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Research, published in the BMJ, reports that Children of mothers prescribed macrolide antibiotics during the first trimester of pregnancy are at an increased risk of birth defects.
Dr Sarah Branch, Director of Vigilance and Risk Management of Medicines (VRMM), Medicines and Healthcare products Regulatory Agency (MHRA), said:
“Untreated infection in pregnancy can cause serious harm, both to the mother and baby, and it is essential that pregnant women receive treatment with an appropriate antibiotic when necessary. Pregnant women who have been prescribed a macrolide antibiotic should continue to take it, and discuss any concerns they have with their healthcare professional.
“We are reviewing the findings of this study in the context of similar studies which have not found this association. Macrolides should continue to be used in pregnancy where there is a clinical need”.
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“This paper clearly describes a well conducted and analysed study. The authors may have had a tendency to over-interpret their findings, as is often the case with observational studies. They have tried hard to reduce differences between those prescribed macrolide antibiotics and those prescribed penicillins, which might explain the differences in congenital anomalies, but they cannot be sure that they have done so fully. There are some features in the data that are compatible with the over-interpretation – for example the excess of cardiovascular anomalies does not show a consistent pattern.
“The message of the paper should be directed at prescribers rather than at patients. It is already well-known that prescribing of drugs, including antibiotics, should be done with caution in pregnancy. The current warning labels for prescribers in the UK are clearest for clarithromycin (a macrolide antibiotic) while they are almost absent for erythromycin. The overall evidence, including this study and others, does not support the implication that erythromycin is safer than others. Even if the evidence for harm of macrolides in general is not as strong as these authors suggest, there is no real evidence of absence of harm. Caution is certainly reasonable. Prescribing for respiratory infections, where the benefits may be largely absent if the primary infection is viral, should be a particular area for caution. Unfortunately, it is not always known that a woman is pregnant in the early stages.
“The paper itself does not address the question of the benefit/risk balance of taking antibiotics. The take-home message of the paper itself is to encourage caution by prescribers. For patients, the statement from the senior author in the press release puts the paper into context. The press release states that “She [Prof Gilbert] underscored that, “Women should not stop taking antibiotics when needed, as untreated infections are a greater risk to the unborn baby.””. This is the message to patients, since raising a scare over antibiotics may result in causing harm to the unborn baby.
“Antibiotics are vital in protecting individuals against serious consequences of infection, but their over-use has led to resistance. It is not simple to reduce their use but being careful in the choice in pregnancy is entirely sensible.”
Dr Sarah Stock, Senior Clinical Lecturer Maternal and Fetal Medicine, University of Edinburgh Usher Institute, said:
“This is a high-quality study investigating whether a type of antibiotics called macrolides can cause birth defects and developmental problems in children.
“A study of this type can never definitively prove a drug causes birth defects, but real care is taken with the methods to ensure the findings are robust.
“The study is large and the link between macrolides and birth defects is consistent, making the finding of a small increased risk of some birth defects pretty convincing.
“Using an alternative antibiotic wherever possible in early pregnancy seems sensible. However, if macrolides are the only treatment option, women can be reassured that the absolute risk of a problem is low. The highest risk was seen with early pregnancy prescriptions, where the additional risk of a heart defect associated with macrolide use was less than half a percent.
“The study showed that nearly a third of woman are prescribed antibiotics at some point in their pregnancy, with around one in ten antibiotic prescriptions being for macrolides.”
Prof Jean Golding, Emeritus Professor of Paediatric and Perinatal Epidemiology, University of Bristol, said:
“This is a very thorough piece of work, based on large numbers of births. It carefully assesses the outcomes of children born to women who took macrolides with those who took penicillin during early pregnancy. They show an association between macrolides antibiotics and congenital malformations which is not found for penicillin. The same association is found when they confine the use of antibiotics to treatment of respiratory infections.
“They tested whether the results were due to characteristics of the mothers rather than the drug – firstly by showing that there were no similar associations for macrolides taken in the year before pregnancy, and secondly by demonstrating that other pregnancies to the women who had taken macrolides in pregnancy did not show any increase in congenital malformations when they did not take the drug. Although this does not prove causation conclusively, the evidence is from this study is strong.”
Dr Pat O’Brien, Consultant Obstetrician and Vice President of the Royal College of Obstetricians and Gynaecologists:
“The findings from this large and well-designed study show that some antibiotics used during pregnancy are associated with a higher risk of birth defects in babies, particularly when used in the first trimester of pregnancy. But it is important to note that the absolute risk of a baby developing a problem is still very small.
“The antibiotics studied are known as the ‘microlide’ antibiotics; the most commonly used of these is erythromycin, often used to treat urine, chest and other infections in pregnancy.
“It is not known if these antibiotics are the cause of this association with a small increased risk of abnormalities, but it is possible – the authors have done their best to exclude other possible ‘confounding’ causes.
“It is important to realise that untreated infections during pregnancy, such as urine and chest infections, can cause harm to both mother and baby, so it’s important that they are treated appropriately.
“On the basis of the findings of this study, it seems reasonable to be cautious about the use of this type of antibiotic during pregnancy until further research is carried out to clarify whether or not there really is an increased risk. Other antibiotics, such as penicillin, which are safe in pregnancy are alternatives.
“In some cases, for example in women allergic to penicillin and where the infecting bacteria are resistant to other antibiotics, erythromycin may be the only suitable antibiotic. In this situation, it seems very likely that the risks of an untreated infection will be greater than the possible risks of using erythromycin.
“As the authors say, further research is urgently needed to clarify this issue. In particular, an analysis pooling the information from all the good studies of this question (including the current one) should be carried out without delay.
“A woman who is pregnant and has been prescribed antibiotics should not stop taking prescribed medications based on this latest study alone. If she has any concerns, she is strongly encouraged to speak to her doctor.”
Prof Andrew Shennan, Professor of Obstetrics, King’s College London, said:
“This is a well conducted, and important study from the UK. It looked at just over 100,000 women, some of whom received Macrolide antibiotics (e.g. erythromycin) in pregnancy. The study found that treatment was linked to some abnormalities in children (mainly in the heart). These specific defects suggest the antibiotic caused the problem directly, rather than it being related to the illness that the antibiotic was prescribed for. The abnormalities were greater than in women who received penicillin, which is safe in pregnancy.
“However, defects were still rare (about 2%), and as these antibiotics may still be necessary to prevent serious infections, they should only be avoided if there are suitable alternatives. Fortunately many antibiotics are safe in pregnancy but Macrolides should be avoided in the first 3 months of pregnancy when the baby is developing rapidly.”
‘Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study’ by Heng Fan et al. was published in the BMJ at 23:30 UK time on Wednesday 19 February 2020.
DOI: 10.1136/bmj.m331
Declared interests
Prof Stephen Evans: “I have no commercial conflicts, but I was a co-author of reference 1 in this paper, and of other papers with Prof. Gilbert, but we have not been co-authors since 2014.”
Dr Sarah Stock: “Dr Sarah Stock receives funding from the Wellcome Trust to study the effects of medicines given in pregnancy.”
Prof Jean Golding: “I have no interests to declare.”
Dr Pat O’Brien: “No conflicts.”
Prof Andrew Shennan: “No conflicts.”
None others received.