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

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m331 (Published 19 February 2020) Cite this as: BMJ 2020;368:m331
  1. Heng Fan, researcher1,
  2. Ruth Gilbert, professor of clinical epidemiology1,
  3. Finbar O’Callaghan, professor of paediatric neuroscience2,
  4. Leah Li, associate professor of medical statistics and epidemiology1
  1. 1Population, Policy and Practice Programme, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
  2. 2Developmental Neurosciences Programme, Great Ormond Street Institute of Child Health, University College London, London, UK
  1. Correspondence to: Heng Fan heng.fan.16{at}ucl.ac.uk
  • Accepted 7 January 2020

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

Footnotes

  • Contributors: All authors were involved in the conception of the research question and designed the protocol. HF did the statistical analysis. HF, LL, and RG designed the tables, figures, and appendices. HF prepared the initial drafts of the manuscript, with input from LL, RG, and FOC. FOC validated the cerebral palsy cases. All authors critically reviewed and approved the final version of the manuscript. RG and LL are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: HF received funding from Child Health Research CIO (CHR CIO) Trust and China Scholarship Council (grant reference No 201606100058). RG receives funding from Health Data Research UK. This work was supported by the National Institute for Health Research. Funders were not involved in the design and conduct of the study; collection, management, analysis, or interpretation of the data; and preparation, review, or approval of the manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Child Health Research CIO (CHR CIO) Trust, China Scholarship Council, Health Data Research UK, and the National Institute for Health Research for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study was approved by the University College London Research Ethics Committee (14569.001).

  • Data sharing: No additional data available.

  • The lead author (HF) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as registered have been explained.

  • Dissemination to participants and related patient and public communities: The results of the research will be disseminated to the public through broadcasts, popular science articles, and newspapers.

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