Diabetes and Pregnancy

In pregnancy, metformin crosses the placenta in significant amounts. This raises the concern that it could affect fetal physiology or cause congenital anomalies. However, congenital malformations take place during the first nine weeks of pregnancy, while the diagnosis of GDM usually takes place at 24 to 28 weeks. Nevertheless, even if safe regarding organogenesis, it will be important to study metformin’s effect on the offspring during the growth years and later in life. Metformin may slightly increase the risk of prematurity [25].

The Metformin in Gestational diabetes (MiG) trial was an important study that assessed the efficacy and safety of metformin in pregnancy. It included 751 women with GDM at 22 to 33 weeks’ gestation and compared the use of insulin to metformin on measures of neonatal hypoglycemia, respiratory distress, neonatal jaundice, birth trauma, Apgar scores, and prematurity [121]. The trial results indicated that almost half of patients using metformin ended up requiring supplemental insulin to meet blood glucose targets [25]. Neonatal complications did not differ significantly between the two groups, and there were no serious adverse events associated with use of metformin. Women who used metformin reported a higher rate of satisfaction compared to insulin. While the results of MiG are promising, guidelines recommend avoiding metformin as routine therapy for GDM pending further clinical trials [10,25,75].

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The MiG Trial Offspring Follow-Up (MiG TOFU) continued to follow the offspring of mothers with GDM who used metformin during pregnancy [123]. The focus of the 2011 MiG TOFU was to examine the body composition of these children at 2 years of age. Results suggest that metformin exposure in utero might lead to improved insulin sensitivity in the fetus and result in a metabolically healthier pattern of growth in early childhood, including less development of visceral fat (central adiposity), a significant component of metabolic syndrome [123]. A 2018 MiG TOFU report showed no significant differences between offspring of those treated with metformin versus insulin at 7 years of age. However, at 9 years of age, metformin offspring were larger by measures of BMI, weight, and arm and waist circumferences. Levels of fasting glucose, triglyceride, insulin, insulin resistance, A1C, cholesterol, liver transaminases, leptin, and adiponectin were similar, as were body fat percentage and abdominal fat percentages [124]. The results of MiG TOFU, while promising at first, now suggest that in utero exposure to metformin may lead to negative implications for the prevention of diabetes in the offspring of women with GDM later in life.

Other studies have shown that metformin may help decrease the risk for macrosomia in the offspring, but it does not appear to help obese mothers lose weight [122]. More follow-up studies and longitudinal research are needed to clarify these results.

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