Elsevier

The Lancet

Volume 357, Issue 9261, 31 March 2001, Pages 979-988
The Lancet

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

https://doi.org/10.1016/S0140-6736(00)04233-1Get rights and content

Summary

Background

Preterm, prelabour rupture of the fetal membranes (pPROM) is the commonest antecedent of preterm birth, and can lead to death, neonatal disease, and long-term disability. Previous small trials of antibiotics for pPROM suggested some health benefits for the neonate, but the results were inconclusive. We did a randomised multicentre trial to try to resolve this issue.

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 ultrasonography before discharge from hospital. Analysis was by intention to treat.

Findings

Two women were lost to follow-up, and there were 15 protocol violations. 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 group. Among the 2260 singletons in this comparison, significantly fewer had the 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 erythromycin had no benefit over placebo with regard to this outcome in all infants or in singletons only. Use of erythromycin was also associated with prolongation of pregnancy, reductions in neonatal treatment with surfactant, decreases in oxygen dependence at 28 days of age and older, fewer major cerebral abnormalities on ultrasonography before discharge, and fewer positive blood cultures. Although co-amoxiclav only and co-amoxiclav plus erythromycin were associated with prolongation of pregnancy, they were also associated 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 childhood disability. However, co-amoxiclav cannot be routinely recommended for pPROM because of its association with neonatal necrotizing enterocolitis. A follow-up study of childhood development and disability after pPROM is planned.

Introduction

Preterm, prelabour rupture of the fetal membranes (pPROM) occurs in 2·0–3·5% of pregnancies and is the commonest antecedent of preterm birth, being present in 30–40% of cases.1 Although the latency period between fetal-membrane rupture and birth varies with gestation, spontaneous labour and birth is a consequence and can result in the complications of prematurity—ie, death; short-term neonatal disease and long-term disability (including cerebral palsy, blindness, and deafness); the complications of infection including chorioamnioitis, maternal wound infection, and neonatal sepsis; and the complications of prolonged oligohydramnios including pulmonary hypoplasia, pneumothorax, and skeletal deformities.1

Usually, fetal-membrane rupture is preceded by structural weakness associated with extracellular-matrix degradation and cellular apoptosis,2, 3 but a substantial proportion of cases are associated with subclinical chorioamnionitis.4 Micro-organisms are believed to degrade the fetal membranes either directly through proteases or phospholipases, or indirectly by the activation of collagenases—members of the matrix metalloproteinase family.5 Evidence for the role of subclinical chorioamnionitis in pPROM comes from case-control and cohort studies that have shown that women with pPROM have a higher rate of abnormal microbial colonisation of the lower genital tracts than women who have normal births, and from microbiological studies of amniotic fluid taken by amniocentesis from women with pPROM. From published studies, the overall prevalence of positive amniotic-fluid cultures in such women is 32–35%.4

Administration of antibiotics to the mother could therefore improve neonatal health and long-term child health by preventing infectious morbidity in the fetus, or by delaying the progression to preterm birth. The most recent Cochrane review of trials of antibiotics in pPROM6 reported that antibiotics seem to be of benefit in the reduction of the rate of maternal infection, delay of delivery, reduction of the rate of neonatal infection, and reduction of the numbers of babies requiring neonatal intensive care and ventilation for more than 28 days. However, the review did not show evidence of benefit for necrotising enterocolitis, major cerebral abnormality, respiratory distress syndrome, or death (either stillbirth or neonatal death).

We aimed to resolve the issue of whether the effects of antibiotics on neonatal outcomes are variable or whether they are the consequence of biases associated with small trials. Additionally, we aimed to test whether the beneficial effects reported are related to the antibiotic type used.7 Observational evidence has implicated a wide range of organisms in the genesis of pPROM. When deciding which antibiotics to test, we considered amoxicillin, coamoxiclav (amoxicillin/clavulanic acid), clindamycin, erythromycin, metronidazole, and tetracycline. Tetracycline would have been the antibiotic of choice, but it is contraindicated in pregnancy because of damage to fetal bones and teeth.8 Co-amoxiclav and erythromycin have the broadest spectrum, the best complementary range of activities, and provided the opportunity to test a β-lactam and a macrolide antibiotic.

Section snippets

Participants

Pregnant women were eligible if their fetuses were at less than 37 weeks of gestation, if pPROM was present, and if the need to prescribe antibiotics was uncertain. These pragmatic entry criteria were designed to reflect normal clinical practice. Women were excluded if antibiotics were already being prescribed, or if they were thought to be needed for infection. Exclusions also included the usual reasons for which a clinician would not give antibiotics—ie, immediate delivery desirable or

Participants

Enrolment was from July 1, 1994, until May 31, 2000. 4826 women with pPROM were randomised—4447 within the UK and 379 from the international collaborating centres. Two women were lost to follow-up and there were 15 protocol violations: four women were enrolled in error or were over 37 weeks' gestation, and 11 were taking contraindicated drugs. 4809 women completed the trial and were analysed (figure). 12 adverse events were reported to the trial director and trial coordinator, and were

Discussion

The results of this trial indicate a range of health benefits, particularly for singleton pregnancies, with the prescription of erythromycin, including reduction in delivery at 7 days after randomisation, reduction in neonatal treatment with surfactant, reduction in the rate of positive neonatal blood cultures, reduction in chronic lung disease (neonatal ventilation or oxygen at >28 days of age), reduction in the rate of major cerebral abnormality by ultrasonography, and reduction in the

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