Women most commonly take metformin for diabetes or polycystic ovary syndrome. Metformin crosses the placenta and reaches fetal plasma concentrations comparable to those in the mother. Animal studies have not shown any harmful effects during pregnancy, embryonic or fetal development, birth, and postnatal development. In 2022, based on the results of the CLUE study, designed and sponsored by Merck pharmaceutical company, and other safety data, the Summary of Product Characteristics for metformin was modified to include the possibility of considering metformin use during pregnancy, as monotherapy or in combination with insulin. Data on the effects of metformin on pregnancy and pregnancy outcomes are still limited. The latest safety data for metformin during pregnancy come from a cohort study conducted in Finland, the CLUE study, with results published in 2022. The study followed pregnancy outcomes in women exposed to metformin only (n=3967), insulin only (n=5273), and a combination of metformin and insulin (n=889) from 2004 to 2016. The primary outcomes were child obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, polycystic ovary syndrome, and developmental disorders (motor, social). The study did not find an increased risk associated with metformin exposure (alone or in combination with insulin) compared to insulin use alone. However, there was an increased risk of low birth weight (a secondary outcome) with metformin compared to insulin, suggesting caution in pregnancies with a risk of fetal malnutrition. A meta-analysis of studies published up to 2014 did not find an increased risk of malformations in children of around 1000 women exposed to metformin during the first trimester of pregnancy. Another cohort study presented as a congress abstract in 2021, which included around 3000 pregnancies with metformin exposure, did not find an increased risk of congenital malformations following metformin use during pregnancy. However, another cohort study with 392 pregnancies exposed to metformin during the first trimester found a higher risk of congenital malformations in women exposed to metformin (5.1% compared to 2.1% in the control group). The authors explained this difference by an increase in intrinsic risk due to diabetes. Two published case-control studies found a possible association between metformin use in the first trimester and an increased risk of congenital malformations (cardiac, pulmonary) in one study and an increased risk of atrial septal defect and limb defects in the other study where metformin was used for infertility treatment. Contradictory study results may be attributed to different indications for use, study design, and overall do not support clear conclusions about potential risks. In clinical practice, available data on monitoring pregnancy outcomes in women taking metformin during pregnancy do not suggest a significant risk of malformations with metformin use in the first trimester, but they do not exclude the possibility of rare malformations. Longer-term data on pregnancy outcomes are needed to better assess the long-term risk of metformin use in early pregnancy. If a pregnant woman requires treatment for elevated glucose levels, insulin remains the first-line treatment since insulin does not cross the placenta. If metformin use is considered, it is important to inform the pregnant woman about its benefits and the still present uncertainties related to potential risks.
Literature:
1. Prescrire Redaction. Metformin during pregnancy: possible risk of malformations. Rev Prescrire 2023; 23: 46-8.
2. Panchaud A, Rousson V, Vial T, et al. Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services. Br J Clin 2018; Pharmacol 2018; 84: 568–78.
3. Brand KMG, Saarelainen L, Sonajalg J, et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diabetes Research and Care 2022;10:e002363.
4. Nguyen L, Chan SY, Teo AKK. Metformin from mother to unborn child - Are there unwarranted effects? EBioMedicine 2018; 35: 394-404.