon thereafter. EOScaused by Listeria monocytogenes is a notable exception;Listeria EOS occurs via hematogenous spread of the or-ganism across the placenta (see below).

EOS Caused by GBSGBS frequently colonizes the human genital and gastroin-testinal tracts and the upper respiratory tract in young in-fants. GBS organisms are facultative diplococci that areprimarily identified by the Lancefield group B carbohy-drate antigen. They are further subtyped into 10 distinct

capsular polysaccharide serotypes (types Ia, Ib, and II–IX). Most GBS EOS in the United States is currentlycaused by types Ia, Ib, II, III, and V GBS. (3) Type IIIGBS is more commonly associated with late-onset sepsisand meningitis. Early-onset GBS infection is acquiredvia colonization of the infant in utero or during passagethrough the birth canal. Approximately 20% to 30% ofUS women are colonized with GBS at any given time, al-though a longitudinal study of GBS colonization in a co-hort of primarily young, sexually active women found thatnearly 60% of women are colonized with GBS at somepoint during a 12-month period. (9)(10) In the absenceof IAP, approximately 50% of infants born to mothers col-onized with GBS are colonized at birth, and 1% to 2% ofcolonized infants develop invasive GBS disease. (5) Lack ofmaternally derived, protective capsular, polysaccharide-specific antibody is associated with the development ofinvasive GBS disease. Other factors that predispose the new-born to GBS disease are less well understood, but relativedeficiencies in complement, neutrophil function, and innateimmunity may be important.

Clinical Factors Associated With GBS EOSA number of studies helped define maternal and neonatalfactors that are associated with an increased risk of GBSand bacterial all-cause EOS (Table 2). Benitz et al (11)performed a literature review and data reanalysis of stud-ies performed in the 1970s to the 1990s, demonstratingthat maternal GBS colonization alone was by far the great-est predictor of GBS-specific EOS. Because only a fewpregnant women are colonized with GBS, the recognitionof the importance of colonization alone provides the basisfor the current recommendation for use of IAP based onmaternal GBS colonization status. GBS bacteriuria duringpregnancy is associated with heavy colonization of the rec-tovaginal tract and is considered a significant risk factor forEOS. Black infants in the United States have a higher bur-den of GBS EOS that is not fully explained by colonizationrates among black women, suggesting there may be socio-economic mediators of EOS. The most recent CDC sur-veillance data indicate twice the incidence of neonatal GBSEOS among black infants compared with white infants. (6)Additional maternal clinical factors predictive of early-on-set GBS disease are listed in Table 2.

Evolution of Guidelines for IAP for thePrevention of Early-Onset GBS InfectionWith the recognition that maternal colonization with GBSwas the greatest risk factor for neonatal GBS disease, mul-tiple trials found that the use of intrapartum penicillin or

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ampicillin significantly reduces the rate of neonatal coloni-zation with GBS and the incidence of early-onset GBS dis-ease. The efficacy of IAP was most substantially revealed ina trial of only 160 women in 1986. (12) IAP for the pre-vention of GBS EOS can be administered to pregnantwomen during labor based on (1) specific clinical risk fac-tors for early-onset GBS infection or (2) the results ofantepartum screening of pregnant women for GBS coloni-zation. The CDC has published consensus guidelines thatendorsed the use of IAP for prevention of neonatal GBSdisease, first in 1996 and subsequently in revised formin 2002 and 2010 recommending universal GBS screeningamong pregnant women. (5)(13)(14) Risk factors to con-sider includematernal GBS colonization status determinedat 35 to 37 weeks’ gestation, documented GBS bacteriuriaduring pregnancy, prior delivery of an infant with GBS dis-ease, preterm labor, unknown GBS status combined withan intrapartum temperature of 100.4°F (38°C), or dura-tion of rupture of membranes of 18 hours or longer. Ad-equate IAP was defined as the administration of one of theendorsed antibiotics 4 or more hours before delivery. Themost current version also endorses intrapartum use of nu-cleic acid amplification tests (NAATs) as an acceptable

