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

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.