Endocrine Abstracts

Background: Metformin is widely used for treatment of gestational diabetes mellitus. Metformin is considered safe in pregnancy but crosses the placenta. The limited available data of follow-up of children exposed to metformin in utero suggests potential for increased adiposity but mechanisms are unknown. As placental DNA methylation has been linked to later obesity and metformin causes global DNA methylation changes in cancer cell lines we hypothesised that this may be a candidate pathway.

Methods: DNA methylation arrays (Illumina^® Infinium Human Methylation 450 BeadChips, USA) were performed on bisulphite-converted DNA (EZ DNA Methylation kit, Zymo Research, UK) extracted from placenta samples (n=100) from women who participated in ‘EMPOWaR’, a randomised controlled trial of treatment with metformin vs placebo in obese pregnant women without diabetes. We analysed the association of DNA methylation and metformin treatment with infant growth at three months (n=89, n=43 (48.3%) Male, n=45 (50.6%) metformin treated). Data were analysed using R programming (CpGassoc package) and adjusted for baby sex with Holm-Bonferroni adjustment for significance.

Results: Decreased DNA methylation at five CpG sites within the ACADS gene (acyl-CoA dehydrogenase short chain, a key enzyme in mitochondrial fatty acid beta-oxidation) was significantly associated with increased infant weight at three months. Decreased methylation in eleven CpG sites within the genes ACADS and CYP11A1 (Cytochrome P450 Family 11 Subfamily A Member 1, involved in synthesis of cholesterol/steroids) was significantly associated with increased infant ponderal index. Metformin treatment was not associated with placental DNA methylation or infant adiposity.

Conclusion: As ACADs has been identified as a gene associated with type 2 diabetes and obesity in both infant and adult in recent genome-wide association studies, our observation of decreased placental DNA methylation and infant adiposity warrants further investigation. Further follow-up studies are needed to determine any longer-term outcomes of metformin exposure in utero.