Professional Documents
Culture Documents
Karen M. Puopolo
NeoReviews 2008;9;e571-e579
DOI: 10.1542/neo.9-12-e571
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Online ISSN: 1526-9906.
Epidemiology of Neonatal
Early-onset Sepsis
Karen M. Puopolo, MD,
Objectives After completing this article, readers should be able to:
PhD*
1. Describe the incidence and microbiology of neonatal early-onset sepsis (EOS).
2. Identify clinical risk factors for neonatal EOS.
Author Disclosure 3. Review the impact of group B streptococcal prophylaxis policies on the epidemiology
Dr Puopolo has of neonatal EOS.
disclosed no financial 4. Delineate the differences in incidence, risk, and microbiology of neonatal EOS between
relationships relevant term and very low-birthweight infants.
to this article. This
commentary does not
contain a discussion
Abstract
Neonatal early-onset sepsis (EOS) continues to be a significant source of morbidity
of an unapproved/
and mortality among newborns, especially among very-low birthweight infants.
investigative use of a Epidemiologic risk factors for EOS have been defined, and considerable resources are
commercial product/ devoted to the identification and evaluation of infants at risk for EOS. The widespread
device. implementation of intrapartum antibiotic prophylaxis for the prevention of early-
onset neonatal group B Streptococcus (GBS) disease has reduced the overall incidence
of neonatal EOS and influenced the microbiology of persistent early-onset infection.
Most early-onset neonatal GBS disease now occurs in preterm infants or in term
infants born to mothers who have negative GBS screening cultures. Ongoing clinical
challenges include reassessment of clinical risk factors for EOS in the era of GBS
prophylaxis; more accurate identification of GBS-colonized women; and continued
surveillance of the impact of GBS prophylaxis practices on the microbiology of EOS,
particularly among very low-birthweight infants.
Introduction
Bacterial sepsis and meningitis continue to be major causes of morbidity and mortality in
newborns, particularly in very-low birthweight (VLBW) infants (birthweight 1,500 g).
Neonatal early-onset sepsis (EOS) is defined by the Centers for Disease Control and
Prevention (CDC) as blood or cerebrospinal fluid culture-
proven infection occurring in the newborn who is younger
than 7 days of age. (1) For the continuously hospitalized
Abbreviations VLBW infant, EOS is defined as culture-proven infection
BWH: Brigham and Womens Hospital occurring at fewer than 72 hours of age. (2) The alternative
CDC: Centers for Disease Control and Prevention definition in VLBW infants is justified by two findings:
EOS: early-onset sepsis 1) the risks for infection in VLBW infants after 72 hours of
GBS: group B Streptococcus age primarily derive from the specifics of ongoing neonatal
IAP: intrapartum antibiotic prophylaxis intensive care rather than from perinatal risk factors, and
MRSA: methicillin-resistant Staphylococcus aureus 2) the organisms causing infection after 72 hours of age
NICHD: National Institute of Child Health and among VLBW infants reflect the nosocomial flora of the
Development neonatal intensive care unit (NICU) more than perinatally
NICU: neonatal intensive care unit acquired maternal flora. (2)
PCR: polymerase chain reaction The overall incidence of EOS in the United States in the
VLBW: very low birthweight past 10 years is 1 to 2 cases per 1,000 live births; the
incidence is 10-fold higher in VLBW infants. (3)(4) Since
*Assistant Professor of Pediatrics, Harvard Medical School; Attending Physician, Channing Laboratory and Department of
Newborn Medicine, Brigham and Womens Hospital and Division of Newborn Medicine, Childrens Hospital, Boston.
multiple gestation now is not considered an independent ampicillin for IAP. In those who have penicillin allergy,
risk factor for EOS. (10) GBS bacteriuria during preg- testing of GBS screening isolates for antibiotic suscepti-
nancy is associated with heavy colonization of the recto- bility is recommended to guide the choice of antibiotic
vaginal tract and is considered a significant risk factor for (erythromycin, clindamycin, cefazolin, or vancomycin)
EOS. Black race is associated with higher rates of GBS for IAP. Adequate IAP is defined as the administration
EOS, although it is not entirely clear whether this simply of one of the endorsed antibiotics 4 or more hours prior
reflects the higher rate of GBS colonization in this pop- to delivery. The revised CDC guideline also includes a
ulation. The most recent CDC surveillance data demon- recommended algorithm for the evaluation of infants
strate a fourfold increased incidence of neonatal GBS born to mothers exposed to IAP.
