According to a Stanford study, paternal metformin use just before conception causes a 40% increase in birth defects.
Despite the advances in health care, birth defects continue to affect infants worldwide, especially in low- and middle-income countries. The most common of these are Down syndrome, heart defects, and neural tube defects. According to the World Health Organization (WHO), an estimated 240,000 newborn deaths occur every year due to congenital disorders. Genetic factors, maternal infections, and drug use during pregnancy are some of the most common causes of these disorders. Although scientists mostly put the blame on maternal factors for the development of these defects, emerging data suggest that paternal factors are also to blame. Now, a recent study has found that paternal metformin use increases the risk of birth defects by 40%.
Given that men contribute half the DNA to a child, it makes sense that there could be some effects that travel through paternal pathways as well.
Dr. Michael Eisenberg, senior author
Gestational diabetes increases the risk of early birth, excessive birth weight, breathing difficulties in babies, and other birth defects. However, the effect of paternal diabetes on offspring’s health is largely unclear. Moreover, the first-line drug for diabetes, metformin, is known for its effects on male reproductive symptoms. Therefore, a team at Stanford Medicine collaborated with researchers in Denmark to investigate metformin’s effect on birth defects rate in children.
Metformin is a first-line treatment for type 2 diabetes. The drug lowers insulin resistance in the body and decreases the liver’s production of glucose. As a result, the person’s blood glucose level remains within a healthy range. It works best when combined with diet and lifestyle changes. The most common side effects are stomach pain, nausea, diarrhoea, and bloating. In some cases, patients can also result in hypoglycemia and lactic acidosis.
Study Tracks More Than a Million Births
As part of the study, researchers tracked more than a million births in Denmark between 1997 and 2016. The nationwide stud compared the risks of birth defects in children exposed to diabetes medication. Moreover, the researchers only included children born to women (under 35 years of age) without diabetes and men under 40.
According to the study, babies were considered exposed to metformin if their fathers filled at least 1 prescription in the 3 months before conception. This is the time it takes the fertilizing sperm to fully mature. Since diabetes itself can also affect sperm quality and male fertility, researchers also included fathers who took insulin and other diabetes drugs such as sulfonylureas.
It wasn’t just taking metformin at any time in a man’s life; it really has to do with taking it in that window when the sperm that is going to become the child is being developed. And it’s not just diabetes because the man likely had diabetes before and after that point.
Dr. Michael Eisenberg, senior author
Out of the more than a million births, 3.3% of the children had at least one major birth defect. However, exposure to metformin increased the rate to 5.2%. The risk was significantly higher for genital birth defects in male babies. The use of metformin before or after the three-month conception period did not affect the risk of birth defects. Moreover, the use of insulin did not cause an increase in birth defects. Thus, confirming that a diabetes diagnosis itself does not contribute to the risk of birth defects.
Furthermore, the researchers compared exposed children to their unexposed siblings and did not find any increased risk of birth defects.
Editorial Suggests Explanation for Metformin and its Role in Birth Defects
Metformin was the only diabetes drug that led to an increase in birth defects in children. The study’s results, therefore, bring to light the role of paternal factors on an offspring’s health. However, the exact mechanism behind the development remains unclear.
In an editorial published accompanying the paper, epidemiologist Germain Buck Louis reports a potential explanation for the increased risk. He states that metformin’s testosterone altering ability might be to blame for the birth defects. Moreover, he called for further clinical guidance for couples to make them aware of all the risks associated with paternal metformin use.
Clinical guidance is needed to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications.
Germaine M. Buck Louis, editorial author
Despite the results, it is important to note that the study has quite a few limitations. Firstly, researchers did not account for paternal diabetes severity or control, and whether the fathers took their medicines regularly. All they based their information on is prescription data. Moreover, all the children born with birth defects had older parents and belonged to a lower socioeconomic status. Thus, suggesting that other factors could also have caused the increased risk.
While many scientists don’t believe that one study is enough to tell men to avoid the drug, they do think men should be offered alternatives to metformin. Nevertheless, the results point to the need for further investigation of paternal factors on offspring’s health.
Reference:
Louis, G. M. (2022). Paternal preconception diabetes drugs and birth defects in offspring: A call for more conclusive study. Annals of Internal Medicine. https://doi.org/10.7326/m22-0770
