Risk Factors and Opportunities for Prevention of Early-onset Neonatal Sepsis: A Multicenter Case-Control Study

DISCUSSION

This multicenter study assessed the incidence of culture-confirmed sepsis in the first week of life. Early-onset disease occurred at a rate of 3.5 cases per 1000 live births and 16.0% of patients died. Consistent with earlier reports, group B streptococcus was the predominant organism identified, accounting for more than 40% of cases. The aggregate rate of early-onset GBS disease during the 1995 to 1996 study period—1.4 per 1000 births—was similar to the estimate of 1.3 per 1000 births derived from population-based surveillance in 4 geographic areas during 1995.¹⁶ Nevertheless, substantial variation in the incidence of early-onset disease caused by GBS and other organisms was identified in the 7 study sites.

Towers et al¹² recently reported that when early-onset GBS rates declined at one institution after increased use of intrapartum antimicrobial prophylaxis, the rate of E coli sepsis increased significantly. Although our surveillance includes 50 000 births, the relatively small numbers of cases in each hospital limited our ability to correlate GBS and non-GBS rates of disease. Longitudinal surveillance is needed to determine if prevention of GBS disease by increased use of intrapartum antibiotics will significantly affect rates of early-onset disease attributable to other organisms.

Comparison of early-onset disease caused by GBS with that attributable to other organisms identified several differences. GBS was significantly more likely to cause disease in full-term infants and to present on the day of birth. Sepsis attributable to other organisms was significantly more likely to result in death (22.3% vs 6.7%), perhaps as a result of the predominance of preterm infants among those infants who developed sepsis caused by other agents.

A subset of early-onset cases were compared with controls to identify risk factors for sepsis caused by GBS or other organisms. As in previous studies, intrapartum fever was significantly more likely to occur in mothers whose infants developed GBS disease. A nearly 3-fold risk of early-onset GBS disease occurred when 6 or more vaginal exams were performed before delivery. Previous studies have also associated frequent vaginal exams with amnionitis, early-onset sepsis, and neonatal infections.^{6 ,17 ,18} Unlike previous studies, early onset GBS disease was not significantly associated with maternal age <20 years.^{14 ,19} The limited racial diversity within each hospital's study patients may explain the lack of an association between GBS disease and race. Although population-based surveillance continues to identify higher rates of early-onset GBS disease among African-Americans, rates of disease have declined more rapidly among this group, resulting in a reduced racial disparity.¹⁶

We did not find that risk factors for early-onset GBS sepsis were associated with increased risk of sepsis attributable to other organisms. Intrapartum fever, ROM ≥ 18 hours before delivery, and frequent vaginal exams were not associated with sepsis attributable to other organisms. This may be partially explained by differences in the route of transmission between GBS and other organisms. For example, GBS is clearly acquired from the mother in nearly all cases of early onset disease; only 7% of GBS cases presented after the first day of life. By contrast, 39% of non-GBS cases presented after the first day of life, and thus, may represent infections acquired during hospitalization or through contact with others. Prematurity may be the overwhelming risk factor for non-GBS infections presenting on the day of birth.

Prevention of early-onset group B streptococcal disease by use of a risk-based strategy to select women for IAP is increasing.⁷ Whether this approach will also reduce infections caused by other organisms is not yet known. The applicability of the risk-based approach to prevention of other infections will depend on the prevalence of risk conditions among these cases and on the effectiveness of intrapartum antibiotics against other causes of early-onset disease. In this study, at least one of the obstetric risk factors was present in 79% of early-onset cases caused by other organisms. Although non-GBS cases were more likely to have an obstetric risk factor, IAP seemed to have lower efficacy against other pathogens compared with GBS, although the small number of study participants enrolled resulted in wide confidence intervals.