EOS among black infants compared with white infants.
(1) Current Status of GBS EOS
CDC active surveillance data for the United States from
IAP for the Prevention of Early-onset 1999 to 2005 demonstrate that the incidence of GBS
GBS infection EOS has fallen to 0.34 cases per 1,000 live births in
After recognizing that maternal colonization with GBS 2003 to 2005 (compared with 1.7 cases per 1,000 live
was the greatest risk factor for neonatal GBS disease, births in 1993). (1) We recently evaluated the reasons for
multiple trials demonstrated that the use of intrapartum persistent GBS EOS despite the use of a screening-based
penicillin or ampicillin significantly reduced the rate of approach to IAP at the BWH. (14)(15) We found that
neonatal colonization with GBS and the incidence of most GBS EOS in term infants now occurs in infants
early-onset GBS disease. The ability to prevent neonatal born to women who have negative antepartum screening
GBS colonization and neonatal EOS was demonstrated results for GBS colonization. Many of the mothers in this
most dramatically in a trial of only 160 women in 1986. study had other intrapartum risk factors for sepsis, un-
(11) IAP for the prevention of GBS EOS can be admin- derscoring the importance of continued evaluation of
istered to pregnant women during labor based on specific infants at risk for EOS in the era of GBS prophylaxis.
clinical risk factors for early-onset GBS infection or the There is a low incidence (approximately 4%) of noncon-
results of antepartum screening of pregnant women for cordance between results of maternal GBS screening
GBS colonization. In 1996, the CDC published consen- performed at 35 to 37 weeks gestation and repeat
sus guidelines for the prevention of neonatal GBS disease screening on presentation for delivery at term, (16)
that endorsed the use of either a risk factor-based or which may account for many cases of persistent GBS
screening-based approach. (10) The CDC later con- EOS.
ducted a large retrospective cohort study of more than Bacterial culture remains the CDC-recommended
600,000 births that demonstrated the superiority of the standard for detection of maternal GBS colonization. In
screening-based approach for the prevention of neonatal 2002, the United States Food and Drug Administration
GBS disease. (12) Based on these results, the CDC issued approved the first polymerase chain reaction (PCR)-
revised guidelines for the prevention of early-onset GBS based rapid diagnostic test for use in detection of mater-
disease in 2002, recommending universal screening of nal GBS colonization. The test can be completed in
pregnant women for GBS by rectovaginal culture at 1 hour and potentially allows for screening of pregnant
35 to 37 weeks gestation and management of IAP based women on presentation for delivery. (17) Although this
on screening results. (13) The revised guidelines can be type of testing could address the risk of antenatal false-
accessed at http://www.cdc.gov/mmwr/preview/ negative GBS screens, the costs and technicalities of
mmwrhtml/rr5111a1.htm or in PDF form at http:// providing continuous support for a real-time PCR-based
www.cdc.gov/mmwr/PDF/rr/rr5111.pdf. diagnostic are considerable, and most obstetric services
The CDC guideline includes specific recommenda- continue to rely on antenatal screening culture alone.
