Diabetes reduces semen quality and increasingly occurs during reproductive years. Whether diabetes medications have glucose-independent effects on the male reproductive system is uncertain. This study examined whether the risk for birth defects in offspring varies with preconception pharmacologic treatment of fathers with diabetes.
Abstract
Background:
Diabetes 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.
Objective:
To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.
Design:
Nationwide prospective registry-based cohort study.
Setting:
Denmark from 1997 to 2016.
Participants:
All liveborn singletons from mothers without histories of diabetes or essential hypertension.
Measurements:
Offspring 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.
Results:
Of 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).
Limitation:
Information on underlying disease status was limited.
Conclusion:
Preconception 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 Source:
National Institutes of Health.
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Author, Article, and Disclosure Information
Maarten J. Wensink,
Department of Epidemiology, Biostatistics and Biodemography, and Interdisciplinary Center on Population Dynamics, University of Southern Denmark, Odense C, Denmark (M.J.W., R.L.)
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California (Y.L., L.T.)
Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California (G.M.S.)
Interdisciplinary Center on Population Dynamics and Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense M, Denmark (S.R.)
Department of Environmental Medicine, University of Southern Denmark, Odense C, Denmark (T.K.J.)
Centre for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen University, Copenhagen, Denmark (E.R.M.)
Juliane Marie Centre, Department of Growth and Reproduction, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (N.E.S.)
Male Reproductive Medicine and Surgery, Department of Urology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California (M.L.E.).
Acknowledgment: The authors thank Matthew Keys for comments.
Grant Support: By grants HD096468 (MJW, YL, SR, TKJ, NES, RL, and MLE) and 1UL1TR003142 (LT and YL) from the National Institutes of Health and grant U01DD001226 (GMS) from the Centers for Disease Control and Prevention.
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-4389.
Reproducible Research Statement: Study protocol: Not available. Statistical code: Available on request from Dr. Wensink (e-mail, mwensink@health.
Corresponding Author: Maarten J. Wensink, MD, PhD, University of Southern Denmark Faculty of Health Sciences, Winsloewsvej 9B, 5000 Odense C, Denmark; e-mail, mwensink@health.
Author Contributions: Conception and design: M.L. Eisenberg, T.K. Jensen, R. Lindahl-Jacobsen, G.M. Shaw, N.E. Skakkebæk, M.J. Wensink.
Analysis and interpretation of the data: M.L. Eisenberg, T.K. Jensen, R. Lindahl-Jacobsen, Y. Lu, E.R. Mathiesen, S. Rizzi, G.M. Shaw, N.E. Skakkebæk, M.J. Wensink.
Drafting of the article: M.L. Eisenberg, R. Lindahl-Jacobsen, E.R. Mathiesen, G.M. Shaw, N.E. Skakkebæk, M.J. Wensink.
Critical revision of the article for important intellectual content: M.L. Eisenberg, T.K. Jensen, R. Lindahl-Jacobsen, Y. Lu, E.R. Mathiesen, S. Rizzi, G.M. Shaw, L. Tian, M.J. Wensink.
Final approval of the article: M.L. Eisenberg, T.K. Jensen, R. Lindahl-Jacobsen, Y. Lu, E.R. Mathiesen, S. Rizzi, G.M. Shaw, N.E. Skakkebæk, L. Tian, M.J. Wensink.
Provision of study materials or patients: R. Lindahl-Jacobsen.
Statistical expertise: Y. Lu, G.M. Shaw, L. Tian, M.J. Wensink.
Obtaining of funding: M.L. Eisenberg, T.K. Jensen, R. Lindahl-Jacobsen, Y. Lu, N.E. Skakkebæk.
Administrative, technical, or logistic support: M.L. Eisenberg, T.K. Jensen, R. Lindahl-Jacobsen.
Collection and assembly of data: R. Lindahl-Jacobsen, S. Rizzi, M.J. Wensink.
This article was published at Annals.org on 29 March 2022.
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