Population, Policy and Practice Programme, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Population, Policy and Practice Programme, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
BMJ. 2020 Feb 19;368:m331. doi: 10.1136/bmj.m331.
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.
Population based cohort study.
The UK Clinical Practice Research Datalink.
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.
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.
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 17.65 per 1000, adjusted risk ratio 1.55, 95% confidence interval 1.19 to 2.03) and specifically cardiovascular malformations (10.60 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 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 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.
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.
ClinicalTrials.gov NCT03948620.
评估孕期使用大环内酯类抗生素与儿童主要畸形、脑瘫、癫痫、注意缺陷多动障碍和自闭症谱系障碍之间的关联。
基于人群的队列研究。
英国临床实践研究数据链。
研究队列包括 1990 年至 2016 年出生的 104605 名儿童，其母亲在妊娠第 4 周到分娩期间接受了一种大环内酯类单药治疗（红霉素、克拉霉素或阿奇霉素）或一种青霉素单药治疗。两个阴性对照队列包括 82314 名母亲在受孕前接受大环内酯类或青霉素治疗的儿童，以及 53735 名研究队列中儿童的兄弟姐妹。
母亲在妊娠早期（4 至 13 孕周）、妊娠中期至晚期（14 孕周至分娩）或任何孕期使用大环内酯类或青霉素类药物后，出现任何主要畸形和特定系统主要畸形（神经、心血管、胃肠道、生殖和泌尿）的风险。此外，还评估了脑瘫、癫痫、注意缺陷多动障碍和自闭症谱系障碍的风险。
在接受大环内酯类治疗的 8632 名儿童中有 186 名（21.55/1000）和接受青霉素治疗的 95973 名儿童中有 1666 名（17.36/1000）发生主要畸形。与青霉素相比，妊娠早期使用大环内酯类药物与任何主要畸形的风险增加相关（27.65 17.65/1000，调整风险比 1.55，95%置信区间 1.19 至 2.03），特别是心血管畸形（10.60 6.61/1000，1.62，1.05 至 2.51）。任何孕期使用大环内酯类药物与生殖畸形风险增加相关（4.75 3.07/1000，1.58，1.14 至 2.19，主要为尿道下裂）。妊娠早期使用红霉素与任何主要畸形的风险增加相关（27.39 17.65/1000，1.50，1.13 至 1.99）。未发现其他特定系统畸形或神经发育障碍与大环内酯类药物有统计学显著相关性。敏感性分析结果稳健。
与青霉素类抗生素相比，妊娠早期使用大环内酯类抗生素与任何主要畸形，特别是心血管畸形的风险增加相关。任何孕期使用大环内酯类药物与生殖畸形风险增加相关。这些发现表明，在怀孕期间应谨慎使用大环内酯类药物，如果可行，应在进一步研究之前选择替代抗生素。
ClinicalTrials.gov NCT03948620。
