ESPE Yearbook of Paediatric Endocrinology

Diabetes Care. 2021 Nov;44(11):2536-2541. doi: 10.2337/dc21-0327. PMID: 34475030.

Brief Summary: This retrospective case control study investigated changes in the metabolic profile in newborn screening of infants born to mothers who had been treated with metformin. Treatment with metformin during pregnancy was associated with subtle changes in metabolites in the newborn screening.

Metformin has clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. It reduces hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut (1). Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase. Despite its multiple effects on metabolic networks, metformin use seems safe during pregnancy. There are limited data on the effects of metformin on neonatal metabolism

The authors hypothesized that maternal hyperglycaemia and or metformin exposure at different stages of pregnancy might produce an analyte pattern reflective of the growing needs of the embryo and fetal cellular differentiation and maturation. So, they analyzed separately the results of infants exposed from the first, second, or third trimester of pregnancy (with exposure continuing until delivery) to hyperglycaemia or metformin use using the newborn screening.

Exposure to hyperglycaemia during the different stages of pregnancy led to subtle (but significant) changes in some of the metabolites in the newborn screening. These changes were mostly in the acyl-carnitines (short, medium and long) and lower levels of the amino acid leucine. Maternal metformin led to higher levels (but within the normal range) of some specific acyl-carnitines, namely butryl-carnitine (C4), isovalerly-carnitine (C5) and glutaryl-carnitine (C5D). These changes varied according to the gestational age at which metformin was started and hence with duration of exposure. The most consistent changes associated with metformin exposure were in isovalerly-carnitine (C5) concentrations, a short-chain fatty acid esterified to carnitine. These acyl-carnitines are usually formed by catabolism of the branched chain amino acids leucine and valine and can easily cross the mitochondrial membrane without the need for transporters, conserving cellular energy.

The observed metabolite profile could represent metformin effects on metabolic networks to preferentially express these energy substrates, which may be advantageous in circumstances of insulin resistance or catabolic stress. The observed changes are subtle and do not present any obvious harm to the fetus or newborn.

Reference: 1. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl JMed 2008;358:2003–2015.