• Maarten J Wensink, Ying Lu, Lu Tian, Gary M Shaw, Silvia Rizzi, Tina Kold Jensen, Elisabeth R Mathiesen, Niels E Skakkebæk, Rune Lindahl-Jacobsen, and Michael L Eisenberg.
• Department of Epidemiology, Biostatistics and Biodemography, and Interdisciplinary Center on Population Dynamics, University of Southern Denmark, Odense C, Denmark (M.J.W., R.L.).
• Ann. Intern. Med. 2022 May 1; 175 (5): 665673665-673.

BackgroundDiabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.ObjectiveTo evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.DesignNationwide prospective registry-based cohort study.SettingDenmark from 1997 to 2016.ParticipantsAll liveborn singletons from mothers without histories of diabetes or essential hypertension.MeasurementsOffspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings.ResultsOf 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073).LimitationInformation on underlying disease status was limited.ConclusionPreconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation.Primary Funding SourceNational Institutes of Health.

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