Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial

Background Preterm, prelabour rupture of the fetal membranes (pPROM) is the commonest antecedent of preterm birth, and can lead to death, neonatal dis ease, and long-term disability. Previous small trials of antibiotics for pP ROM suggested some health benefits for the neonate, but the results were in conclusive. We did a randomised multicentre trial to try to resolve this is sue. Methods 4826 women with pPROM were randomly assigned 250 mg erythromycin (n =1197), 325 mg co-amoxiclav (250 mg amoxicillin plus 125 mg clavulanic acid ; n=1212), both (n=1192), or placebo (n=1225) four times daily for 10 days or until delivery. The primary outcome measure was a composite of neonatal death, chronic lung disease, or major cerebral abnormality on ultrasonograp hy before discharge from hospital. Analysis was by intention to treat. Findings Two women were lost to follow-up, and there were 15 protocol viola tions. Among all 2415 infants born to women allocated erythromycin only or placebo, fewer had the primary composite outcome in the erythromycin group (151 of 1190 [12.7%] vs 186 of 1225 [15.2%],p=0.08) than in the placebo gro up. Among the 2260 singletons in this comparison, significantly fewer had t he composite primary outcome in the erythromycin group (125 of 1111[11.2%] vs 166 of 1149 [14.4%], p=0.02). Co-amoxiclav only and coamoxiclav plus ery thromycin had no benefit over placebo with regard to this outcome in all in fants or in singletons only. Use of erythromycin was also associated with p rolongation of pregnancy, reductions in neonatal treatment with surfactant, decreases in oxygen dependence at 28 days of age and older, fewer major ce rebral abnormalities on ultrasonography before discharge, and fewer positiv e blood cultures. Although co-amoxiclav only and co-amoxiclav plus erythrom ycin were associated with prolongation of pregnancy, they were also associa ted with a significantly higher rate of neonatal necrotising enterocolitis. Interpretation Erythromycin for women with pPROM is associated with a range of health benefits for the neonate, and thus a probable reduction in child hood disability. However, co-amoxiclav cannot be routinely recommended for pPROM because of its association with neonatal necrotising enterocolitis. A follow-up study of childhood development and disability after pPROM is pla nned.