alternative if culture-based screening results are not available.The 2010 CDC statement also contains recommenda-tions for the evaluation of infants at risk for both GBS-specific and all-cause EOS. Evaluation of infants withclinical signs of sepsis and those born to mothers withchorioamnionitis is recommended. In a change from priorstatements, the latest version recommends evaluation ofinfants born in the setting of inadequately indicatedGBS IAP only with the additional risk factors of birth atless than 37 weeks’ gestation or duration of rupture ofmembranes of 18 hours or longer. The revised guidelinescan be accessed at http://www.cdc.gov/mmwr/pdf/rr/rr5910.pdf. With widespread implementation of the CDCrecommendations, the provisional national GBS-specificEOS incidence for 2013 is estimated at 0.24 per 1,000 livebirths (approximately 950 cases per year) with a persistentgap in the incidence among white population (0.21 per1,000 US live births) compared with the black population(0.44 per 1,000 US live births). (6)(14) Most GBS EOSamong term infants now occurs in mothers who havescreened negative for GBS colonization. (15)(16)(17)There is a low incidence (approximately 4%) of noncon-cordance between results of maternal GBS screening

Table 1. Organisms That Cause Neonatal Early-Onset Sepsis

Organism

No. (%) of Organisms

NICHD (n [ 370) BWH (n[335)

GBS 159 (43.0) 139 (41.5)Escherichia coli 107 (28.9) 71 (20.2)Other streptococcia 39 (10.5) 39 (11.6)Enterococcus 10 (2.7) 13 (3.9)Staphylococcus aureus 9 (2.4) 13 (3.8)Coagulase-negative Staphylococcus 3 (0.8) 14 (4.2)Listeria 2 (0.5) 2 (0.6)Bacteroides species 3 (0.8) 15 (4.5)Klebsiella 1 (0.3) 4 (1.2)Hemophili 11 (3.0) 6 (1.9)Other gram-negative organismsb 15 (4.1) 8 (2.6)Otherc 9 (2.4) 8 (2.4)Fungi 2 (0.5) 3 (0.9)Total gram positive 231 (62.4) 228 (68.1)Total gram negative 137 (37.0) 104 (31.0)

The BWH data are from all early-onset sepsis cases among infants born in a single center for the period 1990 to 2007. The NICHD data are from all early-onset sepsis cases among multiple centers from 2006 to 2009.BWH¼Brigham and Women’s Hospital; GBS¼group B Streptococcus; NICHD¼Eunice Kennedy Shriver National Institute of Child Health and HumanDevelopment.aOther streptococci include Streptococcus pneumoniae, Streptococcus bovis, Streptococcus mitis, Peptostreptococcus, group D Streptococcus, a-hemolyticstreptococcus, Streptococcus morbillorum, Streptococcus mutans, Streptococcus oralis, Streptococcus pneumoniae, Streptococcus salivarius, Streptococcus sanguinis,and viridans streptococci.bOther gram-negative organisms include Enterobacter, Citrobacter, Acinetobacter, Pseudomonas, Proteus, Brevundimonas vesicularis, Moraxella species,Capnocytophaga species, Morganella species, and Yersinia.cOther organisms include Bacillus, Actinomyces odontolyticus, gram positive not specified, and Clostridium.Adapted from Stoll et al (1) and Puopolo and Eichenwald (8).

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performed at 35 to 37 weeks’ gestation and repeat screen-ing on presentation for delivery at term, which may ac-count for many cases of persistent GBS EOS. (18) Useof NAATs for intrapartum GBS detection where availablemay facilitate identification among mothers with onset oflabor before 35 to 37 weeks’ gestation or with missed

screening results. The clinical efficacy and cost-effectivenessof an approach that uses NAATs at the time of presenta-tion for delivery to rescreen GBS-negative mothers remainto be determined. Ultimately, the development of effectiveGBS vaccines may be needed to eliminate GBS-specificEOS entirely.

