Metformin Linked to Birth Defects in Male Children: Study

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A new study suggests that metformin, a widely used diabetes drug, could be dangerous for men to use if they’re planning to have children. The research found a higher risk of genital birth defects in boys whose fathers had likely been taking metformin in the three months prior to conception. More data will be needed to understand whether this link represents a true cause-and-effect relationship and if it should change how the drug is prescribed.

Metformin is a generic drug that’s proven to be an invaluable treatment for many people with type 2 diabetes. In combination with diet and exercise, metformin helps keep blood sugar levels in check. It’s also often used off-label as a modest weight loss aid and to manage symptoms of polycystic ovary syndrome, a hormonal condition that can raise the risk of insulin resistance and type 2 diabetes. Some data has even suggested that it may help slow down cognitive decline in older patients.

As important as metformin is, no drug is without side effects. And some studies, largely in animals gold in the lab, have suggested that the drug could negatively affect the male reproductive system. This new research, published Monday in Annals of Internal Medicine, seems to be the first large study of its kind to look for this potential impact in men.

The study authors analyzed population data from Denmark on over a million births recorded from 1997 to 2016. This data included information on prescribed medications filled by the parents of these children. And when they looked at the outcomes of children born to fathers who had filled with a prescription for metformin during the preconception periodthey found an overall higher rate of birth defects: about 5.4% for these children, compared to 3.3% of other children.

After further digging, this increased risk was only found for defects involving the genitals in male children. Even after adjusting for other factors, the researchers found a 3.39-fold higher risk of genital defects in these children compared to others. No increased risk was found in children whose diabetic fathers were taking insulin but not taking metformin, nor in unexposed siblings, nor in children whose fathers had filled a prescription for metformin earlier than three months before conception or afterwards. These latter findings, while not proving a causal link, do bolster the case that taking metformin in that pivotal window of time is the source of the added risk (it takes about three months on average for new sperm cells to be created).

“Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys,” the authors wrote.

The absolute risk of metformin-linked birth defects does still appear to be very small. Only about 0.9% of children in this group developed genital defects, compared to 0.24% of other children. But because metformin is so widely taken, including by younger men who may use it for weight loss, the potential level of exposure may still be substantial, the study authors warn.

For now, it’s too early to know whether there’s a clear cause-and-effect connection between metformin and birth defects. And if even a risk does exist, any decisions on whether would-be fathers should stop taking metformin would have to be balanced against its benefits for controlling type 2 diabetes, itself a health condition that can affect male fertility.

“Further research should replicate these findings and clarify the causation,” the authors say.

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