Study links developmental problems in children to use of antibiotics by some mothers during preterm labour

BMJ 2008; 337 doi: (Published 19 September 2008) Cite this as: BMJ 2008;337:a1725
  1. Zosia Kmietowicz
  1. 1London

    Researchers have emphasised the importance of long term follow-up of clinical trials after finding that giving antibiotics to some women in preterm labour raises the risk of cerebral palsy and mild functional problems in their children.

    The results from the seven year follow up of the ORACLE I and ORACLE II studies show that women in preterm labour with intact membranes who were treated with erythromycin were 18% (95% confidence interval 2% to 37%) more likely to have a child with a functional impairment than women given placebo (Lancet 2008 Sep 18, doi:10.1016/S0140-6736(08)61202-7 and doi:10.1016/S0140-6736(08)61203-9).

    The original ORACLE studies were published in 2001 and led to changes in the care of women in premature labour in the United Kingdom and around the world (Lancet 2001;357:981-90 and 991-6).

    They found that antibiotics can benefit women in preterm labour provided their waters have broken, but that the two antibiotics studied, erythromycin and co-amoxiclav, do not delay birth or improve the survival or health of babies whose mothers have intact membranes.

    Another finding, that co-amoxiclav raised the risk of necrotising enterocolitis in newborn babies, led to the recommendation by the Royal College of Obstetricians and Gynaecologists that erythromycin and not co-amoxiclav should be given to women whose membranes had ruptured prematurely and who could have an infection.

    For the follow-up studies the parents of all 8361 children who completed the original studies were asked to fill in a questionnaire about their child’s health seven years later with an overall response rate of 75% and 71%.

    Altogether 42.3% of children (658 of 1554) whose mothers had taken erythromycin during preterm labour with intact membranes had some mild impairments, such as needing to wear glasses or use a hearing aid or having trouble with day to day problem solving, compared with 38.3% (574 of 1498) of children whose mothers took placebo.

    There was also an unexpected rise in cerebral palsy among the children whose mothers were in premature labour with intact membranes and who took antibiotics. Of 1661 children whose mothers took erythromycin 53 (3.2%) developed cerebral palsy compared with 27 of 1562 (1.7%) whose mothers took placebo. Similar findings were seen with co-amoxiclav. Children whose mothers took erythromycin and co-amoxiclav were at even greater risk of developing cerebral palsy: 35 of 795 children (4.4%) developed the syndrome compared with 12 of 770 (1.6%) children whose mothers took double placebo.

    But taking antibiotics during labour made no difference to how the children did at education tests given in schools and many other problems the researchers looked at, such as the chances of getting attention deficit hyperactivity disorder, wheezing, seizures, or bowel problems. And no differences were found in the function, behaviour, education achievement, or health of children whose mothers took antibiotics because their membranes had ruptured.

    Although they say that the findings could be the result of chance the researchers point out that the excess of children with cerebral palsy whose mothers took both antibiotics indicates that the finding could point to a potential dose-response relation and did not happen by chance alone.

    The researchers say that antibiotics may harm unborn babies whose mothers’ membranes are not broken because they are potentially exposed to antibiotics for a fairly long time because only 15-20% of such women give birth within seven days.

    If a woman has an infection, treatment could delay labour by boosting her defences without clearing the infection, said one of the researchers, Peter Brocklehurst, director of the National Perinatal Epidemiology Unit at the University of Oxford. The infection could then remain around the baby, leading to brain damage. Another possibility is that the antibiotics could harm the fetal brain.

    However, in a letter to doctors and nurses the Department of Health said, “CHM [the Commission on Human Medicines] advised that any association between erythromycin in spontaneous premature labour and cerebral palsy was unlikely to be a direct effect of the antibiotic but rather due to a number of factors involved in disruption of the natural history of preterm labour.”

    The department has sent out the letter in an effort to pre-empt a flood of queries from pregnant women who are concerned about taking antibiotics in pregnancy or in labour. It has also set up a helpline for the women who took part in the study.

    The department and an expert panel, the Medical Research Council, which funded the studies, and the Commission on Human Medicines, the agency that advises the UK government on the safety of drugs, were given early access to the results ahead of their release this week in case public policy needed change. However, no new guidance has been needed.

    The letter says, “Pregnant women should not feel concerned about taking antibiotics to treat infections. Antibiotics save lives and pregnant women with possible or obvious infections must be considered for treatment with antibiotics.”

    In an accompanying comment on the research (doi:10.1016/S0140-6736(08)61248-9) Philip Steer, from Chelsea and Westminster Hospital, London, and Alison Bedford Russell, from Warwick Medical School and Heart of England NHS Trust, say “The lesson to be learnt 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.”

    They warn that there “seems to be an inexorable tendency” for interventions that have proven efficacy in perinatal care to be overused. Such interventions include the administration of antenatal steroids to aid the development of fetal lungs, and caesarean section for breech presentation.

    “It is vital the practice [of prescribing antibiotics to women in premature labour] 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,” said Professor Steer and Dr Russell.

    Catherine Elliott, head of clinical research support and ethics at the Medical Research Council (MRC), said, “The ORACLE children study highlights the importance of conducting long term follow-ups, especially in interventions in pregnancy and early life. The results were unexpected and the MRC is considering what further research could shed more light on these findings. We will be convening an expert group to look at what potential research avenues could be explored to understand what mechanisms may be involved.”


    Cite this as: BMJ 2008;337:a1725


    • The helpline for participants in the study is 0800 085 2411, staffed 9 30 am to 4 30 pm.

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