Metformin use during conception does not increase risk for adverse birth outcomes

Key takeaways:

• Maternal use of metformin with insulin before conception and in early pregnancy lowered the risk for newborns with congenital malformations.
• Similarly, paternal metformin use before conception appeared safe.

Maternal and paternal metformin use during conception did not increase the risk for adverse pregnancy outcomes, two studies in Annals of Internal Medicine showed.

The data conflict with previous studies. For example, a 2022 BMJ Open Diabetes Research and Care study found that metformin use — either alone or combined with other treatment — was tied to increased risks for adverse pregnancy outcomes like preterm birth, large or small for gestational age and hypoglycemia.

Maternal metformin use

Because of a lack of data on the safety of noninsulin medications in early pregnancy, Yu-Han Chiu, MD, ScD, an assistant professor in the division of epidemiology at the Penn State College of Medicine, and colleagues wrote that clinical guidelines recommend switching from noninsulin diabetes medication to insulin therapy “when a pregnancy is planned or recognized.”

However, “around 40% of women with type 2 diabetes continue using noninsulin antidiabetics, mostly metformin, with or without insulin,” they wrote.

The researchers analyzed 2000 to 2018 data from the U.S. Medicaid health care administration database to estimate the risks for non-live births and live births with congenital malformations among metformin vs. nonmetformin users.

The cohort included 12,489 women with type 2 diabetes, among whom 850 discontinued metformin and started insulin within 90 days of their last menstrual period and 1,557 combined metformin and insulin treatment during that time.

Overall, the estimated risk for a non-live birth was:

• 32.7% under insulin monotherapy; and
• 34.3% under insulin combined with metformin (RR = 1.02; 95% CI, 1.01-1.04).

Meanwhile, the estimated risk for a live birth with congenital malformations was

• 8% (95% CI, 5.7-10.2) under insulin monotherapy; and
• 5.7% (95% CI, 4.5-7.3) under insulin combined with metformin (RR = 0.72; 95% CI, 0.51-1.09).

When comparing metformin vs. nonmetformin use among all pregnant women, the researchers estimated that the RR of congenital malformations among live births was 1.25 (95% CI, 1.15-1.37), even after adjusting for diabetes status.

“This higher risk ratio is likely the result of choosing a noncomparable reference because most women in the no metformin group would not have diabetes and, among those with diabetes, the disease would be mild or in early stages,” Chiu and colleagues wrote. “That is, pregnant women receiving metformin have a higher risk for having an infant with a major congenital malformation (MCM) than the general population, but such an increase is likely explained by the underlying diabetes.”

Based on the results, current guidelines that recommend switching from metformin to insulin “may require reconsideration,” they concluded.

Paternal metformin use

A second study evaluating metformin use in men also found that it may be safe to use before conception.

Despite metformin’s established safety record, “effects on androgen homeostasis have raised concerns about potential adverse male reproductive effects,” according to Ran S. Rotem, SM, ScD, a research associate at Harvard T.H. Chan School of Public Health, and colleagues.

Specifically, a recent Danish analysis connected metformin use during the spermatogenesis period before conception, with 40% higher odds for MCMs in newborns.

“However, whether the observed findings reflect a causal effect remains unclear,” the researchers wrote.

In the cohort study, Rotem and colleagues analyzed data from a large Israeli health fund on 383,851 live births from 1999 to 2020 to determine possible associations between metformin use and MCMs during the spermatogenesis period.

The researchers assessed MCMs and parental cardiometabolic conditions through clinical diagnoses, laboratory test results and medication dispensing information.

Overall, the prevalence of cardiometabolic morbidity was significantly higher in fathers who used metformin during spermatogenesis and their spouses vs. fathers who were unexposed.

The OR for paternal metformin exposure in all formulations and MCMs was 1.28 (95% CI, 1.01-1.64); however, when the researchers adjusted for paternal cardiovascular and metabolic comorbid conditions, the association became null.

Additionally, the adjusted ORs for MCMs were:

• 0.86 (95% CI, 0.6-1.23) for metformin monotherapy; and
• 1.36 (95% CI, 1-1.85) for metformin with other diabetes medications.

The researchers suggested that associations for metformin polytherapies “could be related to a worse underlying parental cardiometabolic risk profile” and concluded further studies should examine intergenerational effects of paternal cardiometabolic morbidity.

‘May be time to reconsider’ guidelines

In a related editorial, Sarah Martins da Silva, MBChB, MD, a clinical reader in reproductive medicine at the School of Medicine at the University of Dundee in the United Kingdom, pointed out that men and women prescribed diabetic medicine were likelier to have fertility problems and cardiovascular comorbid conditions.

Thus, the results “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,” she wrote.

She also added that individual risks and benefits should be carefully considered, and the findings should be taken with caution due to a lack of information on glycemic control.

Still, Martins Da Silva reiterated that “it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.”

References:

• Brand K, et al. BMJ Open. 2022;doi:10.1136/bmjdrc-2021-002363.
• Chiu Y, et al. Ann Intern Med. 2024;doi:10.7326/M23-2038.
• Martins da Silva. Ann Intern Med. 2024;doi:10.7326/M24-0883.
• Rotem R, et al. Ann Intern Med. 2024;doi:10.7326/M23-1405.