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.

中文翻译：

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英国大环内酯类抗生素在怀孕期间处方与不良儿童结局之间的关联：基于人群的队列研究。

目的评估妊娠期大环内酯类抗生素与儿童严重畸形，脑瘫，癫痫，注意缺陷多动障碍和自闭症谱系障碍之间的关系。设计基于人群的队列研究。设置英国临床实践研究数据链。参加者该研究队列包括1990年至2016年出生的104605名儿童，其母亲从妊娠第四周到分娩时被处方一种大环内酯类单一疗法（红霉素，克拉霉素或阿奇霉素）或一种青霉素单一疗法。两个阴性对照队列包括82 314名儿童，其母亲在受孕前服用了大环内酯类药物或青霉素，以及53 735名与该研究队列中的孩子为兄弟姐妹的孩子。主要观察指标大环内酯类药物或青霉素处方前三个月（妊娠四个至十三周），第二个中期至妊娠三个月（妊娠周）后，存在任何重大畸形和系统特定的重大畸形（神经，心血管，胃肠道，生殖器和尿道）的风险出生）或任何妊娠中期。此外，还存在脑瘫，癫痫，注意力缺陷多动障碍和自闭症谱系障碍的风险。结果在怀孕期间，在母亲被处方使用大环内酯类药物的8632名儿童中有186名患病（每千人中21.55），在母亲在怀孕期间使用青霉素类药物的95 973名儿童中（1 000.17.36）有1666人。与青霉素相比，大环内酯类药物在头三个月的处方与发生任何重大畸形的风险增加有关（27.65 v 17。每千人65，调整后的风险比1.55，95％置信区间1.19至2.03），尤其是心血管畸形（每千人10.60 v 6.61，1.62，1.05至2.51）。在任何妊娠期开处方大环内酯类药物都会增加生殖器畸形的风险（每千人中分别为4.75 v 3.07、1.58、1.14至2.19，主要是尿道下裂）。头三个月中的红霉素与任何重大畸形的风险增加相关（每千人分别为27.39 v 17.65、1.50、1.13至1.99）。没有发现其他系统特定的畸形或神经发育障碍有统计学意义的关联。调查结果对敏感性分析很可靠。结论与青霉素类抗生素相比，在妊娠前三个月开处方大环内酯类抗生素与任何重大畸形，特别是心血管畸形的风险增加有关。在任何妊娠期服用大环内酯类药物都会增加生殖器畸形的风险。这些发现表明，大环内酯类药物在怀孕期间应谨慎使用，如果可行，应开具替代抗生素的处方，直至进一步研究。试验注册ClinicalTrials.gov NCT03948620。这些发现表明，大环内酯类药物在怀孕期间应谨慎使用，如果可行，应开具替代抗生素的处方，直至进一步研究。试验注册ClinicalTrials.gov NCT03948620。这些发现表明，大环内酯类药物在怀孕期间应谨慎使用，如果可行，应开具替代抗生素的处方，直至进一步研究。试验注册ClinicalTrials.gov NCT03948620。