We estimated the efficacy of intrapartum antibiotics against GBS early-onset disease to be 85%, however, this estimate was not statistically significant. Because antibiotics were frequently given for maternal fever, it was difficult for us to distinguish prophylactic from therapeutic use. We therefore reported efficacy based on bivariate adjustment for the presence of fever. However, this may overestimate the true efficacy of intrapartum prophylaxis. Our study was also too small to assess the efficacy of a single dose of antibiotics or of antibiotics initiated 4 hours before delivery. Both the number of prophylactic doses and the duration of intrapartum prophylaxis before delivery were proposed as criteria to consider in determining the need for diagnostic testing of newborns whose mothers received antibiotics for GBS prevention.^{4 ,9} Because limited data exist to support these criteria,²⁰ future studies are needed to characterize adequacy of prophylaxis.

We found higher efficacy of intrapartum antibiotics against infections presenting on the first day of life (81.8%) compared with those presenting 3 or more days after birth (58.9%). This observation may account for the difference between efficacy of prophylaxis against GBS versus other pathogens, because most GBS disease presents on the first day of life. Intrauterine acquisition of the organism is more likely for cases with the earliest onset, and those episodes, whether caused by GBS or other organisms, may be the most amenable to maternal antibiotic administration.

Our study was completed before consensus guidelines were implemented in most of the centers participating in the study, and therefore provides insight into the proportion of early onset GBS disease that is potentially preventable by the two strategies recommended in mid-1996. We found that nearly all GBS case-mothers had received prenatal care, during which a screening test could have been collected, and 84.4% initiated care before the 7th month, and might have been able to receive a GBS vaccine scheduled for the late second trimester. Based on the assumption that a GBS screening culture with 87% sensitivity¹⁵ could be collected from all women with prenatal care delivering at term, that those delivering preterm were eligible for prophylaxis, and that women admitted for labor at least an hour before delivery had an opportunity for antibiotics to be offered, we estimate that 74% of GBS case-mothers could have been offered intrapartum prophylaxis according to the screening-based strategy. If efficacy of intrapartum antibiotics is 85%, 66% of early-onset GBS cases could have been prevented using the screening-based method. We found that 41% of GBS case-mothers had at least one obstetric risk factor and at least an hour in the hospital after the risk factor was evident before delivery, providing an opportunity to offer antibiotics against the disease; with 85% efficacy, we estimate that 35% of GBS cases could have been prevented with implementation of the risk-based strategy in these hospitals. Our findings suggest that the screening-based approach might have more impact on GBS cases than implementation of the risk-based approach. However, prenatal culture results must be reliably transferred to the labor and delivery setting, and failure to do so would reduce the effectiveness of this strategy.

Assessment of the impact of prevention strategies on early-onset sepsis attributable to other organisms is needed. The screening-based approach offers antibiotic prophylaxis to all women with threatened preterm delivery if a GBS culture result is unavailable. Nearly half (46%) of early onset disease caused by organisms other than GBS occurred in infants delivered before 34 weeks' gestation, and 60% of non-GBS cases delivered before 37 weeks; thus, many mothers of non-GBS cases would also have been offered prophylaxis even under the screening-based approach. Full implementation of the risk-based strategy would have resulted in antibiotic administration to 67% of non-GBS case-mothers; assuming an efficacy of 63% against non-GBS early-onset disease, 42.2% of the non-GBS cases could have been prevented by the risk-based strategy, versus 33.5% of non-GBS cases prevented by the screening-based strategy. It is worth noting that penicillin is less appropriate than ampicillin for prevention of Gram-negative sepsis such as attributable to E coli. The lower efficacy against these agents and high rates of antimicrobial resistance raise questions about the potential risks and benefits for use of broader spectrum agents for prophylaxis.¹²

We confirmed the severity of early-onset sepsis attributable to resistant E coli reported by Joseph et al.⁵ In hospitals participating in our study during 1995 to 1996, 69% of early-onset E coli disease was attributable to ampicillin-resistant organisms, and fatality in these infants was 40.9%, compared with no deaths among sepsis caused by susceptibleE coli. However, infants with resistant E coliwere born after a median of 30 weeks' gestation, compared with 39 weeks' gestation for susceptible E coli sepsis cases, and thus, prematurity confounds the association between resistance and death.

Our data suggest that control of resistant E coli infections will be important in future efforts to address neonatal mortality. More generally, we found that the problem of fatal neonatal sepsis was very closely linked to the larger problem of prematurity. Effective approaches to reduce preterm deliveries are needed.