A study by Norwegian and Taiwanese scientists found that children whose fathers took metformin during the period of active spermatogenesis before conception had no higher incidence of congenital anomalies than children of healthy fathers. Notably, earlier studies demonstrated a link between paternal metformin use and congenital defects in children. The study was published in The BMJ.
The prevalence of type 2 diabetes among men of reproductive age is increasing worldwide. Diabetes can impair fertility in men due to decreased sperm viability and suppressed testosterone production. Furthermore, obesity, which often accompanies type 2 diabetes, impairs spermatogenesis and reduces fertility.
Metformin is one of the main medications used to lower glucose levels in patients with type 2 diabetes. It inhibits glucose production in the liver. Several animal studies have shown that metformin use leads to reduced testicular weight and sperm production. In men with type 2 diabetes, metformin use can reduce testosterone levels and impair sperm quality. A recent Danish study demonstrated that metformin use before conception in men is associated with an increased risk of major congenital malformations in offspring. However, this study did not adequately adjust for the diabetes itself, its severity, or other associated risk factors.
To overcome these limitations, a team of researchers led by Fei-Yuan Hsiao of National Taiwan University and Hedvig Nordeng of the University of Oslo conducted a cross-national cohort study using national databases from Norway and Taiwan to assess the association between paternal metformin use and the risk of birth defects in offspring, taking into account possible confounding factors.
The Norwegian cohort included 2,075 fathers who took metformin during the preconception period. The Taiwanese cohort included 15,276 such fathers. Compared with fathers who did not take metformin, those who did were older and had a higher prevalence of diabetes and other chronic diseases, particularly hypertension, hyperlipidemia, and mental illness. These fathers were also more likely to take other types of hypoglycemic medications, cardiovascular medications, and psychotropic drugs. Their partners were also more likely to be older and to have diabetes and obesity.
In a Norwegian cohort, congenital malformations were observed in 24,041 (3.9 percent) children of fathers who did not take metformin during the period of sperm development, compared with 104 (5 percent) children of fathers who took metformin (unadjusted relative risk 1.29). Similarly, in a Taiwanese cohort, the risk of congenital malformations was slightly increased in fathers who took metformin (unadjusted relative risk 1.08).
However, after fully adjusting for all measured confounders—year of birth, paternal age, severity of diabetes, chronic comorbidities (hypertension, hyperlipidemia, mental illness), and use of other medications—the pooled adjusted risk of congenital malformations was no higher than in the control cohort. An additional analysis of siblings also revealed no increased risk of congenital anomalies with paternal metformin use before conception.
These results could potentially allow metformin to be prescribed to men with diabetes planning to conceive. However, due to two conflicting results in different studies, systematic reviews and meta-analyses are needed to address the safety of metformin in men with diabetes planning to conceive.
Notably, other studies have shown that metformin is safe for the fetus when taken by the mother during pregnancy.