Table 2. Risk Factors for Early-Onset Sepsis

Study Study Specifics Risk Factors Odds Ratio (95% CI)a

Benitz et al, 1999 Pre-IAP era

Maternal GBS colonization

204 (100–419)GBS early-onset sepsis onlyAll newborns

BW <1,000 g 24.8 (12.2–50.2)BW <2,500 g 7.37 (4.48–12.1)ROM >18 hours 7.28 (4.42–12.0)Chorioamnionitis 6.42 (2.32–17.8)Intrapartum fever >99.5˚F(>37.5˚C)

4.05 (2.17–7.56)

Escobar et al, 2000 Post-IAP era

Model 1: No IAP (N[ 1,568)

BW of ‡2,000 gN[2,785 infants, including62 cases

Temperature ‡101.5˚F (38.6˚C) 5.78 (1.57–21.29)ROM ‡12 hours 2.05 (1.06–3.96)Low ANC for age 2.82 (1.50–5.34)Infant asymptomatic 0.27 (0.11–0.65)Meconium in amniotic fluid 2.24 (1.19–4.22)Model 2: Received IAP (N [ 1,217)Fever ‡101.5˚C (38.6˚C) 3.50 (1.30–9.42)Low ANC for age 3.60 (1.45–8.96)Infant asymptomatic 0.42 (0.16–1.11)

Schrag et al, 2003 Post-IAP

Intrapartum fever

6.6 (3.3–13.2)Escherichia coli early-onsetsepsis only

All newbornsN[ 132 cases, 1,212 controls

PROM 3.5 (2.1–5.8)GA £33 weeks 26.5 (15.0–46.8)GA 34–36 weeks 5.3 (3.0–9.7)

Puopolo et al,b 2010 Post-IAP

GA (per day)

0.001 (0.0001–0.014)‡34 weeks’ gestationN[350 cases, 1,063 controls

GBS statusPositive 1.78 (1.11–2.85)Unknown 1.04 (0.76–1.44)

Duration of ROM (per hour) 3.41 (2.23–5.20)Highest intrapartum temperature(per degrees Celsius)

2.38 (2.05–2.77)

GBS IAP given on time or anyantibiotic given <4 hours

0.35 (0.23–0.53)

Broad-spectrum antibioticgiven >4 hours

0.31 (0.13–0.71)

ANC¼absolute neutrophil count; BW¼body weight; CI¼confidence interval; GA¼gestational age; GBS¼group B Streptococcus; IAP¼intrapartum antibioticprophylaxis; PROM¼premature rupture of membranes; ROM¼rupture of membranes.aBenitz et al reported unadjusted odds ratios, whereas the other 3 studies reported adjusted odds ratios.bModel also included a gestational age squared (adjusted odds ratio, 1.09; 95% CI, 1.05–1.13).

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Epidemiology of E coli EOSE coli is the second most common organism that causesEOS in all neonates and the single most common EOSorganism in VLBW infants. (1)(2) E coli are facultative,anaerobic, gram-negative rods found universally in thehuman intestinal tract and commonly in the human va-gina and urinary tract. There are hundreds of differentantigenic types of E coli, but EOS E coli infections, par-ticularly those complicated by meningitis, are primarilydue to strains with the K1-type polysaccharide capsule.With the implementation of IAP against GBS, concernhas been raised regarding increasing incidence of E coli–specific EOS and particularly ampicillin-resistant EOS.Multiple single-center and multicenter studies have pro-duced conflicting results. One analysis of 23 reports ofEOS in the era of GBS prophylaxis concluded that thereis no evidence of an increase in the absolute incidence ofnon-GBS EOS among term infants. (19) Data from theEunice Kennedy Shriver National Institute of ChildHealth and Human Development NRN indicate an over-all decrease in the incidence of EOS among VLBW in-fants (from 19.3 per 1,000 VLBW births in 1991–1993to 11.0 per 1,000 VLBW births in 2006–2009). (1)(7)(20)However, an absolute increase in the incidence ofE coli–specific EOS has been documented since 1991to 1993. An increase in non-GBS EOS in VLBW infantshas also been reported by single centers. (21) In addition,with a decrease in GBS-specific EOS among VLBW in-fants, an increasing proportion of VLBW EOS is due toE coli, much of which is ampicillin-resistant E coli. In con-trast, absolute increases in E coli and/or ampicillin-resistantEOS among term infants have not been found in case-control studies conducted by the CDC or in a single-center study analyzing EOS during an 18-year periodin a large birth center in Boston. (8)(22) Clinicians caringfor both premature and term infants must be aware, how-ever, that with decreases in GBS-specific EOS, a signifi-cant proportion of any EOS that occurs will be due to anampicillin-resistant gram-negative organism. In clinical sit-uations where a critically ill infant has a high likelihood ofEOS, empiric antibiotic coverage for ampicillin-resistantgram-negative organisms is warranted until blood cultureresults are known.

