Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study

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.

Figure 1.

Flow chart of the creation of the data set: registries merged and numbers of inclusion and exclusion. CPR = Centrale Personregister; LASSO = least absolute shrinkage and selection operator.

Figure 2.

Study design. We made 3 comparisons: different drugs during SDev, the same drug at different time points, and exposed versus unexposed siblings. SDev = sperm development.

Figure 3.

Summary of results. The figure displays aORs (points) with their 95% CIs (bars) for the main analysis, sensitivity analyses, sibling analysis, time frame analysis, and birth defect categories. aOR = adjusted odds ratio; SDev = sperm development.