Barbour and Feig (1) have presented a clear discussion of metformin use in women with gestational diabetes mellitus and outline potential effects on the offspring, which require ongoing study. However, some of the relevant findings from the 7- to 9-year-old participants in the Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU) study were not included (2). Also, Barbour and Feig have focused on potential adverse effects of metformin on the offspring and have not discussed data that suggest metformin may be beneficial in specific situations.
With respect to the MiG TOFU data, Barbour and Feig note that the 9-year-old offspring in the Auckland subgroup (n = 99) exposed to metformin, compared with those whose mothers were randomized to insulin, were significantly heavier and had larger arm and waist circumferences and increased waist-to-height ratios. They trended toward higher BMI as well as greater triceps skinfold thickness and abdominal fat volume by MRI. It is important to add that there were no differences between the groups in the percentage of total body fat, abdominal fat, visceral fat, or liver fat as measured by DEXA or MRI. Overall, these data suggest that the metformin children are “larger” rather than necessarily “fatter,” which might otherwise be assumed. Of note, there was a trend to increased fat-free mass as well as fat mass by DEXA in these children.
Considering adverse versus beneficial long-term effects of metformin exposure in utero, Barbour and Feig outline their concerns based on the mechanisms of the action of metformin and its potential to attenuate nutrient flux and fetal growth. The points they raise are important and supported by animal data when metformin is administered to normal pregnant mice eating a normal diet (3). When treating women with gestational diabetes mellitus, however, metformin is generally prescribed when the fetus is exposed to excess nutrients. There are data that show metformin ameliorates several adverse effects of nutrient excess, with subsequent benefits for the exposed offspring. In an obese rodent model, mice exposed to metformin in utero had lower rates of adiposity and impaired glucose tolerance when fed a high-fat diet postnatally (4). In a high-fat diet mouse model, exposure to metformin in utero was associated with improved mitochondrial content and skeletal muscle development (5). In another mouse model, metformin reversed adverse effects of obesity on the blastocyst by decreasing apoptosis and cellular stress. These findings suggest that, in this environment, metformin does not suppress protein synthesis and increase apoptosis, as suggested by Barbour and Feig. Human data that support a potential beneficial effect of metformin come from the 7-year-old MiG TOFU follow-up subgroup (n = 109) from Adelaide. The metformin-exposed offspring did not show an increase in any measures of size, adiposity, or adverse metabolic markers, despite higher maternal glucose levels during treatment and significantly higher rates of birth weight >90th centile.
Until there are further data, at National Women’s Health, Auckland, we consider the fetal nutrient environment when deciding whether to offer metformin rather than using it for specific maternal indications, as suggested by Barbour and Feig.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.