Metformin in Pregnancy and Its Safety Profile
In Finland, a comprehensive analysis of data from the national registry was conducted to assess whether exposure to metformin during intrauterine development is associated with an increased risk of long-term or short-term health problems.
Introduction
Metformin is the first-line treatment for patients with type 2 diabetes mellitus (DM2) when diet and lifestyle measures are insufficient to maintain adequate glycemia. It is increasingly being used in the treatment of gestational diabetes mellitus (GDM). In women with polycystic ovary syndrome (PCOS), it is often prescribed off-label for anovulation therapy to increase the chances of conception. Some studies suggest that if these women continue to use metformin during pregnancy, the risk of adverse complications is reduced.
Use of metformin during pregnancy is generally considered safe, but it should be noted that this antidiabetic drug (unlike insulin) crosses the placenta and can reach plasma concentrations in the baby comparable to those in the mother. Most of the available data on metformin exposure in utero comes from randomized clinical trials involving pregnant women with GDM.
The aim of the presented cohort study was to assess the risk of adverse outcomes of metformin use during pregnancy in all indications except type 1 diabetes, both in monotherapy and in combination with insulin, compared to insulin alone.
Methodology and Parameters
Children from singleton pregnancies in Finland were included in the analysis, where mothers conceived between 2004 and 2016 and used metformin (n = 3967), insulin (n = 5273), or their combination (n = 889), in the indication of GDM, DM2, or PCOS.
The primary monitored parameters were the long-term incidence of obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, PCOS, and motor or social development disorders. In the sensitivity analysis, these parameters were assessed only in children of mothers with GDM. The secondary monitored parameter was adverse clinical outcomes at birth.
Analyses were conducted using the inverse probability of treatment weighting (IPTW) method, with the insulin group considered as the reference.
Results
Exposure to metformin or combined therapy was not associated with an increased risk of long-term adverse events compared to insulin, neither in the overall analysis nor in the sensitivity analysis.
Metformin use was associated with an increased risk of smaller fetal size for gestational age (weighted odds ratio [wOR] 1.65; 95% confidence interval [CI] 1.16–2.34) compared to insulin. However, it is possible that the observed risk is due to weight gain associated with insulin use.
In the combined treatment group, there was an increased risk of larger fetal size for gestational age (wOR 1.58; 95% CI 1.22–2.05), preterm birth (wOR 1.46; 95% CI 1.10–1.95), and neonatal hypoglycemia (wOR 1.29; 95% CI 1.09–1.53). The result may be misleading due to more severe maternal hyperglycemia in this group of pregnant women.
No increased risk of neonatal mortality, hyperglycemia, or major congenital anomalies was observed with metformin use during pregnancy.
Conclusion and Recommendations for Practice
The presented study found no evidence of increased long-term risk associated with metformin use during pregnancy compared to insulin treatment. The increased risk of smaller fetal size for gestational age observed with metformin use should lead to caution in pregnancies with a threatened fetal malnutrition. Orally administered metformin may be better accepted by pregnant women than insulin, and due to its ease of use, it may also be associated with better treatment adherence. In combination with insulin, it may reduce the required dose of insulin.
Based on the cited study1, the SPC2 was changed in February 2022, and this drug can now be administered during pregnancy and the periconceptional phase as a supplement or alternative to insulin when clinically necessary.
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Sources:
1. Brand K. M. G., Saarelainen L., Sonajalg J. et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diabetes Res Care 2022; 10 (1): e002363, doi: 10.1136/bmjdrc-2021-002363.
2. SPC Glucophage. Available at: www.sukl.cz/modules/medication/detail.php?code=0023797&tab=texts
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