• Diabetes medications, such as metformin, have effects on the male reproductive system 
  • Reduces serum testosterone levels independently of glycemic control 
  • Unclear if this association can impact offspring  
• Wensink et al. (Annals of Internal Medicine, 2022) evaluated whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes 

• Nationwide prospective registry-based cohort study 
  • Medical Birth Registry (1997 to 2016) 
  • Contains all registered pregnancies in Denmark >20 weeks  
• Participants 
  • All liveborn singletons  
  • Mothers without a history of diabetes or hypertension 
• Exposures 
  • Paternal diabetes medication exposure 
    • Father filled ≥1 prescriptions for a diabetes drug during the development of fertilizing sperm 
• Study design 
  • Associations were adjusted for  
    • Birth year | Paternal age, income, and education | Maternal age, smoking status, and education 
  • The primary outcomes were compared  
    • Across drugs | Times of exposure | Siblings 
• Primary outcomes 
  • Offspring sex 
  • Frequencies of major birth defects 

• 1,116,779 offspring 
  • Insulin exposure: 5298 | metformin exposure: 1451 
  • Offspring with ≥1 major birth defects: 3.3% 
• Insulin-exposed offspring were not at higher odds of having birth defects than non-exposed offspring 
  • Adjusted odds ratio (aOR) 0.98 (95% CI, 0.85 to 1.14) 
• Metformin-exposed offspring had an elevated birth defect frequency 
  • aOR 1.40 (95% CI, 1.08 to 1.82) 
• There were no differences in birth defect frequencies if fathers filled a metformin prescription in the year before or the year after sperm development 
  • Before: aOR 0.88 (95% CI, 0.59 to 1.31) 
  • After: aOR 0.92 (95% CI, 0.68 to 1.26) 
• Unexposed siblings of exposed offspring also had no differences in birth defect frequencies 
  • Exposed: 3.2% 
  • OR 1.54 (95% CI, 0.94 to 2.53) 
• Among metformin-exposed offspring, genital birth defects, all in boys, were more common 
  • aOR 3.39 (95% CI, 1.82 to 6.30) 
• Proportion of male offspring was lower among metformin-exposed offspring but not significant  
  • Exposed: 49.4%  
  • Non-exposed: 51.4% 
  • P=0.073 

• The paternal use of metformin prior to conception is associated with increased odds of major birth defects, especially genital birth defects in boys 
• Results demonstrate association but not causation, which would require further studies  
• Limitations include lack of data on important confounders such glycemic control or obesity  
  • However, birth defects were not found among insulin group or preconception type 2 diabetes and not receiving metformin 
• The authors state 

The observed effect size is similar to that of maternal age greater than 45 years, a recognized risk factor, with 4.8% birth defects among liveborn singletons in our data 

The sheer size of the diabetes pandemic suggests that treatment of prospective fathers with diabetes, including pharmacologic management and counseling on diet, physical exercise, and weight loss, should be subject to further study 

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