Prescribing macrolide antibiotics in first trimester increases birth defect risk

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Children of mothers prescribed macrolide antibiotics during the first trimester of pregnancy are at an increased risk of major birth defects when compared with penicillin, and the drugs should be used ‘with caution’ according to a University College London (UCL) study.

The study aimed to assess the association between macrolides – a class of drugs used to treat common bacterial infections – and major malformations such as heart and genital defects, 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 using the Clinical Practice Research Datalink (CPRD) 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 (comparison) cohorts.

Major malformations were present in 186 children of 8,632 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 into account other influencing 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 versus 18 per 1,000 births) and specifically cardiovascular malformations (11 v seven per 1,000 births).

Macrolide prescribing in any trimester was also associated with a slightly increased risk of genital malformations (five v three per 1,000 births). No statistically significant associations were found for other system specific malformations or for any of the four neurodevelopmental disorders.

Lead author, PhD candidate Heng Fan (UCL Great Ormond Street Institute of Child Health) said: “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 researchers highlight that cause cannot be determined but as the results were largely unchanged after further analyses, they suggest that the findings withstand scrutiny.

Heng Fan added, “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.”

Professor Ruth Gilbert (UCL Great Ormond Street Institute of Child Health) added: “Our findings suggest it would be better to avoid macrolides during pregnancy if alternative antibiotics can be used."

She underscored that, “Women should not stop taking antibiotics when needed, as untreated infections are a greater risk to the unborn baby.”

The authors were supported by funding from Child Health Research CIO Trust, China Scholarship Council, National Institute for Health Research and from Health Data Research UK.

Abstract
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.

Authors
Heng Fan, Ruth Gilbert, Finbar O’Callaghan, Leah Li

University College London material

BMJ abstract

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