Fast track — ArticlesBroad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial
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.
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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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