tions for pregnant women who have documented GBS
bacteriuria or who previously delivered infants who had EOS Caused by E coli
GBS disease and for the use of IAP in women experienc- E coli is the second most common organism isolated in
ing threatened preterm labor. The revised guidelines also EOS in all neonates and the single most common EOS
address concerns over the documented emergence of organism in VLBW infants. (3)(6) E coli are facultative
GBS resistance to erythromycin and clindamycin, antibi- anaerobic gram-negative rods found universally in the
otics frequently used for IAP in women allergic to peni- human intestinal tract and commonly in the human
cillin. The CDC continues to recommend penicillin or vagina and urinary tract. There are hundreds of different
antigenic types of E coli, but EOS E coli infections, hemolytic, motile bacteria that most commonly infect
particularly those complicated by meningitis, are primar- humans via the ingestion of contaminated food. An
ily due to strains that have the K1-type polysaccharide association with prepared foods held at moderate tem-
capsule. With the implementation of IAP against GBS, perature (particularly cheeses and deli meats) has been
an increasing proportion of EOS cases are caused by documented, occasionally in epidemic outbreaks. These
gram-negative organisms. (4) Whether GBS IAP policies bacteria do not cause significant disease in immunocom-
are contributing to an absolute increase in the incidence petent adults but can cause severe illness in the immuno-
of EOS caused by gram-negative organisms, particularly compromised (ie, renal transplant patients), in pregnant
ampicillin-resistant gram-negative organisms, is contro- women and their fetuses, and in newborns. The true
versial. incidence of listeriosis in pregnancy is difficult to deter-
In 2003, the CDC published a review of 23 reports of mine because many cases are undiagnosed when they
EOS in the era of GBS prophylaxis, (4) which concluded result in spontaneous abortion of the previable fetus.
that there is no evidence of an increase in non-GBS EOS Obligate anaerobic bacteria (primarily the encapsulated
among term infants. A case-control study of 132 cases of enteric organism Bacteroides fragilis) can cause neonatal
neonatal EOS caused by E coli occurring from 1997 to EOS and justify the use of both aerobic and anaerobic
2001 recently published by the CDC concluded that blood culture bottles in the evaluation of EOS. Although
exposure to intrapartum antibiotic therapy did not in- both methicillin-sensitive and methicillin-resistant S au-
crease the odds of invasive early-onset E coli infection. reus (MRSA) cause a large proportion of hospital-
(18) In fact, this study demonstrated a protective effect acquired infection in VLBW infants and represent an
of intrapartum antibiotic exposure on the risk of E coli increasing issue in community-acquired pediatric infec-
EOS among term infants. However, worrisome increases tions, they remain a rare cause of neonatal EOS. A recent
in non-GBS EOS and ampicillin-resistant EOS in VLBW study of 5,732 pregnant women documented a 3.5%
infants have been reported by single centers (19) and by incidence of MRSA in GBS rectovaginal screening cul-
the NICHD Neonatal Research Network. (20) The mul- tures but found no cases of MRSA neonatal EOS in
ticenter NICHD Network documented an increase in E delivered infants. (22) Finally, fungal organisms (primar-
coli EOS in VLBW infants from 3.2 cases per 1,000 live ily Candida sp) rarely cause neonatal EOS. Fungal EOS
births in 1991 to 1993 to 7.0 cases per 1,000 live births is found largely in preterm and VLBW infants and in our
in 2002 to 2003. center is associated with very prolonged antibiotic (24
Trends in the microbiology of EOS likely vary to some h) exposure of pregnant mothers prior to delivery.
extent by institution and may be influenced by local
obstetric practices as well as by local variation in indige- Clinical Risk Factors for EOS
nous bacterial flora. To address this important issue, the Maternal and infant characteristics associated with the
CDC Active Bacterial Core Surveillance Program and the development of EOS have been studied most rigorously
NICHD Neonatal Research Network are conducting with respect to GBS EOS, but much of these data were
active surveillance for early-onset neonatal sepsis from obtained prior to the implementation of IAP for GBS
2007 to 2009 that will include data on intrapartum prevention. Perhaps the most challenging clinical issue in
antibiotic exposure and collection of specific infecting the era of GBS prophylaxis is the identification and
bacterial isolates for microbiologic study. (21) Informa- evaluation of the initially asymptomatic term and late
tion from studies of this type may help guide clinical preterm infant at risk for EOS. Escobar and associates
decisions regarding empiric antibiotic choice for EOS, (23) studied a cohort of more than 18,000 infants born
particularly in VLBW infants. Currently, when there is in 1995 to 1996, cared for in a single health-care plan,
strong clinical suspicion for sepsis in a critically ill infant, whose birthweights were at least 2,000 g, and who had
the possibility of ampicillin-resistant gram-negative in- no major anomalies. Of these, 2,785 infants were evalu-
fection suggests the consideration of empiric use of a ated for EOS with a complete blood count and blood
third-generation cephalosporin such as cefotaxime or culture. Multivariate analyses of predictors of EOS ac-
ceftazidime. counted for intrapartum antibiotic exposure and mod-
eled maternal chorioamnionitis either as a clinical obstet-
Other Organisms Responsible for EOS ric diagnosis or as an entity defined by prolonged rupture
In addition to GBS and E coli, a number of other patho- of membranes and maternal fever. Results of the latter
gens that cause EOS in the United States deserve special model are shown in Table 4, but the overall findings were
note. Listeria monocytogenes are gram-positive, beta- the same in each model: maternal intrapartum fever, the
Figure. Guidelines for the management of asymptomatic infants born at 35 or more weeks gestation who have risk factors for
early-onset sepsis. CBCcomplete blood count, Csxncesarean section delivery, FHRfetal heart rate, GBSgroup B Streptococcus,
IAPintrapartum antibiotic prophylaxis, I:Timmature to total, PMNpolymorphonuclear lymphocytes, PTDprior to delivery,
ROMrupture of membranes, WBC-white blood cell.
