If men take metformin, a common type 2 diabetes drug, during a critical period of sperm development, their offspring may be more likely to develop birth defects, a large study suggests.
In particular, the study found that male babies born to fathers who took metformin during this critical period had a higher risk of genital birth defects than babies whose fathers took metformin outside of that key time window or had never taken the drug. The new research was published Monday (March 28) in the journal Annals of Internal Medicine.
"Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed," Germaine M. Buck Louis, Dean of the College of Health and Human Services at George Mason University in Virginia, wrote in a commentary on the study. "Meanwhile, clinical guidance is needed to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications."
More research is needed to understand whether and how metformin affects developing sperm and the resulting embryo, first author Dr. Maarten Wensink, an epidemiologist and biostatistician at the University of Southern Denmark, told Live Science in an email. In the meantime, diabetic men who plan to have children and are interested in alternative medications should consult a doctor before switching prescriptions, he said.
"In general, metformin is effective, cheap and safe to the person who is taking it. Those are important factors to consider," Wensink said. "Whether or not to take metformin is a decision that every patient should [discuss] with their treating physician."
An increased risk
Both type 1 diabetes, where the body doesn't produce enough insulin, and type 2 diabetes, where cells show insulin resistance, can impair male fertility. For example, diabetes and the associated high blood sugar can disrupt both testosterone and sperm production, contributing to low sperm counts and erectile dysfunction, and the disease has also been linked to DNA damage in sperm cells, studies suggest.
But although it's known that persistently elevated blood sugar can undermine male reproductive health, the effects of diabetes drugs on male fertility and birth outcomes remain uncertain, the study authors noted in their report.
The enormous study included data from more than 1.1 million births in Denmark between 1997 and 2016; these births were cataloged in the nationwide Medical Birth Registry. The research excluded newborns born to mothers diagnosed with diabetes or high blood pressure, so that the analysis could specifically zoom in on how the fathers' diabetes status and medication use affected the offspring.
To determine the rate of birth defects among these babies, the team then checked the nationwide Patient Registry, which includes all diagnoses made in inpatient and outpatient settings. They also used the Prescription Registry to review all the prescriptions the fathers redeemed during the study period. Sperm development and maturation takes about three months, start to finish, so babies were considered "exposed" to a diabetes drug if their father filled at least one prescription in the three-month window before conception.
The team included three classes of diabetes drugs in this analysis: insulin, metformin and sulfonylureas, a class of drugs used to treat type 2 diabetes that work differently from metformin. Metformin works by decreasing the amount of sugar released into the bloodstream by the liver, while also sensitizing cells to insulin, according to the U.K. National Health Service (NHS). Sulfonylureas both sensitize cells to insulin and drive cells in the pancreas to produce more of the hormone, according to the medical database StatPearls.
Of the 1.1 million babies included in the analysis, more than 36,500, or 3.3%, had at least one major birth defect, the analysis showed. More than 7,000 babies out of the total had been exposed to one of the three diabetes medications.
The rate of birth defects among insulin-exposed babies matched that of the general population, indicating insulin was not linked to any increase in risk. But babies whose fathers had filled a metformin prescription had a higher rate of birth defects: 5.2% compared with the baseline rate of 3.3%. Among the metformin-exposed infants, the rate of genital birth defects was particularly high compared with the rest of the study population, and these genital birth defects only appeared in male babies.
Notably, the authors didn't see an increased rate of birth defects among the unexposed siblings of these babies, Buck Louis wrote in her commentary. And in addition, the elevated risk did not affect babies whose fathers took metformin outside the critical three-month window of sperm development.
The number of babies exposed to sulfonylureas was relatively small — about 650 compared with 1,450 in the metformin group — so the authors could not confidently determine whether the drugs carried an associated risk of birth defects, Wensink said. And "many of the fathers who used [sulfonylureas] also used metformin, again complicating the interpretation," he added.
Another limitation of the study is that the data can't reveal how well each father adhered to his diabetes medication or how his blood sugar levels fluctuated through time, Buck Louis wrote. Both of these factors could also influence male fertility and the risk of birth defects, she said.
Although somewhat limited, the study results do hint that metformin increases the risk of birth defects by somehow interfering with sperm development in the father. Future studies in different populations will be needed to confirm the finding and to unpack why the drug might be linked to such a risk, Wensink said.
"Wensink and colleagues' work supports a global call for more conclusive study of the potential risks for paternal use of diabetes drugs to offspring," Buck Louis wrote.
Originally published on Live Science.
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Nicoletta Lanese is the health channel editor at Live Science and was previously a news editor and staff writer at the site. She holds a graduate certificate in science communication from UC Santa Cruz and degrees in neuroscience and dance from the University of Florida. Her work has appeared in The Scientist, Science News, the Mercury News, Mongabay and Stanford Medicine Magazine, among other outlets. Based in NYC, she also remains heavily involved in dance and performs in local choreographers' work.