Early onset neonatal sepsis (EOS) continues to be an important cause of serious illness and death among very low birth weight (VLBW) preterm infants.1–3 The organisms that cause infection influence risk of complications and death. While several studies have reported a significantly higher risk of death among infants with late onset sepsis caused by Gram-negative and fungal organisms,4–6 it is not clear whether the specific organism causing EOS is as important a risk factor for death. The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network previously reported a change in the distribution of pathogens associated with EOS among VLBW infants born in 1998–2000 compared with those born in 1991–1993. Whereas Gram-positive organisms were the most common pathogens in the earlier period, Gram-negative organisms predominated in the later period.1 This review of Network registry data was undertaken to determine whether the predominance of Gram-negative organisms was a unique time-limited event or has continued.
Infants 401–1500 g who were born at the 16 centers of the NICHD Neonatal Research Network (see “Appendix”) between January 1, 2002 and December 31, 2003 and survived at least 12 hours were studied (2002–2003 cohort). The composition of the Network has changed over time. In our earlier published studies, data were reported from 15 sites (1998–2000)1 and 12 sites (1991–1993).7
Because blood culture data were not available for infants who died in the first 12 hours (N = 557), they were excluded. The Network maintains a registry of all VLBW infants born or cared for at participating centers.8 Trained research staff collect data on mothers at the time of delivery and on infants from birth to 120 days, hospital discharge or death, whichever comes first. The registry includes data on early onset sepsis, infecting organisms and maternal and infant demographic and clinical data. The clinician's presumed cause of death was recorded for all infants who died. Coded causes of death related to infection include the following: proven sepsis/infection; suspected sepsis/infection (cultures negative but intent to treat with antibiotics for ≥5 days); respiratory distress syndrome with infection; bronchopulmonary dysplasia with infection; necrotizing enterocolitis with sepsis and other (infection-related). External audits are done periodically to review the quality and reliability of data extracted from patient records.
Early onset sepsis was defined by clinical symptoms and a positive blood culture drawn within 72 hours of birth. Cultures positive for organisms generally considered to be contaminants (Propionibacterium, Corynebacterium, diphtheroids, Micrococcus) were excluded. Study sites were queried about newborns with early cultures positive for coagulase-negative staphylococci (CONS) and were asked whether the case was considered a true infection or a probable contaminant and to provide treatment history and antibiotic susceptibilities for the organism, if available. Cases considered probable contaminants by the study site were excluded. In the 1998–2000 cohort, we used a standard definition to distinguish between probable contaminant and possible/definite CONS infection based on number of positive CONS cultures, type and length of antibiotic therapy and C-reactive protein values if available.1 Such detailed culture, therapy and C-reactive protein data were not collected for the most recent cohort. For all other pathogens, sepsis was defined by the presence of the organism in blood culture. There were no differences in blood culture practices during the last 2 study periods.
Antibiotic susceptibility data are not collected as part of the registry. For this analysis, sites were asked to provide susceptibility data for all cultures positive for E. coli and sensitivities to ampicillin, gentamicin and cephalosporins were reviewed and compared between the 1998–2000 period and that for 2002–2003.
To determine whether there have been changes in either overall rates of EOS or pathogen-specific rates of infection, infants in the 2002–2003 cohort were compared with those in cohorts previously studied for EOS (1991–1993 and 1998–2000).1,7 Demographic data (birth weight, gestational age, race and sex) were compared for infants in the 3 cohorts. Maternal characteristics, including age, antibiotic use before delivery and time of rupture of membranes (ROM) were reviewed. Statistical significance for comparisons between cohorts was determined by χ2 or Fisher exact tests.
Rates of Infection and Demographic Characteristics.
Between January 1, 2002 and December 31, 2003, 5999 VLBW infants born at participating centers who survived at least 12 hours were studied. Of these, 113 infants evidenced positive blood cultures in the first 72 hours; 11 were considered probable contaminants (including 6 CONS) and not included in the analysis. Thus 102 of 5999 infants had EOS, a rate of 17 per 1000 live births of infants 401–1500 g. There was no significant difference in the overall incidence of EOS in the latest cohort compared with the 2 previously studied cohorts (1991–1993, 19.3; 1998–2000, 15.4; and 2000–2003, 17.0 per 1000 VLBW infants, respectively).
Demographic characteristics of infants in the 2002–2003 cohort are compared with the previous cohorts in Table 1. There was a change in the racial distribution of the cohort in the study periods with fewer black infants in the latest cohort. Although the earliest cohort was somewhat heavier than the 1998–2000 cohort, no differences in birth weight were found in the 2 latest cohorts. There were no significant differences between the cohorts in sex or gestational age.