Other Organisms Responsible for EOSIn addition to GBS and E coli, there are a number ofpathogens that cause EOS in the United States that de-serve special note. L monocytogenes are gram-positive,b-hemolytic, motile bacteria that most commonly infecthumans via the ingestion of contaminated food. An asso-ciation with prepared foods held at moderate temperature

(particularly cheeses and deli meats) has been docu-mented, occasionally in epidemic outbreaks. These bacte-ria do not cause significant disease in immunocompetentadults but can cause severe illness in pregnant womenand their fetuses and in newborns. The true incidence oflisteriosis in pregnancy is difficult to determine becausemany cases are undiagnosed when they result in spontane-ous abortion of the previable fetus. Obligate anaerobicbacteria (primarily the encapsulated enteric organism Bac-teroides fragilis) can cause neonatal EOS and justify the useof both aerobic and anaerobic blood culture bottles in theevaluation of EOS. Although methicillin-sensitive Staphy-lococcus aureus and methicillin-resistant S aureus causea large proportion of hospital-acquired infection in VLBWinfants and are increasing issues in community-acquiredpediatric infections, these remain rare causes of neonatalEOS. A recent study of 5,732 pregnant women docu-mented a 3.5% incidence of MRSA in GBS rectovaginalscreening cultures but found no cases of MRSA neonatalEOS in delivered infants. (23) Finally, fungal organisms(primarily Candida species) rarely cause neonatal EOS.Fungal EOS is largely found in preterm and VLBW infants,often associated with very prolonged antibiotic (>24 hours)exposure of pregnant mothers before delivery.

Approaching the Risk of EOSThe goal of clinical risk assessment in EOS is to use find-ings from validated research studies to identify high-risknewborns and subsequently prevent the onset and/orprogression of the disease. Current approaches use algo-rithms to identify the highest-risk infants, followed bymedical examination and diagnostic evaluations, withor without administration of empiric antibiotics pendinglaboratory tests (or clinical status). Recommendations arepublished by the CDC and the American Academy of Pe-diatrics for term and preterm infants to evaluate risk ofEOS. (14)(24)(25) Although some minor details differ,the principles include consideration of the following:

1. Perinatal risk factors. These risk factors participate indisease pathogenesis or susceptibility (eg, maternalGBS colonization, prolonged duration of membranerupture, maternal fever, and gestational age) (Table 2).

2. Clinical status of the newborn. A total of 60% to 90%of EOS cases, depending on the population studied,will become symptomatic in the first 24 to 48 hours.(26)(27) Asymptomatic status is associated with de-creased risk. (26)(28)

3. Laboratory results. The most commonly used labora-tory diagnostics are complete blood cell count (withcomponents of the white blood cell differential),

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C-reactive protein, and blood cultures. A variety of bio-markers are subject to investigation (eg, CD64 or pro-calcitonin) but are either not clinically available or notvalidated in EOS. The components of the completeblood cell count and C-reactive protein perform rela-tively poorly when used as single values to assess EOSrisk; the low incidence of EOS among term infantsmeans there is little value in their positive and negativepredictive values. A full discussion of the use of labo-ratory results to predict EOS is beyond the scope ofthis review.

Both the CDC and the American Academy of Pediat-rics advocate evaluation of infants who are born withsigns of illness, well-appearing infants born in the settingof maternal chorioamnionitis (with maternal intrapartumfever often used as a surrogate for that condition), andinfants born to women who received inadequately indi-cated GBS IAP, with consideration given to gestationalage at birth and duration of rupture of membranes.(14)(24)(25) Individual care centers often implementthese recommendations with local variation in practice.We recently surveyed EOS risk assessment practicesamong 23 NICUs in Massachusetts. Three-quarters ofthe surveyed units had local written protocols for EOSevaluation of term and late preterm infants. Most werealigned with the CDC 2010 recommendations, (14) ap-proximately 10% were aligned with the American Acad-emy of Pediatrics recommendations, (24)(25) and onecenter still adhered to the CDC 2002 recommendations.(13) Significant variation was reported with respect tochorioamnionitis as a risk factor and in the use of labora-tory tests for EOS evaluation.

