Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring

Details

• Alternative Title:
  Ann Intern Med
• Personal Author:
  Wensink, Maarten J. ; Lu, Ying ; Tian, Lu ; Shaw, Gary M. ; Rizzi, Silvia ; Jensen, Tina Kold ; Mathiesen, Elisabeth R. ; Skakkebæk, Niels E. ; Lindahl-Jacobsen, Rune ; Eisenberg, Michael L.
• Description:
  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 1116779 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.
  
  
• Subjects:
  Cohort Studies Diabetes Mellitus Humans Hypoglycemic Agents Male Metformin Semen Analysis
• Source:
  Ann Intern Med. 175(5):665-673
• Pubmed ID:
  35344380
• Pubmed Central ID:
  PMC9844982
• Document Type:
  Journal Article
• Funding:
  R21 HD096468/HD/NICHD NIH HHSUnited States/ ; U01 DD001226/DD/NCBDD CDC HHSUnited States/ ; U01DD001226/ACL/ACL HHSUnited States/ ; UL1 TR003142/TR/NCATS NIH HHSUnited States/
• Volume:
  175
• Issue:
  5
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:97d90cf70ce277bfcdcbb67d89b18b0092ec4b0237974af35f4598ce2c62977f70a94ef8b55fc356c5bd3a0a30afb7ba673de31b314995aadb1e9aab31ea1e17
• Download URL:
  https://stacks.cdc.gov/view/cdc/123831/cdc_123831_DS1.pdf
• File Type:
  [PDF - 965.37 KB ]