A total of 5312 mothers were included in the analysis because 28% of the 5999 infants born in 2002–2003 were from multiple gestations. The mother's median age was 27 years (range, 12–49). During the hospitalization for delivery, 69% of mothers received antibiotics, a statistically significant increase compared with the 1998–2000 cohort [3638 of 5303 (data missing for 9 mothers), 69% versus 3186 of 4887, 65%, P < 0.001]. The interval between rupture of membranes and birth was >48 hours for 21% of the mothers. The percent of infants with EOS was higher among those with ROM >48 hours compared with those with ROM ≤48 hours, P < 0.001 (<6 hours, 1.1%; 6–24 hours, 1.3%; 25–48 hours, 1.2%; >48 hours, 3.6%).
Distribution of Pathogens and Antibiotic Susceptibility.
The majority of EOS infections in the 2002–2003 cohort were caused by Gram-negative organisms (52.9%; Table 2). E. coli was the most frequent pathogen, accounting for 41.2% of all EOS infections. Gram-positive pathogens accounted for 45.1% of infections, with CONS occurring in 14.7% of patients. Fungal pathogens were rare (2%).
The distribution of pathogens associated with EOS was compared between the 3 time periods (Table 3). There was no significant change in the distribution of pathogens between the 1998–2000 and the 2002–2003 cohorts, P = 0.5. Whereas Gram-positive infections were responsible for the majority of infections between 1991 and 1993, Gram-negative infections were the most frequent cause in both the 1998–2000 and 2002–2003 cohorts. After a significant decline in the rate of group B streptococcal (GBS) infections from 1991–1993 to 1998–2000, there was no significant change in the rate between 1998–2000 and 2002–2003 (1.7 per 1000 VLBW live births and 1.8 per 1000 VLBW live births, respectively). Although not statistically significant, CONS infections increased from 1.7 per 1000 VLBW live births to 2.5 per 1000 VLBW live births between 1998–2000 and 2002–2003. After a significant increase in the rate of E. coli from 3.2 per 1000 VLBW live births in 1991–1993 to 6.8 per 1000 VLBW live births in 1998–2000, the rate remained stable in 2002–2003 (7.0 per 1000 VLBW live births).
In the 2002–2003 cohort, information on susceptibility to antibiotics was available for 39 of the 42 isolates of E. coli: 30 of 39 were resistant to ampicillin (77%); 3 were resistant to gentamicin (8%; 2 of 3 resistant to both ampicillin and gentamicin) and 1 was resistant to cephalosporins (3%; tested for resistance to cephazolin, cephalothin, cefuroxime, cefotetan, cefotaxime and ceftazidime). Although laboratories varied in the range of drugs to which susceptibility testing was performed, isolates were sensitive to third generation cephalosporins. No statistically significant differences were found in the percentage of resistance in the current versus the 1998–2000 cohort (ampicillin resistant, 77% versus 28 of 33 = 85%, P = 0.5; gentamicin resistant, 8% versus 1 of 33 = 3%, P = 0.6; cephalosporin-resistant, 3% versus 0 of 26 = 0%, P = 1.0).
Overall 689 of the 5999 infants died (11%). Infants with EOS were more likely to die than those without EOS [36 of 102 (35%) versus 653 of 5897 (11%), P < 0.001, odds ratio adjusted for gestational age, 2.7 (1.7–4.2)]. It is often difficult to assign a cause of death for VLBW infants with complicated illnesses. The coded cause of death included infection for 25 of 36 (69%) of those with EOS who died versus 211 of 653 (32%) without EOS who died. Death rates did not differ significantly by pathogen type: 35% for Gram-negative (19 of 54) versus 37% for Gram-positive infections (17 of 46) overall; 19% (10 of 54) versus 17% (8 of 46) in the first 72 hours of life. Neither of the 2 infants with fungal infections died. No statistically significant differences were detected in the death rates by pathogen type between the current cohort and the 1998–2000 cohort (Gram-negative, 35% versus 21 of 51 = 41%, P = 0.6; Gram-positive, 37% versus 8 of 31 = 26%, P = 0.3; fungal, 0% versus 2 of 2 = 100%, P = 0.3).
