• Ran S Rotem, Marc G Weisskopf, Krista F Huybrechts, and Sonia Hernández-Díaz.
• 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.).
• Ann. Intern. Med. 2024 Jul 1; 177 (7): 851861851-861.

BackgroundMetformin 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.ObjectiveTo 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.DesignNationally representative cohort study.SettingA large Israeli health fund.Participants383 851 live births linked to fathers and mothers that occurred in 1999 to 2020.MeasurementsMCMs 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.ResultsCompared 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.LimitationLaboratory test results for hemoglobin A1c to assess underlying diabetes severity were available only for a subset of the cohort.ConclusionPaternal 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.Primary Funding SourceNone.

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