Basic Research

Offspring of Diabetics Taking Metformin Have Higher Risk of Birth Defects

A collaboration between Stanford University School of Medicine and University of Southern Denmark shows that men taking metformin pre-conception increases risk of birth defects.

By Yedida Bogachkov, Ph.D.

Key Points:

  • Sperm exposure to metformin — a diabetes medication — three months before conception leads to increased birth defects.
  • The frequency of metformin-induced birth defects was higher than birth defects from treatment with insulin or the type 2 diabetes medication sulfonylurea.
  • Conception during metformin exposure was less likely to result in male offspring.

When it comes to reproduction, obesity has long been seen as a problem for women, leading to increased birth weights and unfavorable birth outcomes. But, overall, men are more likely to be diagnosed with diabetes than women, and, as it relates to childbirth, the ramifications include decreased semen quality and impaired male fertility. To this end, insulin and metformin are among the fastest-rising medications given to prospective fathers.

While some research suggests that metformin can improve reproductive success, a new nationwide study out of Denmark published in the Annals of Internal Medicine highlights that using metformin may actually be detrimental to child development. The study, encompassing births across nearly two decades (1997-2016), examined birth defects among the offspring of fathers treated with diabetes medications, including metformin. The researchers found an increased frequency of birth defects, particularly genital birth defects, for those exposed to metformin in the 3-month preconception period compared to those exposed to insulin. That 3-month preconception period is crucial because that is roughly how long new sperm take to mature into fully functional sperm cells.

In an editorial published alongside the study, Germain Buck Louis, a reproductive and perinatal epidemiologist at George Mason University who was not involved in the research, said, “Clinical guidance is needed to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications.” 

(Wensink et al., 2022 | Annals of Internal Medicine) Birth defects are caused by fathers taking metformin. This plot shows the elevated birth defect frequencies among metformin-exposed offspring but not among insulin-exposed offspring, unexposed siblings, or offspring of fathers filling a metformin prescription before or after sperm development (SDev). Metformin-exposed offspring more often had a genital birth defect, all in boys, while the proportion of boys was lower.

Metformin Exposure During Sperm Development Leads to Genital Birth Defects

Wensink and colleagues scanned through over a million birth records. The Danish researchers were able to identify over 7,000 newborns who were exposed to paternal diabetes medications, including insulin, metformin, and sulfonylureas, based on data regarding filled prescriptions. They found that the odds of offspring exposed to metformin having birth defects was 1.4 times higher than those exposed to insulin. Additionally, the researchers found that beta-blockers — a commonly used medication for cardiovascular disease — also increased the odds of birth defects (specifically cardiovascular defects), but not to the same extent as the 25% increase seen with metformin. Furthermore, the investigators showed that genital birth defects were more likely to occur among those exposed to metformin than others.

Metformin Used During Pre-conception Leads to Fewer Male Offspring

The Danish scientists found that fathers exposed to metformin were less likely to have male offspring by a couple of percent. The authors state that this may be due to various factors, including the offspring with more severe defects being more likely to be aborted, either naturally or medically, before birth. Additionally, an increase in the number of females may indicate male reproductive impairment, which has been seen with certain pesticides and other environmental toxins. Furthermore, low semen quality has been linked to the inability to sire male offspring.

Metformin Used Before or After Sperm Development Did Not Affect Birth Defect Frequency

The characteristics of fathers taking metformin before or after sperm development were similar to those on metformin during preconception sperm development, including advanced age and socioeconomic status. However, the birth defect frequency was only increased in those exposed to metformin during that crucial 3-month preconception period, indicating that it is the metformin exposure rather than other possibly confounding factors, such as increased paternal age, leading to the increased birth defects.

Also, Wensink and colleagues found that the birth defect frequency increased steadily as metformin exposure approached the crucial three months of sperm development prior to conception. After those three months, the birth defect frequency declined to normal levels for fathers taking metformin more than one year after conception. Birth defect frequencies were similar to levels for metformin exposure a year before and after sperm development. Additionally, unexposed siblings of those with birth defects due to metformin exposure were unaffected, suggesting genetic inheritance was not a critical factor.

Should One Stop Taking Metformin Before Conception?

The investigators indicate that in Denmark, roughly 120 offspring per year are born to fathers who have filled a metformin prescription per year, which translates to about an increase of 2 defects per year. And some of these defects may be lifelong conditions imposing emotional, social, and economic costs. Granted, more research is needed, even though the researchers accounted for the increased age and increased use of other medications using a large population-based approach. Additionally, the investigators determined that any unmeasured factors would need fairly strong increased odds to explain away the association between metformin exposure and these birth defects.

Given that it can take a long time for people to conceive, the increased frequency of birth defects seen in this study calls into question whether metformin should be the diabetes medication of choice for men planning on having children in the near future. There is surmounting evidence that metformin can lead to increased birth defects. Numerous preclinical trials have shown that metformin exposure during pregnancy or lactation leads to changes in male rat reproductive behavior. Additionally, when pregnant mice are exposed to metformin, it decreases testicular size in both the fetuses and the newborn pups. There have also been studies showing that metformin leads to reduced testosterone secretion.

“The sheer size of the diabetes pandemic suggests that treatment of prospective fathers with diabetes, including pharmacologic management and counseling on diet, physical exercise, and weight loss, should be subject to further study,” the scientists wrote. The evidence against the use of metformin for those planning to conceive is worthy of more discussion between patients and their doctors.

Source

Wensink MJ, Lu Y, Tian L, Shaw GM, Rizzi S, Jensen TK, Mathiesen ER, Skakkebæk NE, Lindahl-Jacobsen R, Eisenberg ML. Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring: A Nationwide Cohort Study. Ann Intern Med. 2022 Mar 29. doi: 10.7326/M21-4389. Epub ahead of print. PMID: 35344380.

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