Elsevier

The Lancet

Volume 357, Issue 9261, 31 March 2001, Pages 989-994
The Lancet

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Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial

https://doi.org/10.1016/S0140-6736(00)04234-3Get rights and content

Summary

Background

Preterm birth after spontaneous preterm labour is associated with death, neonatal disease, and long-term disability. Previous small trials of antibiotics for spontaneous preterm labour have reported inconclusive results. We did a randomised multicentre trial to resolve this issue.

Methods

6295 women in spontaneous preterm labour with intact membranes and without evidence of clinical infection were randomly assigned 250 mg erythromycin (n=1611), 325 mg co-amoxiclav (250 mg amoxicillin and 125 mg clavulanic acid; n=1550), both (n=1565), or placebo (n=1569) four times daily for 10 days or until delivery, whichever occurred earlier. 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

None of the trial antibiotics was associated with a lower rate of the composite primary outcome than placebo (erythromycin 90 [5·6%], co-amoxiclav 76 [5·0%], both antibiotics 91 [5·9%], vs placebo 78 [5·0%]). However, antibiotic prescription was associated with a lower occurrence of maternal infection.

Interpretation

This trial provides evidence that antibiotics should not be routinely prescribed for women in spontaneous preterm labour without evidence of clinical infection.

Introduction

The annual number of preterm births worldwide is estimated at nearly 13 million,1 of which about a third result from uncomplicated spontaneous preterm labour.2 Preterm birth is the major cause of neonatal morbidity and mortality, and results in 75–90% of all neonatal deaths not due to lethal congenital malformation, and 50% of childhood neurological disabilities, including cerebral palsy, blindness, and deafness.3

Observational evidence suggests that subclinical infection is implicated in the genesis of spontaneous preterm labour. This evidence comes from systemic, intrauterine, and intracervical inoculation studies in pregnant animals,4, 5 from case-control and cohort studies of cervicovaginal microbial colonisation in women with preterm labour, and from the higher rate of histological chorioamnionitis found after spontaneous preterm labour and birth.6, 7, 8 Additionally, microbiological cultures of amniotic fluid taken from women presenting with spontaneous preterm labour have shown that microbial pathogens are present in about 10–15% of cases.9 The organisms that have the strongest associations with spontaneous preterm labour are Gardnerella vaginalis, Ureaplasma urealyticum, and the sexually transmitted organisms Chlamydia trachomatis and Neisseria gonorrhoeae. Other organisms such as group B streptococci, Escherichia coli, Klebsiella spp, Haemophilus influenzae, and Mycoplasma hominis have also been implicated in the genesis of spontaneous preterm labour. Treatment of pregnant women in spontaneous preterm labour with antibiotics could therefore prolong pregnancy, thereby reducing the frequency of preterm birth and the consequences of prematurity.

A Cochrane meta-analysis10 of the use of antibiotics on pregnant women in spontaneous preterm labour showed a mixed pattern of results—ie, a decrease in necrotizing enterocolitis and trends towards longer time to delivery and reductions in neonatal sepsis and intraventricular haemorrhage, but a trend towards increases in respiratory distress syndrome and perinatal mortality. Additionally, there is debate about whether β-lactam or macrolide antibiotics should be prescribed in this clinical situation. To resolve these uncertainties, we did a randomised trial of antibiotics for spontaneous preterm labour.

Section snippets

Methods

We enrolled women at less than 37 weeks' gestation who were in suspected or definite preterm labour with intact fetal membranes and in whom there was substantial uncertainty as to whether antibiotics should be prescribed. Since there is no agreed definition of preterm labour or a reliable method of diagnosing it, the diagnosis of labour was left to the clinician caring for the woman. This situation is characteristic of normal clinical practice, and ensured that the results of the trial could be

Results

Enrolment was from July 1, 1994, until May 31, 2000. Of 6295 women randomised, 40 were lost to follow-up and there were 14 protocol violations (four were at more than 37 weeks' gestation, and ten were taking contraindicated drugs); 6241 women were therefore included in the analyses (figure). 4377 women were enrolled in the UK and 1918 from international maternity units. The data set was 100% complete within the UK and 99·3% complete overall.

The baseline characteristics in each group were

Discussion

The results of this trial of 6241 women indicate that neither β-lactam nor macrolide antibiotics prolong pregnancy or improve neonatal health when prescribed to women in spontaneous preterm labour with intact membranes and without clinical evidence of infection.

There are a number of possible explanations for these results including antibiotic activity, maternal compliance, timing of the intervention, postrandomisation prescription of antibiotics, and overestimation of the role of subclinical

References (19)

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