Can taking Metformin (metformin) during pregnancy have any teratogenic effects on the child?

From the Guidelines

Teratogenic Effects of Metformin During Pregnancy

Taking Metformin during pregnancy can have teratogenic effects on the child, particularly in terms of increased risk of higher BMI and obesity in childhood.

• The evidence from multiple studies, including the Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU) study 1, suggests that metformin exposure in utero is associated with smaller neonates and accelerated postnatal growth, resulting in higher BMI in childhood.
• A meta-analysis concluded that metformin exposure resulted in smaller neonates with an acceleration of postnatal growth, resulting in higher BMI in childhood 1.
• Follow-up studies of offspring exposed to metformin in utero have shown higher BMI, weight-to-height ratios, and waist circumferences at ages 4-10 years 1.
• However, it is essential to note that metformin is also associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin in systematic reviews and RCTs 1.
• The most recent and high-quality study from 2023 1 supports the notion that metformin use during pregnancy may have teratogenic effects on the child, particularly in terms of increased risk of obesity and higher BMI in childhood.

From the FDA Drug Label

Limited data with metformin hydrochloride tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5-times, respectively, a 2550 mg clinical dose, based on body surface area

The use of metformin during pregnancy has not been shown to have a clear association with major birth defects or miscarriage risk, but limited data are available to determine a drug-associated risk.

• Animal studies have not reported adverse developmental effects.
• However, due to methodological limitations of human studies, including small sample size and inconsistent comparator groups, no conclusion can be drawn about the absence of any metformin-associated risk 2. Conservative clinical decision: Metformin should be used during pregnancy only if clearly needed, considering the potential risks and benefits.

From the Research

Teratogenic Effects of Metformin on the Child

• The study published in the Annals of internal medicine 3 found that continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy.
• The same study 3 reported that the estimated risk for live birth with congenital malformations was 8.0% under insulin monotherapy and 5.7% under insulin plus metformin, with a risk ratio of 0.72.
• A systematic review published in Metabolism: clinical and experimental 4 found no demonstrable teratogenic effects, intra-uterine deaths, or developmental delays with the use of metformin.
• Another study published in Acta obstetricia et gynecologica Scandinavica 5 reported that teratogenic effects are not associated with metformin use in pregnancy, but noted that long-term data regarding offspring outcomes are still lacking.
• A meta-analysis published in Medicine 6 found that metformin was not teratogenic based on the limited data, and that it could help lower the rate of early pregnancy loss and preterm delivery in women with polycystic ovary syndrome.

Potential Long-term Effects on Offspring

• A review published in Trends in developmental biology 7 discussed the potential longer-term impact of intrauterine metformin exposure on the development of key organs, including the liver, central nervous system, heart, gut, and endocrine pancreas.
• The same review 7 noted that further studies are needed to fully elucidate the effects of metformin exposure on fetal programming and adult metabolic health.
• The study published in Acta obstetricia et gynecologica Scandinavica 5 reported that independent of maternal glycemic control, recent meta-analyses found lower birthweight but accelerated postnatal growth and higher body mass index in metformin-exposed children.