Although relatively uncommon, early onset neonatal sepsis remains an important potentially lethal disease among VLBW infants. This update on the epidemiology of early onset neonatal sepsis among VLBW infants born at centers of the NICHD Neonatal Research Network reveals that despite increasing use of intrapartum antibiotics over the last decade,1 overall rates of infection have not changed since our earliest published report (1991–1993 cohort).7 During the past 13 years, ∼2% of VLBW infants born at Network centers have been diagnosed with blood culture-proved early onset sepsis. Although rates of Gram-positive infections declined significantly between 1991–1993 and 1998–2000,1,7 predominantly as a result of a significant decline in group B streptococcal infections, there have been no significant changes since 1998–2000. Rates of group B streptococcal infection remain low, a reflection of successful national programs to reduce this infection in both term and preterm infants.9,10 Although we used a more stringent definition of possible/definite CONS infection in the 1998–2000 cohort, there is a suggestion that rates of early onset CONS sepsis among VLBW infants may be increasing. It will be important to monitor rates of early onset CONS sepsis to determine whether these organisms are emerging as important maternally acquired pathogens.11 The most troubling finding of this large prospective study is that Gram-negative infections are a continuing threat to VLBW infants. E. coli remains the most frequently isolated Gram-negative pathogen, and rates of early onset infection continue to be double what they were in the early 1990s.
In recent years, there has been an increase in the use of antibiotics during labor, resulting from national programs to reduce vertical transmission of group B streptococcal infections and from an effort to prolong pregnancy and to prevent neonatal illness in the case of preterm rupture of the membranes.12,13 Whereas previous U.S. Centers for Disease Control and Prevention guidelines for the prevention of maternal-infant transmission of GBS supported either a screening or risk based approach to prevention, revised guidelines recommend universal screening at 35 or more weeks of gestation and intrapartum chemoprophylaxis for all GBS-colonized women.12 It is unlikely that these changes would affect the numbers of infants in our study receiving chemoprophylaxis because study infants were born at gestational ages below the recommended age for GBS screening, thus had at least 1 risk for GBS sepsis (prematurity) and were already candidates for chemoprophylaxis. Revised guidelines will, however, result in more women overall receiving intrapartum antibiotics, raising concerns about possible effects on pathogens associated with EOS in both term and preterm infants.
In the latest Network cohort, 69% of women received antibiotics during the admission for delivery, more than twice the percentage who received antibiotics in 1991–1993 (31%)7 and a significant increase over that of the 1998–2000 study period (65%).1 Such widespread use of antibiotics during labor raises concerns about the emergence of non-GBS infections (especially Gram-negative infections) and about increased antibiotic resistance. Studies from the NICHD Neonatal Research Network and others have reported high rates of ampicillin resistance among E. coli isolates and a link between maternal intrapartum ampicillin and E. coli resistance.1,14,15 Although antibiotic resistance among E. coli isolates remains high, we found no significant changes in their resistance pattern in the current cohort. If a mother has received intrapartum antibiotics and the VLBW infant develops EOS, it is important to consider that the isolate may be resistant to the antibiotic given to the mother. In clinical practice, this may affect choice of antibiotic therapy for the newborn.
In summary, despite an increase in maternal antibiotic use during labor, the overall rate of EOS has not decreased in VLBW infants. We have, however, observed a persistent change in the distribution of pathogens associated with EOS; Gram-negative organisms remain the predominant early onset sepsis pathogens among VLBW preterm infants. The pathogens responsible for early onset sepsis generally reflect the predominant vaginal flora of the mother. It is unclear whether the widespread use of intrapartum antibiotics has resulted in a true change in vaginal flora or simply a reduction in GBS transmission. Studies to understand the vaginal ecology of pregnant women in the context of preterm labor and intrapartum antibiotic use will increase our understanding of the change in pathogens associated with early onset neonatal sepsis among VLBW infants. Limitations of the study include the use of hospital-based data rather than population-based surveillance and inclusion of only VLBW infants in the study. Expanded surveillance of the pathogens associated with EOS among infants of all birth weights and gestational ages is needed.
1. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med
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6. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics
7. Stoll BJ, Gordon T, Korones SB, et al. Early-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr
8. Hack M, Horbar JD, Malloy MH, Tyson JE, Wright L. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Network. Pediatrics
9. Schrag SJ, Zywicki S, Farley M, et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med
10. Schrag SJ, Zell ER, Lynfield R, et al. A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates. N Engl J Med
11. Stoll BJ, Fanaroff A. Early-onset coagulase-negative staphylococcal sepsis in the preterm neonate. Lancet
12. Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease revised guidelines from the CDC. MMWR
13. Klein LL, Gibbs RS. Use of microbial cultures and antibiotics in the prevention of infection-associated preterm birth. Am J Obstet Gynecol
14. Towers CV, Briggs GG. Antepartum use of antibiotics and early-onset neonatal sepsis: the next 4 years. Am J Obstet Gynecol
15. Alarcon A, Peña P, Salas S, Sancha M, Omeñaca F. Neonatal early onset Escherichia coli
sepsis: trends in incidence and antimicrobial resistance in the era of intrapartum antimicrobial prophylaxis. Pediatr Infect Dis J
APPENDIX. NICHD Neonatal Research Network (2001–2006)