Two studies published early online and in an upcoming edition of The Lancet find that when antibiotics are given to pregnant women experiencing premature labor, even with intact membranes and no infection, there is an increase in risk of functional impairment and/or cerebral palsy. These unexpected findings are the results of a study of long-term follow-up data from the ORACLE Children's Study, authored by Dr Sara Kenyon (University of Leicester, UK) and colleagues from the ORACLE study group.

Completed in 2001, the original ORACLE I and II trials were designed to see if the antibiotics erythromycin and co-amoxiclav could halt underlying infections in women threatening to give birth prematurely, and therefore delay or prevent premature birth and possibly improve outcomes in the first four weeks of life. The experiment was structured as a factorial randomized design, where mothers received placebo and erythromycin, placebo and co-amoxiclav, both antibiotics, or double-placebo. The ORACLE Children Study I and II were designed to analyze the long-term effects of the antibiotics on the children at 7 years of age that were born to these mothers.

In the ORACLE Children Study II, researchers looked at mothers who had spontaneous premature labor with intact membranes surrounding the unborn children and no obvious infection signs. Seven years after birth, a structured parental questionnaire was used to gather follow-up data on the health status of the children of the 4,221 women who had completed the study. The researchers were able to recover data for 71% (3196) of eligible children. The study revealed that in children whose mothers received erythromycin, there was an increase in functional impairment compared to children of mothers who had not received erythromycin - 42·3% to 38.3%, respectively. This translates to an increase in relative risk of 18% for receiving erythromycin. The researchers found no effect on children whose mothers received Co-amoxiclav - with or without erythromycin - concerning functional impairment.

Further, the investigators discovered that children were more likely to develop cerebral palsy who were born to mothers who had received the antibiotics - an unexpected finding. Specifically, 3.3% of children with mothers who received erythromycin (with or without co-amoxiclav) and 1.7% of children with mothers who did not receive the antibiotic had cerebral palsy. Similar numbers were found for children of mothers given co-amoxiclav (with or without erythromycin) - 3.2% and 1.9% developed cerebral palsy, respectively. For children of mothers given both antibiotics, the risk of cerebral palsy was highest - 4.4% of children had the disease compared to 1.6% of children with mothers who received double placebo. This is a tripling of risk.

The researchers did not conclude that either antibiotic had an effect on the number of deaths, other medical conditions, behavioral patterns, or educational attainment. "The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at seven years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low," conclude Dr Kenyon and colleagues.

In the ORACLE Children Study I, researchers followed up 4,148 eligible children whose mothers joined the trial with preterm rupture of the membranes without obvious infection signs. Erythromycin is currently the recommended treatment since the original trial found that this antibiotic resulted in reductions in short term neonatal death. Seventy-five percent of eligible children (3,298) were assessed in The Children Study, and the researchers found no differences in functional impairment, behavioral difficulties, medical conditions, or educational achievement with either antibiotic. The researchers conclude that: "The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at seven years of age."

Professor Philip J Steer (Chelsea and Westminster Hospital, London, UK) and Dr Alison Bedford Russell (Warwick Medical School and Heart of England NHS Trust, UK) write in an accompanying editorial that: "The lessons to be learned seem clear; contrary to popular opinion ('might as well give them, they don't do any harm'), antibiotics are not risk-free. There are good reasons not to give them in association with threatened preterm labour unless there is clear evidence of infection. It is vital the practice is not extended by stealth beyond that which is justified by the evidence, and interventions given in pregnancy should always be evaluated with proper long-term follow-up."

Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial
S Kenyon, K Pike, D R Jones, P Brocklehurst, N Marlow, A Salt, D J Taylor
The Lancet (2008).
DOI:10.1016/S0140-6736(08)61202-7
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: Peter M Crosta