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Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study
Maarten J Wensink1, Ying Lu2, Lu Tian2
1Department of Epidemiology, Biostatistics and Biodemography, and Interdisciplinary Center on Population Dynamics, University of Southern Denmark, Odense C, Denmark (M.J.W., R.L.).
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.
Insights
Paternal diabetes medication use, specifically metformin, is linked to an increased risk of major birth defects in offspring, particularly genital defects in boys. Further research is needed to confirm these findings and understand the causes.
Area of Science:
- Reproductive Medicine
- Developmental Biology
- Pharmacology
Background:
- Diabetes mellitus affects semen quality and is prevalent during reproductive years.
- Diabetes medications may have glucose-independent effects on the male reproductive system.
- The association between paternal diabetes treatment and offspring birth defects is not well-established.
Purpose of the Study:
- To investigate the association between paternal preconceptional diabetes medication use and the risk of major birth defects in offspring.
- To compare the risk of birth defects across different diabetes medications and exposure timings.
Main Methods:
- A nationwide, prospective, registry-based cohort study was conducted in Denmark from 1997 to 2016.
- Included were liveborn singletons whose mothers had no history of diabetes or hypertension.
- Offspring were categorized based on paternal exposure to diabetes medications (insulin, metformin, sulfonylurea) during sperm development.
Main Results:
- Among 1,116,779 offspring, 3.3% had major birth defects.
- Paternal metformin exposure was associated with an increased risk of major birth defects (aOR, 1.40).
- Metformin-exposed offspring had a higher incidence of genital birth defects, exclusively in boys (aOR, 3.39), and a slightly lower proportion of males.
Conclusions:
- Preconception paternal metformin treatment is associated with an increased risk of major birth defects, particularly genital defects in male offspring.
- The findings suggest a potential teratogenic effect of metformin exposure through fathers.
- Further research is warranted to validate these findings and elucidate the underlying mechanisms.
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