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