Unintended Consequences of CurrentEvaluation ApproachThe low incidence of EOS in United States, particularlyamong term and late preterm infants, leads to a relativelyhigh incidence of evaluation and empiric antibiotic treat-ment of uninfected newborns. We have studied the effectof implementing the CDC 2010 recommendations ata large perinatal center in Massachusetts. (29) We foundthat approximately 7% of the lowest-risk group (asymp-tomatic term and near-term newborns) was evaluatedfor EOS, and 75% of those evaluated received broad-spectrum empiric antibiotics. During a 12-month period,these evaluations had significant economic costs and usedhundreds of hours of specialized care. In a separate studythat examined breastfeeding practices among term, well-appearing infants undergoing EOS evaluation, we foundthat infants separated from their mothers for the

evaluation within 2 hours of birth were more likely tohave delayed breastfeeding initiation and increased for-mula supplementation. (30) Studies have also found as-sociations between antibiotic exposure in the newbornperiod and subsequent risk of necrotizing enterocolitisin VLBW infants and wheezing in the general population.(31)(32)

Risk Stratification Using Bayesian ModelingThe low absolute risk of EOS and the effect of currentevaluation algorithms suggest a need to improve the ef-ficiency of EOS risk assessment. Standard approaches toEOS risk assessment use individual risk factors in isolationand usually in dichotomized form. Such algorithms donot account for interactions between risk factors and im-pose cut-off points that can result in loss of information.For example, determining EOS risk due to rupture ofmembranes by dichotomizing the infant as being ornot being at risk suggests a sudden change of risk at pre-cisely 18 hours, when in reality risk due to rupture ofmembranes is more likely to change in a graded fashion.Puopolo et al (4) developed a multivariate model thatuses established EOS risk factors in a multivariate mannerto quantitatively determine risk among infants born at 34weeks’ gestation or greater. These investigators took aBayesian approach, starting with the prior probabilityof EOS in the population. This probability is modified us-ing objective data from intrapartum risk factors for EOSand then subsequently modified by the newborn’s clinicalcondition to establish a final posterior probability of in-fection. The model was developed using a nested case-control design, with 350 EOS cases and 1,063 controlsobtained from a birth cohort of more than 600,000 livebirths in 14 different centers. The intrapartum risk model(the maternal prior probability) uses gestational age, du-ration of rupture of membranes, and highest maternal in-trapartum temperature as continuous variables and GBSstatus and type and timing of intrapartum antibiotics ascategorical variables. Using split validation, the investiga-tors found that use of this maternal prior probabilityalone would reduce unnecessary evaluations by 60%.Newborn examination results and vital signs at 6, 12,and 24 hours after birth were used to classify infants intocategories of clinical illness, equivocal appearance, andwell-appearing. (24) The likelihood ratios from the new-born examination were combined with the multivariaterisk predictions to generate a final predicted posteriorprobability of infection. A proposed management path-way for EOS risk using this objective approach is shownin the Figure. The number needed to treat refers to thenumber of infants needed to be evaluated to identify each

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EOS case. User-friendly versions of this combined modelcan be found at http://www.dor.kaiser.org/external/DORExternal/research/InfectionProbabilityCalculator.aspx and www.newbornsepsiscalculator.org. The use ofthis type of objective, multivariate approach is estimatedto safely reduce the number of infants evaluated and em-pirically treated for EOS by 80,000 to 240,000 infantsper year. (24)

References1. Stoll BJ, Hansen NI, Sánchez PJ, et al; Eunice Kennedy ShriverNational Institute of Child Health and Human Development NeonatalResearch Network. Early onset neonatal sepsis: the burden of group B strep-tococcal and E. coli disease continues. Pediatrics. 2011;127(5):817–8262. Weston EJ, Pondo T, Lewis MM, et al. The burden of invasiveearly-onset neonatal sepsis in the United States, 2005-2008.Pediatr Infect Dis J. 2011;30(11):937–9413. Phares CR, Lynfield R, Farley MM, et al; Active Bacterial Coresurveillance/Emerging Infections Program Network. Epidemiol-ogy of invasive group B streptococcal disease in the United States,1999-2005. JAMA. 2008;299(17):2056–20654. Puopolo KM, Draper D, Wi S, et al. Estimating the probabilityof neonatal early-onset infection on the basis of maternal riskfactors. Pediatrics. 2011;128(5):e1155–e11635. Centers for Disease Control and Prevention. Prevention ofperinatal group B streptococcal disease: a public health perspective.MMWR Recomm Rep. 1996;45(RR-7):1–246. Centers for Disease Control and Prevention. Active bacterial coresurveillance report, emerging infections program network, group B strep-tococcus, 2013 [Internet]. Updated 2013. http://www.cdc.gov/abcs/reports-findings/survreports/gbs13.pdf. Accessed September 18, 20147. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogenscausing early-onset sepsis in very-low-birth-weight infants.N Engl JMed. 2002;347(4):240–247

