In early 2020, the British Medical Journal (BMJ) urged caution regarding the use of some antibiotics in pregnancy. A study they published had found that children of mothers prescribed macrolide antibiotics during early pregnancy were at an increased risk of major birth defects, namely heart defects, when compared with children of mothers who received penicillin. The researchers therefore stated at the time that this meant macrolides should be used with caution throughout pregnancy and if appropriate alternative options can be prescribed, that would be best until further research is able to give more evidence as to the apparent risk macrolides present.
Macrolide antibiotics include erythromycin, clarithromycin and azithromycin, and are often used to treat common bacterial infections, particularly as an alternative for patients with penicillin allergy. The BMJ (2020) did state that research in the past suggested evidence of rare yet serious adverse outcomes of macrolide use, particularly in unborn babies.
In order to address the uncertainties surrounding macrolide use, a team of researchers at UCL carried out research to analyse the association between macrolide antibiotics prescribed during pregnancy and major malformations, as well as four neurodevelopmental disorders (cerebral palsy, epilepsy, ADHD, and autism spectrum disorder) in children.
Data were analysed from 104 605 children born in the UK between 1990–2016 with a median follow-up of 5.8 years after birth. A further 82 314 children whose mothers were prescribed macrolides or penicillins before pregnancy, and 53 735 children who were siblings of children in the study group acted as negative control cohorts. The study found that major malformations were recorded in 186 of 8 632 children whose mothers were prescribed macrolides at any point during pregnancy and 1 666 of 95 973 children whose mothers were prescribed penicillins during pregnancy. Potentially influential factors were considered yet despite this, the researchers concluded that macrolide prescribing during the first trimester of pregnancy in particular was associated with an elevated risk of major malformation in comparison with the use of penicillin. The difference was large, finding the defects in 28 of 1 000 babies of the erythromycin group and 18 per 1 000 in the penicillin group. Cardiovascular malformations specifically were found in 11 per 1 000 of the erythromycin group and 7 per 1 000 of those whose mothers received penicillin.
‘Researchers stated at the time that macrolides should be used with caution throughout pregnancy’
The study was however observational, and therefore could not establish cause, and of course treatment exposure could not be examined due to the historical data gathering design, which would have benefited the analysis of use of such antibiotics in known critical periods for specific malformations and neurodevelopmental disorders.
Since the potential risk was identified, a new study by Worm et al (2021), also published in the BMJ, seems to provide further clarity on the association between use of macrolides in pregnancy and risk of major birth defects. This was a nationwide register-based cohort study thus carrying some of the same limitations, set in Denmark between 1997 and 2016.
Of 1 192 539 live-birth pregnancies, pregnancies during which macrolides had been used (13 019) were compared with those during which penicillin had been used, matching the groups in a 1:1 ratio on propensity scores. Other comparative groups were pregnancies where macrolides had been used recently but prior to the pregnancy (matched 1:1) and pregnancies where no antibiotics had been used at all (matched 1:4). The team identified the main outcomes measures to be the association with an outcome of any major birth defect and specific subgroups of birth defects. These were assessed by relative risk ratios and absolute risk differences.
Worm et al (2021) found that in matched comparisons, 457 infants were born with major birth defects to women who had used macrolides during pregnancy (35.1 per 1000 pregnancies) compared with 481 infants (37.0 per 1000 pregnancies) to women who had used penicillin, corresponding to an absolute risk difference of -1.8 per 1000 pregnancies. The risk of major birth defects was found to not be significantly increased for women who had received macrolides during pregnancy in comparison to women who had used macrolides recently but before becoming pregnant, showing an absolute risk difference of -0.1. Similarly, there was no significant risk increase found when comparing the macrolides in pregnancy groups with women who did not use any antibiotics at all. For all three comparative group analyses and in the analyses of use of individual macrolides, the team found there to be no significant increased risk of specific subgroups of birth defects associated with the use of macrolides.
Worm et al (2021) therefore concluded that the use of macrolide antibiotics in pregnancy was not associated with an increased risk of major birth defects, therefore completely disagreeing in effect with the outcome of the other study a year earlier. Analyses of the associated risk of 12 specific subgroups of birth defects with the use of macrolides in pregnancy were not significant.
This highlights how ongoing research investigating the same topic can certainly influence a potential change in practice (yet to be confirmed) and a change in the knowledge base surrounding use of certain medications in certain types of patients. Of course, midwives are required to follow current national guidelines which will aim to reflect the limitations present in different studies, as well as arriving at a more reliable conclusion based on a mass of research. Currently, erythromycin is the only macrolide that can be used in pregnancy, and it would be recommended to keep up to date with NHS and BNF recommendations in case of any change.