low birth weight neonates: the experience of the NICHD Neonatal perinatal group B streptococcal disease. MMWR Morbid Mortal
Research Network. Pediatrics. 2002;110:285291 Wkly Rep. 2002;51:122
3. Stoll BJ, Hansen NI, Higgins RD, et al. Very low birth weight 14. Puopolo KM, Madoff LC, Eichenwald EC. Early-onset group
preterm infants with early onset neonatal sepsis: the predominance B streptococcal disease in the era of maternal screening. Pediatrics.
of gram-negative infections continues in the National Institute of 2005;115:1240 1246
Child Health and Human Development Neonatal Research Net- 15. Puopolo KM, Madoff LC. Type IV neonatal early-onset group
work, 20022003. Pediatr Infect Dis J. 2005;24:635 639 B streptococcal disease in a United States hospital. J Clin Microbiol.
4. Moore MR, Schrag SJ, Schuchat A. Effects of intrapartum 2007;45:1360 1362
antimicrobial prophylaxis for prevention of group-B-streptococcal 16. Yancey MK, Schuchat A, Brown LK, Ventura VL, Markenson
disease on the incidence and ecology of early-onset neonatal sepsis. GR. The accuracy of late antenatal screening cultures in predicting
Lancet Infect Dis. 2003;3:201213 genital group B streptococcal colonization at delivery. Obstet Gy-
5. Arias E, MacDorman MF, Strobino DM, Guyer B. Annual necol. 1996;88:811 815
summary of vital statistics2002. Pediatrics. 2003;112:12151230 17. Davies HD, Miller MA, Faro S, Gregson D, Kehl SC, Jordan
JA. Multicenter study of a rapid molecular-based assay for the
6. Hyde TB, Hilger TM, Reingold A, Farley MM, OBrien KL,
diagnosis of group B Streptococcus colonization in pregnant women.
Schuchat N. Trends in incidence and antimicrobial resistance of
Clin Infect Dis. 2004;39:1129 1135
early-onset sepsis: population-based surveillance in San Francisco
18. Schrag SJ, Hadler JL, Arnold KE, Martell-Cleary P, Reingold
and Atlanta. Pediatrics. 2002;110:690 695
A, Schuchat A. Risk factors for invasive, early-onset Escherichia coli
7. Slotved HC, Kong F, Lambertsen L, Sauer S, Gilbert GL.
infections in the era of widespread intrapartum antibiotic use.
Serotype IX, a proposed new Streptococcus agalactiae serotype.
Pediatrics. 2006;118:570 576
J Clin Microbiol. 2007;45:2929 2936
19. Bizarro MJ, Dembry LM, Baltimore RS, Gallagher PJ. Chang-
8. Meyn LA, Moore DM, Hillier SL, Krohn MA. Association of ing patterns in neonatal Escherichia coli sepsis and ampicillin resis-
sexual activity with colonization and vaginal acquisition of group B
tance in the era of intrapartum antibiotic prophylaxis. Pediatrics.