Figure. Quantitative risk stratification for early-onset sepsis. A quantitative risk stratification scheme is shown for infants bornat 34 weeks’ gestation or more. Stratification is based on newborn clinical condition during the first 12 hours after birth and thesepsis risk at birth estimated from maternal/intrapartum risk factors. Infants who have a sepsis risk at birth of 1.54 per 1,000 livebirths or more or who have a sepsis risk at birth of 0.65 or more per 1,000 live births and an equivocal presentation fall into thetreat empirically group, which has a number needed to treat (NNT) of 118 and accounts for 4% of all live births. Infants with anequivocal presentation or who are well-appearing but whose sepsis risk at birth is 0.65 to 1.54 per 1,000 fall into the observeand evaluate group; these groups together have an NNT of 823 and account for 11% of all live births. The largest group, well-appearing infants with a sepsis risk at birth of less than 0.65 per 1,000, has an NNT of 9,370 and accounts for 85% of all livebirths. Adapted from Escobar et al. (24)

American Board of Pediatrics Neonatal–PerinatalContent Specifications

• Know the clinical manifestations,laboratory features, and differentialdiagnosis of neonatal sepsis.

• Know the infectious agents that causeneonatal sepsis.

• Know the maternal, perinatal, andneonatal risk factors for neonatal sepsis.

• Know the epidemiology, prevention, and pathogenesis ofperinatal/neonatal group B streptococcal infections.

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8. Puopolo KM, Eichenwald EC. No change in the incidence ofampicillin-resistant, neonatal, early-onset sepsis over 18 years.Pediatrics. 2010;125(5):e1031–e10389. Campbell JR, Hillier SL, Krohn MA, Ferrieri P, Zaleznik DF,Baker CJ. Group B streptococcal colonization and serotype-specificimmunity in pregnant women at delivery. Obstet Gynecol. 2000;96(4):498–50310. Meyn LA, Moore DM, Hillier SL, Krohn MA. Association ofsexual activity with colonization and vaginal acquisition of group BStreptococcus in nonpregnant women. Am J Epidemiol. 2002;155(10):949–95711. Benitz WE, Gould JB, Druzin ML. Risk factors for early-onsetgroup B streptococcal sepsis: estimation of odds ratios by criticalliterature review. Pediatrics. 1999;103(6):e7712. Boyer KM, Gotoff SP. Prevention of early-onset neonatalgroup B streptococcal disease with selective intrapartum chemo-prophylaxis. N Engl J Med. 1986;314(26):1665–166913. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention ofperinatal group B streptococcal disease: revised guidelines fromCDC. MMWR Recomm Rep. 2002;51(RR-11):1–2214. Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases,National Center for Immunization and Respiratory Diseases,Centers for Disease Control and Prevention (CDC). Preventionof perinatal group B streptococcal disease—revised guidelines fromCDC, 2010. MMWR Recomm Rep. 2010;59(RR-10):1–3615. Van Dyke MK, Phares CR, Lynfield R, et al. Evaluation ofuniversal antenatal screening for group B streptococcus. N Engl JMed. 2009;360(25):2626–263616. Puopolo KM, Madoff LC, Eichenwald EC. Early-onset groupB streptococcal disease in the era of maternal screening. Pediatrics.2005;115(5):1240–124617. Puopolo KM, Madoff LC. Type IV neonatal early-onset groupB streptococcal disease in a United States hospital. J Clin Microbiol.2007;45(4):1360–136218. Yancey MK, Schuchat A, Brown LK, Ventura VL, MarkensonGR. The accuracy of late antenatal screening cultures in predictinggenital group B streptococcal colonization at delivery. ObstetGynecol. 1996;88(5):811–81519. Moore MR, Schrag SJ, Schuchat A. Effects of intrapartumantimicrobial prophylaxis for prevention of group-B-streptococcaldisease on the incidence and ecology of early-onset neonatal sepsis.Lancet Infect Dis. 2003;3(4):201–21320. Stoll BJ, Hansen NI, Higgins RD, et al; National Institute ofChild Health and Human Development. Very low birth weightpreterm infants with early onset neonatal sepsis: the predominance

