Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study

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.

Trial registration: ClinicalTrials.gov NCT03948620.

Fig 1

Flowchart of study cohort. Mothers could have had more than one pregnancy. *Acceptable patients were those who met the Clinical Practice Research Datalink (CPRD) threshold for data quality in general practices defined as contributing up to standard data. †9484 children were included in both negative control cohorts

Fig 2

Antibiotic prescriptions during pregnancy in this study. *9698 and 101 969 children were prenatally exposed to only one monotherapy of macrolides and penicillins, respectively. Study cohort included 8632 and 95 973 children exposed to antibiotics between four gestational weeks and birth (fig 1)

Fig 3

Association between adverse child outcomes and macrolide (v penicillin) antibiotics prescribing before or during pregnancy by timing of prescription: 50-10 weeks before pregnancy; during first trimester (fromfour to13 gestational weeks); during second to third trimester (from 14 gestational weeks to delivery); and during any trimester (from four gestational weeks to delivery). To protect confidentiality of patient data, <5 is given for less than five events, and - is given to avoid deduction. ADHD=attention deficit hyperactivity disorder; ASD=autism spectrum disorder; Mac=macrolide; Pen=penicillin

Fig 4

Association between adverse child outcomes and macrolide (v penicillin) prescribing during pregnancy for any indication (main analyses) and restricted to mothers in whom antibiotics were prescribed for respiratory tract infections by timing of prescription: during first trimester (fromfour to13 gestational weeks); and during second to third trimester (from 14 gestational weeks to delivery). To protect confidentiality of patient data and to be concise, outcomes are only given when all four analyses had at least five events in macrolides group. ASD=autism spectrum disorder; Mac=macrolide; Pen=penicillin; RTI=respiratory tract infection