Treatment of Diabetes in Pregnancy with Metformin Does Not Increase the Risk of Low Birth Weight
In several studies, it has been observed that exposure to metformin during pregnancy, compared to insulin exposure, is associated with an increased relative risk of the newborn being small for gestational age. The authors of the presented cohort study aimed to clarify this risk in comparison to women with gestational diabetes who were not pharmacologically treated.
Metformin in Pregnancy
The use of metformin during pregnancy is increasing worldwide, due to both pregnant women who were already treated for type 2 diabetes (DM2) before conception and its introduction for gestational diabetes (GDM). It is also prescribed off-label for women with polycystic ovary syndrome (PCOS) to induce ovulation and improve pregnancy outcomes. Since metformin crosses the placenta, the fetus is exposed to its plasma concentrations similar to those in the mother’s bloodstream.
Several studies have documented the effectiveness of metformin in terms of glycemic control without short-term adverse effects and with potential additional benefits in the neonatal period. Early in 2022, the use of original metformin (both regular and XR once-daily forms) was approved at the European level for use during pregnancy and in the periconceptional period.
Previous Results from the CLUE Study
A significant basis for this decision was provided by findings from the Finnish population-based cohort study CLUE, which used registry data to study exposure to metformin during pregnancy in mothers and assessed both short-term and long-term adverse outcomes in children (up to 11 years after birth). The CLUE study did not show an increased long-term risk associated with metformin exposure during pregnancy but did suggest an increased risk of the newborn being small for gestational age (SGA) and a decreased risk of being large for gestational age (LGA), compared to in-utero insulin exposure. Similar results were observed in children born to mothers with GDM who were not exposed in utero to antidiabetic treatment, compared to in-utero insulin exposure results.
The authors of the CLUE study hypothesized that the observed higher risk of SGA and lower risk of LGA could be linked to the use of insulin as the reference control. It is known that insulin administration is associated with increased weight. In the follow-up study, they examined whether metformin administration would be associated with an increased risk of SGA and a decreased risk of LGA when compared to non-pharmacological antidiabetic treatment.
Currently Studied Population
The population-based cohort study used registry data of children born from singleton pregnancies of mothers aged 18–45 years between 2004–2016. The main analysis used birth outcomes from the metformin cohort regardless of the indication for administration (n = 3964) and the drug-naïve cohort of mothers with GDM (n = 82 675). Additional analyses were performed on the subgroup of the metformin cohort, which included only children born to mothers with GDM (n = 2361).
Results
As for the SGA indicator, no difference was found between the cohorts in the main analyses (weighted odds ratio [wOR] 0.97; 95% confidence interval [CI] 0.73–1.27) or in the additional analyses (wOR 1.01; 95% CI 0.75–1.37). Regarding the risk of LGA, no difference was found between the cohorts in the main analyses (wOR 0.91; 95% CI 0.75–1.11); however, in the additional analyses, a reduced risk was observed (wOR 0.72; 95% CI 0.56–0.92).
Conclusion
The results of the described follow-up support previous findings that in-utero exposure to metformin, compared to pharmacologically untreated GDM, is not associated with an increased risk of SGA or LGA. Despite the observed risk of fetal intrauterine growth restriction, other treatment options should still be considered. Large prospective studies evaluating metformin alone compared to placebo during pregnancy with GDM, such as EMERGE, might soon shed further light on the issue.
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Sources:
1. Brand K. M. G., Thoren R., Sõnajalg J. et al. Metformin in pregnancy and risk of abnormal growth outcomes at birth: a register-based cohort study. BMJ Open Diabetes Res Care 2022 Dec; 10 (6): e003056, doi: 10.1136/bmjdrc-2022-003056.
2. Brand K. M. G., Saarelainen L., Sõnajalg J. et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diabetes Res Care 2022 Jan; 10 (1): e002363, doi: 10.1136/bmjdrc-2021-002363.
3. SPC Glucophage. Available at: www.sukl.cz/modules/medication/download.php?file=SPC193868.pdf&type=spc&as=glucophage-spc
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