of gram-negative infections continues in the National Institute ofChild Health and Human Development Neonatal Research Net-work, 2002–2003. Pediatr Infect Dis J. 2005;24(7):635–63921. Bizzarro MJ, Dembry LM, Baltimore RS, Gallagher PG.Changing patterns in neonatal Escherichia coli sepsis and ampicillinresistance in the era of intrapartum antibiotic prophylaxis. Pediat-rics. 2008;121(4):689–69622. Schrag SJ, Hadler JL, Arnold KE, Martell-Cleary P, ReingoldA, Schuchat A. Risk factors for invasive, early-onset Escherichia coliinfections in the era of widespread intrapartum antibiotic use.Pediatrics. 2006;118(2):570–57623. Andrews WW, Schelonka R, Waites K, Stamm A, Cliver SP,Moser S. Genital tract methicillin-resistant Staphylococcus aureus: riskof vertical transmission in pregnant women. Obstet Gynecol. 2008;111(1):113–11824. Polin RA; Committee on Fetus and Newborn. Management ofneonates with suspected or proven early-onset bacterial sepsis.Pediatrics. 2012;129(5):1006–101525. Brady MT, Polin RA. Prevention and management of infants withsuspected or proven neonatal sepsis. Pediatrics. 2013;132(1):166–16826. Escobar GJ, Puopolo KM, Wi S, et al. Stratification of risk ofearly-onset sepsis in newborns ‡ 34 weeks’ gestation. Pediatrics.2014;133(1):30–3627. Cantoni L, Ronfani L, Da Riol R, Demarini S; Perinatal StudyGroup of the Region Friuli-Venezia Giulia. Physical examinationinstead of laboratory tests for most infants born to motherscolonized with group B Streptococcus: support for the Centers forDisease Control and Prevention’s 2010 recommendations. JPediatr. 2013;163(2):568–57328. Escobar GJ, Li DK, Armstrong MA, et al. Neonatal sepsisworkups in infants >/¼2000 grams at birth: A population-basedstudy. Pediatrics. 2000;106(2, pt 1):256–26329. Mukhopadhyay S, Dukhovny D, Mao W, Eichenwald EC,Puopolo KM. 2010 perinatal GBS prevention guideline andresource utilization. Pediatrics. 2014;133(2):196–20330. Mukhopadhyay S, Lieberman ES, Puopolo KM, et al. Effect ofearly-onset sepsis evaluations on breastfeeding among asymptom-atic term neonates. Hosp Pediatr. In press31. Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposurein the newborn intensive care unit and the risk of necrotizingenterocolitis. J Pediatr. 2011;159(3):392–39732. Goksör E, Alm B, Thengilsdottir H, Pettersson R, Åberg N,Wennergren G. Preschool wheeze - impact of early fish introduc-tion and neonatal antibiotics. Acta Paediatr. 2011;100(12):1561–1566

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1. A 4-day-old infant who was born at 24 weeks’ gestational age with a birth weight of 600 g is noted to havea positive blood culture result. The culture was obtained at age 48 hours. Which of the following regarding thetiming of infection and definitions of sepsis in newborns is correct?

A. If this patient is diagnosed as having sepsis, it would be correctly categorized as early-onset sepsis.B. For infants with birth weight greater than 1,500 g, culture-proven infection occurring before 48 hours is

considered as early-onset sepsis and after 48 hours as late-onset sepsis.C. The risk of infection in very low-birth-weight infants after 72 hours up to age 1 week derives primarily

from prenatal and maternal risk factors.D. The organisms found in blood cultures of very low-birth-weight infants at this age (48 hours) are more

likely to reflect the nosocomial flora of the neonatal intensive care unit (NICU) than positive cultureobtained later in hospitalization.

