The ORACLE trial: Antibiotics for preterm, prelabor rupture of membranes [Classics Series]

1. Among infants born to women with preterm, premature rupture of membranes, those whose mothers were randomized to treatment with erythromycin experienced a lower incidence of adverse neonatal outcomes and prolongation of pregnancy compared to the placebo group.

Original Date of Publication: March 2001

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials, 2e (The Classics Series).

Study Rundown: Preterm, premature (prelabor) rupture of membranes (PPROM) is a common cause of preterm birth. Following PPROM, approximately 50% of women will deliver within one week. As such, the majority of infants born to women with PPROM are exposed to risks associated with prematurity including respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage and retinopathy of prematurity as well as risks of cerebral palsy, blindness and deafness. Further, leakage of amniotic fluid in PPROM can expose the fetus to oligohydramnios and associated Potter sequence complications such as pulmonary hypoplasia, pneumothorax, and skeletal deformities. Lastly, because PPROM involves a breech in the integrity of the amniotic membrane, fetuses exposed to PPROM are at increased risk of complications associated with intrauterine infection, including chorioamnionitis, neonatal sepsis and hypoxemic ischemic encephalopathy. Previous research has demonstrated that subclinical chorioamnionitis plays a role in degrading the amniotic membrane such that most experts agree that the etiology of PPROM is infectious. Researchers theorized that administering antibiotics to women who experience PPROM would improve neonatal health and well-being. As of the late 1990s, trials of antibiotics in PPROM demonstrated an association with prolongation of pregnancy but did not identify reduced risks of common neonatal adverse events. In this large randomized controlled trial, researchers investigated the impact of three different antibiotic regimens: erythromycin, amoxicillin-clavulanic acid or both compared to placebo on neonatal outcomes in infants born to women with PPROM.

This landmark study was the first to demonstrate neonatal benefit to maternal antibiotic use following preterm premature rupture of membranes. In contrast to existing literature, this study employed a large sample size and four treatment arms to distinguish the impact of various treatments compared with placebo. Additional strengths included multicenter randomized trial at more than 150 sites and strict exclusion criteria. The study was conducted in the United Kingdom and results may not apply to populations with differing demographic compositions.

Click to read the study in the Lancet

In-Depth [randomized controlled trial]: A total of 4826 women with PPROM were randomized to receive erythromycin (n=1197), amoxicillin-clavulanic acid (n=1212), both (n=1192) or placebo (n=1225) 4 times daily for 10 days or until delivery, whichever came first. Intention-to-treat analysis was applied to evaluate the composite outcome of neonatal death, chronic lung disease or major cerebral abnormality between treatment groups.

Among singleton infants born to women with PPROM randomized to erythromycin or placebo, fewer infants experienced the composite primary outcome of severe adverse neonatal events in the erythromycin group (11.2% vs 14.4%, p=0.02). Erythromycin use was also associated with prolongation of pregnancy and reduction in need for surfactant. Use of both antibiotic regimens containing amoxicillin-clavulanic acid was associated with a higher incidence of neonatal necrotizing enterocolitis (p= 0.0005).

Image: PD

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