One of the world’s most widely prescribed diabetes drugs may be linked to major birth defects in the offspring of male patients who were taking it ahead of the babies being conceived, according to a new study from Denmark released on Monday.
Metformin, available as a generic drug, is the first-line treatment for type 2 diabetes, a growing epidemic worldwide. It is usually prescribed when diet and physical activity are not enough to control blood sugar levels.
Taking metformin appeared to affect sperm that developed during a critical time before a male child was conceived. Female children were not affected.
Previous studies have linked diabetes with fertility problems in men, but the latest study is the first to show that these problems can result from treatment rather than the disease itself, according to the researchers, whose findings appear in the March 28 issue of Annals of Internal Medicine.
Since this is the first study to suggest that a father’s use of metformin may be associated with genital birth defects in his children, any changes based on the data would be “early,” according to Michael Eisenberg, MD, director of male reproductive medicine and surgery at Stanford University School of Medicine in California and one of the study’s authors. If the findings of other studies are confirmed, doctors may begin discussing the possibility with patients.
For the new study, Eisenberg and his colleagues analyzed records in a database of all 1.25 million births that occurred in Denmark between 1997 and 2016. The database included information on birth defects and parents’ drug prescriptions.
Children were considered exposed to a diabetes drug if a father had filled one or more prescriptions for the medications during the 3 months prior to conception, when the fertilizing sperm would have been produced.
The final analysis included over one million children, of whom about 7,000 were exposed to diabetes drugs via the father, and about 36,000 had one or more major birth defects.
Among nearly 1,500 male children whose fathers had taken metformin, there were 3.4-times as many major birth defects of the genitals and urinary tract, according to the researchers. The researchers did not find significant associations between birth defects and the use of insulin or sulfonylurea-based drugs.
The researchers discovered no risk of birth defects in the children of men who were prescribed metformin in the year before or after the development of their fertilizing sperm. They also found no increased risk in the siblings of the boys with birth defects who were not thought to have been exposed to the medication.
“Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed,” Germaine Buck Louis, PhD, a reproductive and perinatal epidemiologist, writes in an editorial accompanying the journal article.
Louis, the dean of the George Mason University College of Health and Human Services in Washington, DC, notes a key limitation of the research is the lack of data on how much the men in the study took the drugs they were prescribed.