Paternal Use of Metformin Linked to Birth Defects

Men taking metformin were more likely to have offspring with birth defects, a Danish study found.

Newborns with fathers who took metformin during the development of fertilizing sperm had a 40% higher frequency of birth defects compared with newborns whose fathers used insulin (adjusted OR 1.40, 95% CI 1.08-1.82), reported Maarten J. Wensink, MD, PhD, of the University of Southern Denmark, and colleagues.

The same did not hold true for offspring with fathers who took sulfonylureas versus insulin (aOR 1.34, 95% CI 0.94-1.92), they pointed out in the Annals of Internal Medicine.

Of note, the researchers found that only genital birth defects — all of which occurred in boys — had a significantly elevated frequency in the metformin-exposed newborns (aOR 3.39, 95% CI 1.82-6.30). The frequencies of other types of birth defects, such as digestive, urinary, heart, chromosomal, and limb, among others, were not significantly higher.

“The fact that the risk associates with one specific paternal medication during the specific window when sperm that would lead to a pregnancy are developing surprised us,” Wensink told MedPage Today. “There are papers on fish and rats where metformin affects the male reproductive system, but such findings may not carry over into humans, and these papers did not focus on sperm development.”

As for some reassuring news, Wensink’s group found that fathers who filled a metformin prescription the year prior to sperm development didn’t see this higher rate of birth defects among their offspring (aOR 0.88, 95% CI 0.59-1.31). Likewise, there wasn’t an increased frequency of birth defects if men filled a metformin prescription after sperm development (aOR 0.92, 95% CI 0.68-1.26).

In addition, unexposed siblings of metformin-exposed children didn’t see a higher frequency of birth defects (exposed vs unexposed OR 1.54, 95% CI 0.94-2.53).

“These are the first data to suggest that paternal metformin may be associated with birth defects in children. As such, it would be early to begin to alter clinical practice,” Wensink pointed out. “However, if it is confirmed in other populations, then it may begin to enter counseling discussions.”

“For now, I would just re-emphasize that paternal health is important in its own right, but also because it may affect offspring,” he added. “We should be aware of this and do research on it.”

“Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed,” wrote Germaine M. Buck Louis, PhD, MS, of George Mason University in Fairfax, Virginia, in an accompanying editorial.

“If corroborated, metformin would not be the first medication to pose iatrogenic risk or be recognized as a human teratogen,” she noted.

She suggested that clinical guidance should address this potential risk, especially for couples planning a pregnancy, in order to help patients weigh the risks and benefits of metformin use compared with other diabetes agents.

For this nationwide prospective cohort study, data on all registered pregnancies from 20 weeks of gestation were collected from the Medical Birth Registry in Denmark from 1997 to 2016. The median ages of mothers and fathers were 30 and 33, respectively. Of note, offspring born to mothers with diabetes were excluded.

Of the 1,116,779 newborns included in the study, 7,029 were exposed to paternal diabetes medications — 5,298 were exposed to insulin, 1,451 to metformin, and 647 to sulfonylureas. Since too few fathers were taking other diabetes agents, they weren’t included in the analysis.

Overall, there was a slightly lower proportion of male offspring in the metformin-exposed population (49.4% vs 51.4% for girls).

About 3% of the newborns had one or more major birth defects in the first year of life, according to the EUROCAT guidelines.

The study did not take paternal adherence to diabetes medications into account, which was a limitation, Wensink and team acknowledged.