Summary: Mothers who were prescribed macrolide antibiotics, including erythromycin and azithromycin, early in pregnancy had an increased risk of their child being born with malformations, specifically cardiovascular malformations. However, researchers found no link between exposure to these antibiotics and an increased risk of neurodevelopmental disorders.
Source: British Medical Journal
Children of mothers prescribed macrolide antibiotics during early pregnancy are at an increased risk of major birth defects, particularly heart defects, compared with children of mothers prescribed penicillin, finds a study published by The BMJ today.
The researchers say these findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available.
Macrolide antibiotics (including erythromycin, clarithromycin, and azithromycin) are—widely used to treat common bacterial infections. They are often used as alternatives for patients with penicillin allergy.
Previous studies suggest evidence of rare but serious adverse outcomes of macrolide use, especially for unborn babies. The adverse outcomes might be associated with the pro-arrhythmic (heart rhythm problems) potential of macrolides. Policy advice about macrolide use in pregnancy varies.
To address these uncertainties, a team of researchers based at UCL set out to assess 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.
Researchers analysed data from 104,605 children born in the UK 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 negative control cohorts.
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.
After taking account of potentially influential factors, the researchers found macrolide prescribing during the first three months (the first trimester) of pregnancy was associated with an increased risk of any major malformation compared with penicillin (28 v 18 per 1000) and specifically cardiovascular malformations (11 v 7 per 1000).
The increased risks were not observed in children of mothers whose macrolides were prescribed in later pregnancy (during the second to third trimester).
Macrolide prescribing in any trimester was also associated with a slightly increased risk of genital malformations (5 v 3 per 1000). No statistically significant associations were found for other system specific malformations or for any of the four neurodevelopmental disorders.
This is an observational study, so can’t establish cause, and the researchers point to some limitations, such as being unable to examine treatment exposure during known critical periods for specific malformations and neurodevelopmental disorders.
However, results were largely unchanged after further analyses, suggesting that the findings withstand scrutiny.
If the associations are shown to be causal, the researchers estimate that an additional 4 children with cardiovascular malformations would occur for every 1000 children exposed to macrolides instead of penicillins in the first trimester.
“These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available,” they conclude.
Source:
British Medical Journal
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Original Research: Open access
“Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study”. Heng Fan, Ruth Gilbert, Finbar O’Callaghan, Leah Li.
BMJ doi:10.1136/bmj.m331.
Abstract
Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study
Objective
To assess the association between macrolide antibiotics prescribing during pregnancy and major malformations, cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder in children.
Design
Population based cohort study.
Setting
The UK Clinical Practice Research Datalink.
Participants
The study cohort included 104 605 children born from 1990 to 2016 whose mothers were prescribed one macrolide monotherapy (erythromycin, clarithromycin, or azithromycin) or one penicillin monotherapy from the fourth gestational week to delivery. Two negative control cohorts consisted of 82 314 children whose mothers were prescribed macrolides or penicillins before conception, and 53 735 children who were siblings of the children in the study cohort.
Main outcome measures
Risks of any major malformations and system specific major malformations (nervous, cardiovascular, gastrointestinal, genital, and urinary) after macrolide or penicillin prescribing during the first trimester (four to 13 gestational weeks), second to third trimester (14 gestational weeks to birth), or any trimester of pregnancy. Additionally, risks of cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder.
Results
Major malformations were recorded in 186 of 8632 children (21.55 per 1000) whose mothers were prescribed macrolides and 1666 of 95 973 children (17.36 per 1000) whose mothers were prescribed penicillins during pregnancy. Macrolide prescribing during the first trimester was associated with an increased risk of any major malformation compared with penicillin (27.65 v 17.65 per 1000, adjusted risk ratio 1.55, 95% confidence interval 1.19 to 2.03) and specifically cardiovascular malformations (10.60 v 6.61 per 1000, 1.62, 1.05 to 2.51). Macrolide prescribing in any trimester was associated with an increased risk of genital malformations (4.75 v 3.07 per 1000, 1.58, 1.14 to 2.19, mainly hypospadias). Erythromycin in the first trimester was associated with an increased risk of any major malformation (27.39 v 17.65 per 1000, 1.50, 1.13 to 1.99). No statistically significant associations were found for other system specific malformations or for neurodevelopmental disorders. Findings were robust to sensitivity analyses.
Conclusions
Prescribing macrolide antibiotics during the first trimester of pregnancy was associated with an increased risk of any major malformation and specifically cardiovascular malformations compared with penicillin antibiotics. Macrolide prescribing in any trimester was associated with an increased risk of genital malformations. These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available.
Trial registration
ClinicalTrials.gov NCT03948620
