Long-term follow-up data on a trial to assess the effects of antibiotics given to pregnant women experiencing premature labour, with intact membranes and no obvious infection, has revealed an unexpected increased risk of functional impairment and/or cerebral palsy in some children. This is among the conclusions of the ORACLE Children's Study, published in two early Online Articles and in an upcoming edition of The Lancet. Both studies are authored by Dr Sara Kenyon, University of Leicester, UK, and colleagues from the ORACLE study group, and were funded by the Medical Research Council, UK. They emphasise the importance of long-term follow-up for clinical trials.
The original ORACLE I and II trials*, completed in 2001, were set up to determine whether possible underlying infection in women threatening to give birth prematurely could be tackled by the antibiotics erythromycin and co-amoxiclav, thereby delaying or preventing premature birth and potentially improving outcome in the short term (first 4 weeks of life) . Mothers received placebo plus erythromycin, placebo plus co-amoxiclav, both antibiotics and double-placebo, using a factorial randomized design. The ORACLE Children Study I and II were carried out in the UK to discover whether these antibiotics had any long-term effects on the children at 7 years of age born to these mothers.
ORACLE Children Study II looked at mothers in spontaneous premature labour with intact membranes surrounding their unborn child and no obvious sign of infection**. The children born to the 4221 women who had completed the study were followed-up after seven years using a structured parental questionnaire to assess the child's health status; data for 3196 (71%) of eligible children was available. The researchers found that functional impairment*** was increased in children of mothers who received erythromycin (42.3% / 658 children) compared with no erythromycin (38.3% / 574) – an increase in relative risk of 18% for receiving erythromycin. Co-amoxiclav (with or without erythromycin) had no effect of the proportion of children with any functional impairment. The researchers also made the unexpected discovery that more children whose mothers had received the antibiotics developed cerebral palsy than those who did not. For mothers receiving erythromycin (with or without co-amoxiclav), 53 (3.3%) children had cerebral palsy compared with 27 (1.7%) receiving no erythromycin. For mothers given co-amoxiclav (with or without erythromycin) 50 (3.2%) children had cerebral palsy versus 30 (1.9%) for receiving no co-amoxiclav. The risk was clearest for mothers given both antibiotics: 35 (4.4%) of children had cerebral palsy compared with 12 (1.6%) for mothers receiving double placebo — a near-trebling of relative risk. No effects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. The authors conclude in relation to this part of the study: "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."
The ORACLE Children Study I followed up 4148 eligible children whose mothers joined the trial with preterm rupture of the membranes without obvious signs of infection. The original trial reported that prescription of erythromycin to these women resulted in reductions in short term neonatal morbidity and erythromycin is now recommended treatment. , The Children Study, which assessed data from 3298 (75%) eligible children, found no differences in functional impairment with either antibiotic, and no differences in behavioural difficulties, medical conditions, or educational achievement. In relation to this part of the study, the authors conclude: "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."
In an accompanying Comment, 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, say: "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."
For Dr Sara Kenyon, University of Leicester, UK, and other members of the ORACLE study group please contact Laure Thomas, Medical Research Council Press Office T) +44 (0) 207 670 5139 / +44 (0) 7818 428 297 E) Laure.Thomas@headoffice.mrc.ac.uk
Dr Alison Bedford Russell, Heart of England NHS trust, Birmingham, UK T) +44 (0) 7905 115499 E) alison.bedfordrussell@heartofengland.nhs.uk
Notes to editors:
*For copies of original ORACLE trials from 2001, please e-mail pressoffice@lancet.com
**prescription of antibiotics to mothers in spontaneous premature labour, with intact membranes surrounding their unborn child and no obvious sign of infection, is not routine practice in the UK.
***Functional impairment was assessed using a validated tool which examined vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain. These were classified into mild, moderate and severe. Mild functional impairment included poor eyesight, difficulty walking, or struggling with day-to-day problem solving.
for full Articles and comment see: http://press.thelancet.com/oracle2008final.pdf
for original Oracle studies see: http://press.thelancet.com/oracle2001.pdf
for patient leaflet sent to parents involved the study from ORACLE investigators see: http://press.thelancet.com/ORACLEpatientleaflet.pdf
and see attached for other relevant documents
Journal
The Lancet