Metformin found safe for use while trying to conceive, studies find

Use of metformin in monotherapy among fathers during spermatogenesis and mothers in the first trimester of pregnancy does not increase the risk for major congenital malformations (MCMs), two studies found.

In one study, researchers used a large Israeli health fund to link 383,851 live births to medication use by fathers and mothers in 1999 to 2020. The study was published June 18 by Annals of Internal Medicine.

Before adjustment, paternal metformin exposure in all formulations was slightly associated with MCMs (odds ratio [OR], 1.28; 95% CI, 1.01 to 1.64), but the association disappeared after adjustment (OR, 1.00; 95% CI, 0.76 to 1.31). The adjusted difference was not significant with metformin monotherapy (adjusted OR, 0.86; 95% CI, 0.60 to 1.23) but was slightly so with metformin in polytherapy (OR, 1.36; 95% CI, 1.00 to 1.85). The study authors noted that polytherapy was more common in patients with more poorly controlled diabetes, possibly explaining the association.

A second study, which used Medicaid data, found that compared with switching to insulin monotherapy, continuing metformin resulted in little to no increased risk for nonlive birth. The study, which was also published by Annals on June 18, used an observational cohort of pregnant women with pregestational type 2 diabetes who were receiving metformin monotherapy before their last menstrual period (LMP).

Using Medicaid data from 2000 to 2018, researchers compared pregnant patients who discontinued metformin treatment and started insulin within 90 days of LMP or continued metformin and started insulin within 90 days of LMP. The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated and adjusted for covariates. There were 850 women in the insulin monotherapy group and 1,557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin (risk ratio, 1.02; 95% CI, 1.01 to 1.04). The estimated risk for live birth with congenital malformations was 8.0% (95% CI, 5.7% to 10.2%) with insulin monotherapy and 5.7% (95% CI, 4.5% to 7.3%) with insulin plus metformin (risk ratio, 0.72; 95% CI, 0.51 to 1.09).

It may be time to reconsider current prenatal care guidelines for men and women that advocate switching to insulin therapy, according to an editorial accompanying both studies.

Although unadjusted findings suggested that metformin was associated with increased MCM, this association did not persist with adjustment for paternal cardiovascular and metabolic comorbidity, the editorial continued. Fathers prescribed diabetic medication were more likely to be older, to have coexistent cardiovascular and metabolic conditions, to smoke, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbid conditions and to have experienced fertility problems. Children with MCM were more likely to have been conceived following medically assisted reproduction and to be of lower socioeconomic standing.

"These findings underscore the importance of considering paternal health in the context of reproductive planning and prenatal care, advocating for both parents to adopt healthier lifestyles to optimize their children's health," the editorial stated.