Children of mothers prescribed macrolide antibiotics during early pregnancy are at an increased risk of major birth defects, and particularly heart defects, compared with children of mothers who are prescribed penicillin, according to the results of a study by researchers at University College London (UCL). The investigators say their findings indicate that macrolides should be used with caution during pregnancy, and if feasible alternative antibiotics should be prescribed until further data is available.

“If the associations are shown to be causal, these findings suggest that an additional four children would be born with cardiovascular malformations for every 1,000 children exposed to macrolides instead of penicillins in the first trimester of pregnancy,” commented Heng Fan, a PhD student at UCL Great Ormond Street Institute of Child Health, who is lead author of the team’s study, which is published in The BMJ, and titled, “Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the U.K.: population based cohort study.”

Macrolide antibiotics, including erythromycin, clarithromycin, and azithromycin, are among the most frequently prescribed antibiotics during pregnancy in Western countries, but national policy advice and warnings about their use in pregnant women varies, the authors noted. “A recent systematic review on the use of macrolides during pregnancy showed consistent evidence of an increased risk of miscarriage, but less consistent evidence for congenital malformations, cerebral palsy, and epilepsy.”

The UCL researchers carried out a large, retrospective cohort study using data from the UK Clinical Practice Research Datalink (CRPD), to investigate any association between macrolide antibiotic use by mothers during pregnancy and major malformations and neurodevelopmental disorders in their children. The five system-specific malformations included in the assessment were nervous, cardiovascular, gastrointestinal, genital, and urinary, and the four neurodevelopmental disorders were cerebral palsy, epilepsy, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD).

The team analyzed data from 104,605 children born in the U.K. from 1990 to 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 control cohorts.

Overall, mothers of 31% of the children in the target population were prescribed at least one antibiotic during pregnancy. Penicillins accounted for 69% of prescriptions, and macrolides for another 10%. Results from the analyses showed that there were major malformations in 186 of the 8,632 children whose mothers were prescribed macrolides at any point during pregnancy, and 1,666 of the 95,973 children whose mothers were prescribed penicillin antibiotics during pregnancy. After taking into account potential confounding factors, the results indicated that macrolide prescribing during the first trimester of pregnancy was associated with an increased risk of any major malformation, compared with penicillin (28 versus 18 per 1,000 births), and specifically with the risk of cardiovascular malformations (11 versus seven per 1,000 births).

Macrolide prescribing during any trimester was also associated with a slightly increased risk of genital malformations (five versus three per 1,000 births). No statistically significant associations were found for other system-specific malformations or for any of the four neurodevelopmental disorders. “However, we observed a borderline association with gastrointestinal malformations,” the team stated.

Overall, they reported, “Assuming the associations are causal, we estimate that for every 1,000 mothers prescribed macrolides instead of penicillins during the first trimester, an additional 4.1 (95% confidence interval 0.4 to 9.4) children would have cardiovascular malformations; the corresponding figures for prescriptions during any trimester and genital malformations would be 1.7 (0.4 to 3.5). Subgroup and sensitivity analyses did not change these findings.”

Fen commented, “Macrolide antibiotics are used to treat a wide variety of bacterial infections, and are among the most frequently prescribed antibiotics during pregnancy in Western countries. This work builds on previous evidence of rare but serious adverse outcomes of macrolide use, especially for unborn babies. These adverse outcomes were assumed to be associated with the arrhythmic effect of macrolides and policy advice about their use in pregnancy varies.”

As an observational study, the reported research does not establish cause, and the researchers point to some limitations of the study, such as being unable to examine treatment exposure during known critical periods for specific malformations and neurodevelopmental disorders. Nevertheless, as co-author Ruth Gilbert, PhD, a professor at UCL Great Ormond Street Institute of Child Health, commented, while women “should not stop taking antibiotics when needed, as untreated infections are a greater risk to the unborn baby … Our findings suggest it would be better to avoid macrolides during pregnancy if alternative antibiotics can be used.”

The authors concluded in their paper, “These findings call for cautious use of macrolides during pregnancy. Drug safety leaflets should report that there are concerns about the safety of macrolides, including erythromycin, and recommend the use of alternative antibiotics when feasible until further research is available.”

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