Paternal Use of Metformin Linked to Increased Birth Defects

Metformin is one of the most widely prescribed and well-researched drugs for the treatment of type 2 diabetes mellitus. However, a new observational study by Stanford Medicine and their collaborators in Denmark has shown evidence of birth defects that raise questions and concerns among patients with a diabetes diagnosis. Data from this study has shown that men who take metformin within three months before a conception are more likely to have male offspring with genital birth defects. Please continue reading to learn more.

Medications and genital birth defects

It is well known that certain medications are linked to birth defects when taken by pregnant women. However, it is a possibility that the father can also contribute to birth defects, which is not surprising, given that fathers account for half of a child’s DNA.

Specifically, metformin, one of the most commonly prescribed oral diabetes pharmacologic agents, has recently been in the medical world's spotlight. As mentioned above, an observational study has shown that paternal (the father) metformin use can increase the risk of genital birth defects in baby boys.

Is metformin use safe during pregnancy? Is it linked to major birth defects?

Metformin is an oral medication currently approved by the U.S. Food and Drug Administration to treat type 2 diabetes mellitus. It is not recommended to use metformin during pregnancy; its use during pregnancy is not contraindicated. Clinicians will use their clinical judgment to evaluate this medication's risks and benefits in pregnant women.

Metformin’s use off-label to treat infertility caused by polycystic ovary syndrome (PCOS) is increasing. Metformin is known to help women with polycystic ovary syndrome conceive. Studies also indicate that metformin use during pregnancy can decrease the risk of spontaneous abortion in women with PCOS and gestational diabetes (diabetes diagnosed for the first time during pregnancy).

An important fact to consider is that poor diabetes management during pregnancy can be linked to birth defects. If you become pregnant while taking metformin, you should inform your doctor immediately; do not stop taking metformin without speaking to your doctor first. Moreover, metformin can have beneficial effects during pregnancy by improving the metabolic status of the pregnant woman and reducing the impact of insulin resistance on the baby’s development.

Babies born to mothers who took metformin during pregnancy do not demonstrate a higher birth defect rate. Therefore, it would appear that metformin is probably safe and perhaps even beneficial during pregnancy.

Paternal metformin use and birth defects

Until recently, there was very little knowledge about how diabetes or diabetes medications taken by men can impact a baby.

A new study published in the Annals of Internal Medicine by Stanford Medicine researchers and their collaborators at the University of Southern Denmark has shown that the use of diabetes drug metformin by men can lead to an increased risk of genital birth defects in their male offspring.

As part of this observational study, investigators in Denmark looked at more than 1 million records from health registries. They found that metformin used by men in the three months before conception (when sperm development is taking place) can lead to higher birth defect rates among babies compared to men who did not take metformin and men who took insulin or other medications for diabetes.

Notably, genital birth defects occurred only in male offspring born after paternal exposure to metformin. Also, interestingly, compared to the general population, the offspring born to these men were less likely to be males. The researchers postulate that the reason for fewer male offspring could be that the harm caused by metformin to male babies was so great that they were spontaneously aborted.

What did the study show?

Here are some factors to consider about this study:

The researchers did not include babies born to women with hypertension or a diabetes diagnosis.
The study included men who took a diabetes medication 3 months prior to conception.
Researchers accounted for confounding factors that could skew the study's results, such as maternal and paternal age, education, higher or lower socioeconomic status, and smoking.

The exact mechanism by which metformin affects men’s reproductive health is unclear. Here’s what the study found:

More than 1 million babies were studied. Of these, 3.3% had one major birth defect at least. Just over half were boys.
Approximately 1,500 babies had metformin exposure, and approximately half were male. Birth defects occurred at a rate of 5.2% among metformin-exposed babies. In other words, birth defects increased with metformin use by the father.
The type of birth defect that was most common was genital defects. They occurred only in male offspring.
Men who took metformin outside the 3-month period of sperm development did not have babies with a higher birth defect rate. Therefore, it’s not only taking metformin but the timing of the treatment that’s important.
The researchers compared exposed babies to siblings who were not exposed to metformin and found that offspring without metformin exposure did not have increased rates of birth defects compared to the general population. Therefore, the risk was not coming from the father.

Besides paternal metformin exposure, can other medications cause a birth defect?

The researchers looked at how taking metformin compared to two other medications commonly used to treat diabetes — sulfonylureas and insulin.

Insulin exposure did not affect the birth defect rate or the sex ratio. In the babies that had paternal exposure to sulfonylureas, birth defects occurred in 5.1%. Just about half of these babies were boys.

While these trends are similar to metformin, sulfonylureas did not cause a statistically significant increase in birth defects, did not show a link to the three-month preconception period, and did not demonstrate a consistent pattern of genital defects.

Should men planning fatherhood avoid metformin?

This observational study has shown that paternal metformin exposure leads to an increased frequency of birth defects in babies, specifically genital defects in male offspring.

However, without further confirmation in other patient populations outside Denmark, it is premature to make changes in clinical practice and advise against metformin use by men of reproductive age with type 2 diabetes who require this medication for glycemic control.

Couples planning pregnancy should discuss the use of metformin or any medication in general with their doctors to weigh the risks and benefits of metformin use. This study has emphasized that we need to think beyond maternal factors in reproductive health. The link between paternal metformin use and birth defects has shown that the father’s health can significantly affect the baby’s health.

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