Paternal preconception diabetes drugs and birth defects in offspring

Buck Louis, 2022. Paternal Preconception Diabetes Drugs and Birth Defects in Offspring: A Call for More Conclusive Study. Ann Intern Med

The older you are, the more likely you are to have diabetes^[1]. As the prevalence of diabetes rises in Australia^[2] and men have children later in life^[3], diabetes is becoming increasingly common in men of reproductive age.

Women who have diabetes before pregnancy are more likely than normal to give birth to babies with a variety of birth defects^[4] but the effect of fathers’ diabetes is unknown.

A recent Danish study^[5] used the country’s birth registry, and linked patient (parental) and prescription registries, to investigate associations between birth defects, and paternal (presumed) use of antidiabetic medications. The researchers could not examine the effects of paternal diabetes per se because the patient registry data may not include such diagnoses.

Of 1,116,779 births examined, there was no paternal prescription of antidiabetic medications in 1,109,750. Insulin prescriptions were filled in 5,298 cases, metformin in 1,451 and sulfonylureas in 647. It is assumed that medications were taken around the time that the prescriptions were filled.

The investigators reasoned (perhaps post hoc) that potential effects on development would be mediated by pharmacological action during the development of sperm, so they initially compared data from the offspring of fathers who filled prescriptions for antidiabetic medications during the three months prior to conception (calculated from recorded gestational age at birth and birth date) with data from unexposed babies.

There were major birth defects in 3.3% of babies whose fathers were not prescribed antidiabetic drugs (unexposed) or filled insulin prescriptions during the three months prior to conception. Major birth defects occurred in 5.2% of babies whose fathers filled prescriptions for metformin in the three months prior to conception, and in 5.1% whose fathers filled prescriptions for sulfonylureas. This translated into a statistically significant 40% increase in major birth defects in babies whose fathers filled prescriptions for metformin in the three months prior to conception, compared to the unexposed group.

This effect of paternal metformin was confirmed by observations that prescriptions filled at times either before or after the three-month preconception window were not associated with higher-than-normal rates of birth defects, and that unexposed siblings had a birth defect rate (3.2%) not different from that of unexposed infants.

These are worrying findings, given that metformin is the first-line therapy for type II diabetes. There’s an urgent need to corroborate these observations, and for research aimed at identifying the causal mechanisms^[6]. In the meantime, clinicians will need to guide patients using metformin about this potential risk.