The impact of metformin on placental ageing in humans and mice

Placental ageing refers to the physiological accumulation of a senescent phenotype over healthy pregnancy. In pregnancies affected by complications such as pre-eclampsia and fetal growth restriction, placental ageing is notably accelerated and observed at an earlier gestational age. Metformin is used during pregnancy for an increasing variety of indications, including treatment of gestational diabetes and may have a role in slowing cellular ageing. It is therefore essential to understand the potential impact of metformin on placental ageing. Placental samples (n=105) were obtained from women with BMI ≥30kg/m2 randomised to treatment with metformin or placebo during pregnancy. Ageing was assessed by measuring telomere length, histological examination, and using array-based technologies to investigate gene expression and methylation. Results were validated using isolated human trophoblasts treated in vitro with metformin, and in a complementary mouse model. There were no differences between metformin-exposed and control placentas in terms of telomere length, fibrosis, or calcification. There were no differences in placental gene expression or methylation patterns by metformin status. In our mouse model, no genes classically associated with cellular ageing were differentially expressed and no senescence pathway showed evidence of enrichment with metformin treatment. There was no evidence that metformin either slows or accelerates placental ageing pathways in the complementary models that we investigated. Our findings are reassuring with regards to the safety of metformin used to treat gestational diabetes, but do not support a role for metformin in the prevention of adverse pregnancy outcomes in non-diabetic women.