Cord serum metabolome and birth weight in patients with gestational diabetes treated with metformin, insulin, or diet alone

INTRODUCTION: Recent research has demonstrated the benefits of metformin treatment in gestational diabetes (GDM) on short-term pregnancy outcomes (including excessive fetal growth and pre-eclampsia), but its effects on fetal metabolism remain mostly unknown. Our aim was to study the effects of metformin treatment compared with insulin or diet on the cord serum metabolome and also to assess how these metabolites are related to birth weight (BW) in pregnancies complicated by GDM. RESEARCH DESIGN AND METHODS: Cord serum samples were available from 113, 97, and 98 patients with GDM treated with diet, insulin, and metformin, respectively. A targeted metabolome was measured using nuclear magnetic resonance spectroscopy. The patients in the metformin and insulin groups had participated in a previous randomized trial (NCT01240785). RESULTS: Cord serum alanine was elevated in the metformin group (0.53 mmol/L) compared with the insulin (0.45 mmol/L, p<0.001) and the diet groups (0.46 mmol/L, p<0.0001). All other measured metabolites were similar between the groups. The triglyceride (TG)-to-phosphoglyceride ratio, average very low-density lipoprotein particle diameter, docosahexaenoic acid, omega-3 fatty acids (FAs), and ratios of omega-3 and monounsaturated FA to total FA were inversely related to BW. The omega-6-to-total-FA and omega-6-to-omega-3-FA ratios were positively related to BW. Cholesterol in very large and large high-density lipoprotein (HDL) was positively (p<0.01) associated with BW when adjusted for maternal prepregnancy body mass index, gestational weight gain, glycated hemoglobin, and mode of delivery. CONCLUSIONS: Metformin treatment in GDM leads to an increase in cord serum alanine. The possible long-term implications of elevated neonatal alanine in this context need to be evaluated in future studies. Although previous studies have shown that metformin increased maternal TG levels, the cord serum TG levels were not affected. Cord serum HDL cholesterol and several FA variables are related to the regulation of fetal growth in GDM. Moreover, these associations seem to be independent of maternal confounding factors. TRIAL REGISTRATION NUMBER: NCT01240785.