E. The incidence of early-onset sepsis for very low-birth-weight infants in the United States is 10 per 1,000live births in recent years.

2. A term newborn infant has respiratory distress soon after birth and is admitted to the NICU. Blood culture isobtained, and antibiotics are administered in case the patient has sepsis. Which of the following is trueregarding the microorganisms that cause neonatal sepsis?

A. With increasing colonization in the general population, the incidence of early-onset sepsis caused by groupB Streptococcus (GBS) has increased steadily during the past 4 decades.

B. Intrapartum antibiotic prophylaxis has reduced the severity of GBS early-onset sepsis in newborns but hasnot had any effect on its incidence.

C. Early-onset sepsis caused by gram-negative enteric bacteria is found in term infants but not in preterminfants.

D. The pathogenesis of early-onset sepsis involves ascending colonization of the fetal compartment throughruptured and less frequently intact amniotic membranes.

E. Clostridium difficile is the most common cause of early-onset sepsis in both term and preterm infants.

3. The patient’s blood culture yields GBS. Which of the following statements concerning GBS is correct?

A. GBS is always a pathogenic organism and is found only in humans during pregnancy complicated bychorioamnionitis or in newborns after intrapartum infection.

B. Most early-onset sepsis caused by GBS in the United States is currently caused by capsular polysaccharideserotypes Ia, Ib, II, III, and V.

C. Early-onset sepsis associated with GBS is most often caused by transmission through breastfeeding duringthe first 24 hours after birth.

D. Maternal GBS colonization has no effect on the development of GBS sepsis in newborns.E. Current recommendations from the Centers for Disease Control and Prevention (CDC) do not suggest any

benefit of routine testing for GBS or a benefit of prophylactic intrapartum antibiotics for prevention ofGBS sepsis.

4. A male infant is born at 26 weeks’ gestational age after spontaneous preterm labor. A blood culture is obtainedin the NICU soon after admission and later yields Escherichia coli. Which of the following is correct regardingearly-onset sepsis in very low-birth-weight infants?

A. E coli is currently the most common organism causing early-onset sepsis in very low-birth-weight infants.B. All large epidemiologic studies have found that increased use of intrapartum prophylactic antibiotics leads

to an absolute decrease in E coli–specific early-onset sepsis and a decreased proportion of sepsis caused byE coli for very low-birth-weight infants.

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C. Methicillin-resistant Staphylococcus aureus is strongly associated with early-onset sepsis in very low-birth-weight infants when mothers have recently ingested contaminated foods, such as soft cheeses anddeli meats.

D. Because the likelihood of anaerobic bacteria causing neonatal early-onset sepsis is exceedingly low, onlyaerobic blood cultures are warranted.

E. Since the introduction of intrapartum antibiotic prophylaxis, more than 50% of neonatal early-onsetsepsis by S aureus is methicillin resistant.

5. Your maternal child unit is developing guidelines for risk assessment and practice surrounding neonatal early-onset sepsis. Which of the following statements concerning risk assessment for early-onset sepsis is correct?

A. Because of conflicting studies, the CDC and the American Academy of Pediatrics have both declined tomake overarching recommendations surrounding this issue.

B. Because clinical status can often be misleading, infant symptoms should not be included in risk assessmentstrategies.

C. Single components of the complete blood cell count or C-reactive protein level can perform very well aspredictors of early-onset sepsis, and it is up to each unit to determine which component to use as its maintest for risk assessment.

D. Use of a multivariable model that takes into account prior probability of sepsis based on multiple variables,including maternal factors, can help to reduce the number of infants evaluated and empirically treated forearly-onset sepsis.

E. The most pragmatic approach that leads to highest sensitivity and specificity for diagnosis of early-onsetsepsis is to evaluate and treat all infants whose mother had more than 18 hours of ruptured membranes.

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DOI: 10.1542/neo.16-4-e2212015;16;e221NeoReviews 

Sagori Mukhopadhyay and Karen M. PuopoloNeonatal Early-Onset Sepsis: Epidemiology and Risk Assessment

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DOI: 10.1542/neo.16-4-e2212015;16;e221NeoReviews 

Sagori Mukhopadhyay and Karen M. PuopoloNeonatal Early-Onset Sepsis: Epidemiology and Risk Assessment

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