Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, and Kahn-Sagol-Maccabi Research and Innovation Institute, Maccabi Healthcare Services, Tel Aviv, Israel (R.S.R.).
Department of Environmental Health and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (M.G.W.).
Ann Intern Med. 2024 Jul;177(7):851-861. doi: 10.7326/M23-1405. Epub 2024 Jun 18.
Metformin is the most used oral antidiabetic medication. Despite its established safety profile, it has known antiandrogenic and epigenetic modifying effects. This raised concerns about possible adverse developmental effects caused by genomic alterations related to paternal use of metformin during the spermatogenesis period preceding conception.
To assess the potential adverse intergenerational effect of metformin by examining the association between paternal metformin use during spermatogenesis and major congenital malformations (MCMs) in newborns.
Nationally representative cohort study.
A large Israeli health fund.
383 851 live births linked to fathers and mothers that occurred in 1999 to 2020.
MCMs and parental cardiometabolic conditions were ascertained using clinical diagnoses, medication dispensing information, and laboratory test results. The effect of metformin use on MCMs was estimated using general estimating equations, accounting for concurrent use of other antidiabetic medications and parental cardiometabolic morbidity.
Compared with unexposed fathers, the prevalence of cardiometabolic morbidity was substantially higher among fathers who used metformin during spermatogenesis, and their spouses. Whereas the crude odds ratio (OR) for paternal metformin exposure in all formulations and MCMs was 1.28 (95% CI, 1.01 to 1.64), the adjusted OR was 1.00 (CI, 0.76 to 1.31). Within specific treatment regimens, the adjusted OR was 0.86 (CI, 0.60 to 1.23) for metformin in monotherapy and 1.36 (CI, 1.00 to 1.85) for metformin in polytherapy, a treatment that was more common in patients with more poorly controlled diabetes.
Laboratory test results for hemoglobin A to assess underlying diabetes severity were available only for a subset of the cohort.
Paternal use of metformin in monotherapy does not increase the risk for MCMs. Association for metformin in polytherapy could potentially be explained by worse underlying parental cardiometabolic risk profile.
None.
二甲双胍是最常用的口服抗糖尿病药物。尽管其安全性已得到证实，但它具有已知的抗雄激素和表观遗传修饰作用。这引起了人们的关注，即与父亲在受孕前精子发生期间使用二甲双胍相关的基因组改变可能导致后代发育不良。
通过检查父亲在精子发生期间使用二甲双胍与新生儿主要先天性畸形（MCMs）之间的关联，评估二甲双胍的潜在代际不良影响。
全国代表性队列研究。
一个大型的以色列健康基金。
1999 年至 2020 年间发生的 383851 例与父母相关的活产。
使用临床诊断、药物配给信息和实验室检测结果确定 MCMs 和父母的心血管代谢状况。使用一般估计方程估计二甲双胍使用对 MCMs 的影响，同时考虑其他抗糖尿病药物的同时使用和父母的心血管代谢发病率。
与未暴露的父亲相比，在精子发生期间使用二甲双胍的父亲及其配偶的心血管代谢发病率明显更高。虽然所有制剂和 MCMs 的父亲二甲双胍暴露的粗比值比（OR）为 1.28（95%CI，1.01 至 1.64），但调整后的 OR 为 1.00（CI，0.76 至 1.31）。在特定的治疗方案中，二甲双胍单药治疗的调整后 OR 为 0.86（CI，0.60 至 1.23），而二甲双胍联合治疗的调整后 OR 为 1.36（CI，1.00 至 1.85），联合治疗更常见于糖尿病控制较差的患者。
评估潜在糖尿病严重程度的血红蛋白 A 的实验室检测结果仅适用于队列的一部分。
父亲在单药治疗中使用二甲双胍不会增加 MCMs 的风险。对于联合治疗，二甲双胍的关联可能可以通过更差的潜在父母心血管代谢风险状况来解释。
无。
