Commentary and Review by:
Title: Antibiotic Therapy for Reduction of Infant Morbidity After Preterm Premature Rupture of the Membranes. A Randomized Controlled Trial.
Ref: JAMA. 1997;278:989-995
Authors: Brian M. Mercer, MD; Menachem Miodovnik, MD; Gary R. Thurnau, MD; Robert L. Goldenberg, MD; Anita F. Das, MS; Risa D. Ramsey, BSN; Yolanda A. Rabello, MSEd; Paul J. Meis, MD; Atef H. Moawad, MD; Jay D. Iams, MD; J. Peter Van Dorsten, MD; Richard H. Paul, MD; Sidney F. Bottoms, MD; Gerald Merenstein, MD; Elizabeth A. Thom, PhD; James M. Roberts, MD; Donald McNellis, MD
Study Design: RCT
Context: Intrauterine infection is thought to be one cause of preterm premature rupture of the membranes (PPROM). Antibiotic therapy has been shown to prolong pregnancy, but the effect on infant morbidity has been inconsistent.
Objective: To determine if antibiotic treatment during expectant management of PPROM will reduce infant morbidity.
Study Design: Randomized, double-blind, placebo-controlled trial.
Setting: University hospitals of the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
Patients: A total of 614 of 804 eligible gravidas with PPROM between 24 weeks’ and 0 days’ and 32 weeks’ and 0 days’ gestation who were considered candidates for pregnancy prolongation and had not received corticosteroids for fetal maturation or antibiotic treatment within 1 week of randomization.
Interventions: Intravenous ampicillin (2-g dose every 6 hours) and erythromycin (250-mg dose every 6 hours) for 48 hours followed by oral amoxicillin (250-mg dose every 8 hours) and erythromycin base (333-mg dose every 8 hours) for 5 days vs a matching placebo regimen. Group B streptococcus (GBS) carriers were identified and treated. Tocolysis and corticosteroids were prohibited after randomization.
Main Outcome Measures: The composite primary outcome included pregnancies complicated by at least one of the following: fetal or infant death, respiratory distress, severe intraventricular hemorrhage, stage 2 or 3 necrotizing enterocolitis, or sepsis within 72 hours of birth. These perinatal morbidities were also evaluated individually and pregnancy prolongation was assessed.
Results: In the total study population, the primary outcome (44.1% vs 52.9%; P=.04), respiratory distress (40.5% vs 48.7%; P=.04), and necrotizing enterocolitis (2.3% vs 5.8%; P=.03) were less frequent with antibiotics. In the GBS-negative cohort, the antibiotic group had less frequent primary outcome (44.5% vs 54.5%; P=.03), respiratory distress (40.8% vs 50.6%; P=.03), overall sepsis (8.4% vs 15.6%; P=.01), pneumonia (2.9% vs 7.0%; P=.04), and other morbidities. Among GBS-negative women, significant pregnancy prolongation was seen with antibiotics (P <.001).
Conclusion: We recommend that women with expectantly managed PPROM remote from term receive antibiotics to reduce infant morbidity.
Fully a third of preterm births are due to preterm premature rupture of the membranes (PPROM), the significance of optimizing the management of this problem are obvious. There has been a growing body of literature supporting the use of antibiotics for PPROM and this study provides some of the key pieces of this puzzle.
Previous work has not been able to demonstrate a change in neonatal outcome although there is significant support for the use to antibiotics to prolong latency. This trial restricted the enrollment to 24-32 weeks gestation, generating a population which has a high chance of demonstrating the parameters the investigators want to study. This study was initiated prior to the NIH consensus conference recommending antenatal steroids thus the design was not confounded by the use of steroids which were in fact exclusions for the study. This fortuitous sequence allowed the authors to attribute the improvement in neonatal outcome to the use of the antibiotic rather than face an inevitable challenge that the improvement in outcome was due to variations in steroid use. These confounders have created a lot of discussion in the doctor’s lounge as to whether the use of antibiotic therapy was indeed prudent for PPROM. However, Mercer et al have clearly demonstrated that antibiotics have an independent effect on neonatal outcome.
The following significant differences were noted in the total study population:
The results clearly demonstrate that in addition to prolonging latency, the use of antibiotics also decreased the incidence of respiratory distress syndrome, BPD, , and patent ductus arteriosus. The maternal measures noted a prolongation of latency and clinical amnionitis was decreased in the treatment group.
It is interesting that the authors adopted a policy of a separate analysis for the Group B strep (GBS) culture positive group. The finding with this subanalysis is that there was no demonstrated difference in the GBS positive control group which received antibiotic treatment (for the GBS) and GBS positive study group which received antibiotic treatment (study intervention).
This information reinforces that there is no single selection of antibiotic regimen which is optimum to achieve these improvements in outcome. Certainly in this case, the study treatment regimen of IV ampicillin and erythromycin for 48 hours followed by oral ampicillin and erythromycin for five days had the same outcome as the treatment therapy for the strep GBS positive cohort.
The use of a composite morbidity as the primary outcome parameter is very interesting and somewhat novel. While previous studies had identified prolongation of latency, they have been unsuccessful in describing a decrease in individual morbidities. The authors have used a composite morbidity to address this issue. This morbidity outcome was positive if the neonate had any one of the following problems: RDS, fetal or infant death, severe IVH, Stage 2 or 3 NEC, or sepsis within 72 hours of birth
From a theoretical perspective, this design feature would ironically have the potential to either increase or decrease the power of the study. For example, by using multiple morbidities and only requiring the presence of one for analysis with the morbidity group, a slight reduction across those morbidities and a clustering of the patients with only one morbidity would certainly dramatically increase the power of the study; on the other hand, for those early pregnancies where a much higher percentage display multiple morbidities, a significant decrease in one could be masked by the near universal appearance of other problems (i.e. RDS). The authors, in their discussion, claim that this made it more difficult to demonstrate a benefit since failure to prevent all serious complications was considered a treatment failure.
This work provides the keystone to changing the management of PPROM. I believe we can expect a statement from a national organization supporting the universal adoption of antibiotics with PPROM.