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Paternal use of metformin linked to birth defects

A photo of a metformin tablet laying on a blister pack.

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

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

The same does not apply to 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.

From knowledge, the researchers found that only gender birth defects – which all occurred in boys – had a significantly increased 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 system, urinary, cardiac, chromosomal and limb, among others, were not significantly higher.

“The fact that the risk is associated with one specific paternal medication during the specific window when sperm would lead to a pregnancy surprised us,” Wensink said. MedPage Today. “There are papers on fish and rats where metformin affects the male reproductive system, but such findings may not be passed on to humans, and these papers have not focused on sperm development.”

As for reassuring news, Wensink’s group found that fathers who completed a metformin prescription the year before sperm development did not see this higher rate of birth defects among their offspring (aOR 0.88, 95% CI 0.59- 1.31). Similarly, there was no increased frequency of birth defects when men filled a metformin prescription after sperm development (aOR 0.92, 95% CI 0.68-1.26).

In addition, exposed siblings of metformin-exposed children did not see a higher frequency of birth defects (exposed versus exposed 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 start changing clinical practice,” Wensink pointed out. “However, if it is confirmed in other populations, then it may start having counseling conversations.”

“For now, I just want to emphasize again that paternal health is important on its own, but also because it can affect offspring,” he added. “We need to be aware of this and do research on it.”

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

“If confirmed, metformin will not be the first medication that carries iatrogenic risk or is recognized as a human teratogen,” she noted.

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

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

Of the 1,116,779 newborns included in the study, 7,029 were exposed to paternal diabetes medication – 5,298 were exposed to insulin, 1,451 to metformin and 647 to sulfonylureas. Because too few fathers used other diabetes drugs, they were not included in the analysis.

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

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

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

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    Kristen Monaco is a staff writer focusing on endocrinology, psychiatry and nephrology news. Based out of the New York City office, she has been working for the company since 2015.

Disclosures

The study was funded by the National Institutes of Health.

Wensink did not report any revelations. Other co-authors have reported several relationships, including with Novo Nordisk and Gilead.

Buck Louis did not report any revelations.

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