Streptococcus in nonpregnant women. Am J Epidemiol. 2002;155: 2008;121:689 696
949 957 20. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens
9. Benitz WE, Gould JB, Druzin ML. Risk factors for early-onset causing early-onset sepsis in very-low-birth-weight infants. N Engl
group B streptococcal sepsis: estimation of odds ratios by critical J Med. 2002;347:240 247
literature review. Pediatrics. 1999;103:e77 21. Centers for Disease Control and Prevention. Inventory of
10. Centers for Disease Control and Prevention. Prevention of Projects Progress Report: Implementation of a Public Health Action
perinatal group B streptococcal disease: a public health perspective. Plan to Combat Antimicrobial Resistance. Progress Through 2007.
MMWR Morbid Mortal Wkly Rep. 1996;45:124 Available at: htttp://www.cdc.gov/drugresistance/actionplan/
11. Boyer KM, Gotoff SP. Prevention of early-onset neonatal 2007_report/ann_rept.pdf. Accessed September 2008
group B streptococcal disease with selective intrapartum chemopro- 22. Andrews WW, Schelonka R, Waites K, Stamm A, Cliver SP,
phylaxis. N Engl J Med. 1986;314:16651669 Moser S. Genital tract methicillin-resistant Staphylococcus aureus:
12. Schrag SJ, Zell ER, Lynfield R, et al. Active Bacterial Core risk of vertical transmission in pregnant women. Obstet Gynecol.
Surveillance Team. A population-based comparison of strategies to 2008;111:113118
prevent early-onset group B streptococcal disease in neonates. 23. Escobar GJ, Li DK, Armstrong MA, et al. Neonatal sepsis
N Engl J Med. 2002;347:233239 workups in infants /2000 grams at birth: a population-based
13. Centers for Disease Control and Prevention. Prevention of study. Pediatrics. 2000;106:256 263
NeoReviews Quiz
5. Widespread implementation of intrapartum antibiotic prophylaxis has altered the epidemiology of early-
onset sepsis (occurring at less than 72 hours after birth) in the newborn. The incidence of group B
Streptococcus (GBS) early-onset sepsis has decreased; the incidence of non-GBS early-onset sepsis is
unchanged or decreasing. Of the following, the national incidence of GBS early-onset sepsis, as estimated
in 2003 through 2005, is closest to:
A. 0.03 per 1,000 live births.
B. 0.30 per 1,000 live births.
C. 0.60 per 1,000 live births.
D. 0.90 per 1,000 live births.
E. 0.20 per 1,000 live births.
6. The spectrum of microorganisms causing early-onset sepsis in the era of intrapartum antibiotic prophylaxis
is different between term neonates (>2,000 g birthweight) and very low-birthweight neonates (<1,500 g
birthweight). Of the following, the most common microorganism attributable to early-onset sepsis in term
neonates, as reported by the Centers for Disease Control and Prevention, is:
A. Coagulase-negative Staphylococcus.
B. Escherichia coli
C. Group B Streptococcus.
D. Haemophilus influenzae.
E. Listeria monocytogenes.
7. The spectrum of microorganisms causing early-onset sepsis in the era of intrapartum antibiotic prophylaxis
is different between term neonates (>2,000 g birthweight) and very low-birthweight (VLBW) neonates
(<1,500 g birthweight). Of the following, the most common microorganism attributable to early-onset
sepsis in VLBW neonates, as reported by the National Institute of Health and Human Development Neonatal
Research Network, is:
A. Coagulase-negative Staphylococcus.
B. Escherichia coli.
C. Group B Streptococcus.
D. Haemophilus influenzae.
E. Listeria monocytogenes.
8. Most cases of early-onset sepsis attributable to GBS in the United States currently are caused by GBS
serotypes Ia, Ib, II, III, and V. Intrapartum antibiotic prophylaxis for prevention of GBS sepsis was advocated
following several studies examining the maternal and neonatal risk factors for early-onset GBS sepsis. Of
the following, the clinical risk factor most predictive of neonatal early-onset GBS sepsis in the absence of
intrapartum antibiotic prophylaxis is:
A. Chorioamnionitis.
B. Extremely low birthweight (<1,000 g).
C. Intrapartum fever (temperature >99.5F [37.5C]).
D. Maternal GBS colonization.
E. Prolonged rupture of membranes (>18 hours).