A study by Norwegian and Taiwanese scientists has shown that children whose fathers took metformin during active spermatogenesis before conception have no higher incidence of congenital anomalies than children of healthy fathers. It is noteworthy that earlier studies demonstrated a link between paternal metformin use and congenital defects in children. The work was published in The BMJ.
The prevalence of type 2 diabetes among men of reproductive age is increasing worldwide. Diabetes in men can impair fertility by reducing sperm viability and suppressing testosterone production. In addition, obesity, which often accompanies type 2 diabetes, impairs spermatogenesis and reduces fertility.
Metformin is one of the main drugs used to lower glucose levels in people with type 2 diabetes. It inhibits the production of glucose in the liver. Several animal studies have shown that metformin use reduces testicular mass and sperm production, and in men with type 2 diabetes, metformin use may reduce testosterone levels and impair sperm quality. A recent Danish study found that preconception metformin use in men was associated with an increased risk of major birth defects in offspring. However, this study did not adequately adjust for diabetes itself, its severity, or other associated risk factors.
To overcome these limitations, a team of researchers led by Fei-Yuan Hsiao from National Taiwan University and Hedvig Nordeng from 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 used metformin during the sperm maturation period before conception. The Taiwanese cohort included 15,276 such fathers. Compared with fathers who did not use metformin, those who used metformin 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 use other types of hypoglycemic drugs, cardiovascular drugs, and psychotropic drugs. Their female partners were also more likely to be older and to have diabetes and obesity.
In the Norwegian cohort, congenital malformations occurred 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 the Taiwanese cohort, the risk of congenital malformations was slightly increased in fathers who took metformin (unadjusted relative risk 1.08).
However, after full adjustment for all measured confounders—year of birth, father's age, his diabetes severity, chronic comorbidities (hypertension, hyperlipidemia, mental illness), and use of other medications—the pooled adjusted risk estimate for birth defects was no higher than that in the control cohort. Additional sibling analysis also found no increased risk of birth defects with paternal metformin use before conception.
These results may potentially allow metformin to be prescribed to men with diabetes who are planning to conceive. However, due to the two conflicting results in different studies, systematic reviews and meta-analyses are needed to address the safety of metformin in men with diabetes who are planning to conceive.
Notably, other studies have shown that metformin is safe for the fetus when taken by the mother during pregnancy.
