Paternal metformin use before conception increases risk for birth defects
Children whose fathers who took metformin before conception are more likely to have major birth defects, especially male genital birth defects, compared with no paternal preconception exposure, according to study findings.
“This study is first of its kind showing such an effect of paternal exposure,” Maarten J. Wensink, MD, PhD, assistant professor in the department of public health at the University of Southern Denmark, told Healio. “As it is an observational study, findings will have to be confirmed, but this is yet another reason for expectant fathers to take good care of their health.”
Wensink and colleagues collected data from newborns and parents in Denmark’s Medical Birth Registry from 1997 to 2016. Data on birth defects were collected from Denmark’s Patient Registry up to 1 year after birth, and the country’s Prescription Registry was used to determine medication exposure. Medication exposure of offspring was defined as a father filling a prescription for a diabetes drug 3 months before conception.
There were 1,116,779 singleton births included in the analysis. Birth defects occurred in 3.3% of offspring, and 51.4% of infants with a birth defect were boys. There were 7,029 offspring exposed to parental diabetes medication, including 5,298 exposed to insulin, 1,451 to metformin and 647 to sulfonylureas.
Metformin exposure linked to birth defects
The birth defect frequency for offspring exposed to insulin was the same as the overall rate at 3.3%, and the sex ratio was similar with 51.3% of defects occurring in boys. Those exposed to metformin had a 5.2% birth defect rate with 49.4% of defects occurring in boys, and offspring exposed to sulfonylureas had a 5.1% birth defect rate with 49.3% of defects occurring in boys.
In adjusted analysis, offspring exposed to metformin had an increased likelihood for birth defects compared with those not exposed to diabetes medication (adjusted OR = 1.4; 95% CI, 1.08-1.82). No increased odds for birth defects were found for offspring exposed to insulin or sulfonylureas.
The likelihood for birth defects increased the closer fathers took metformin to conception. No increased odds for birth defects were observed in fathers who took metformin 1 year or more before conception or 1 year or more after conception. Exposure to metformin during sperm development 3 months before conception was associated with increased odds for birth defects (aOR = 1.75; 95% CI, 1.18-2.61).
For offspring exposed to metformin, the risk for genital birth defects was higher compared with the full study cohort (aOR = 3.39; 95% CI, 1.82-6.3), and all genital birth defects occurred in boys. There were no increased odds for genital birth defects in other medication categories.
“The decision to take a drug is a complex one that each patient should take together with their treating physician,” Wensink said. “Metformin is generally a safe drug for the father; however, men aspiring to fatherhood may consider switching to a different drug or aggressive lifestyle intervention.”
More studies, clinical guidance needed
In a related editorial, Germaine M. Buck Louis, PhD, MS, dean of the College of Health and Human Services at George Mason University in Fairfax, Virginia, wrote that the findings need to be further explored in more studies. If replicated, however, the importance of expectant fathers with type 2 diabetes on medication use should be educated about the possible risk for birth defects, according to Buck Louis.
“Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed,” Buck Louis wrote. “Meanwhile, clinical guidance is needed to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications. Important in this guidance will be communicating that the adverse relationship was specific to metformin during the period of spermatogenesis.”
Reference:
Buck Louis GM, et al. Ann Intern Med. 2022;doi:10.7326/M22-0770.
For more information:
Maarten J. Wensink, MD, PhD, can be reached at mwensink@health.sdu.dk.
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