The impact of metformin exposure on placental ageing, metabolism, and mitochondrial function

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Metformin is a commonly prescribed medication in pregnancy across many global settings. Over the past 5 years, metformin has been endorsed as an acceptable and economic alternative to insulin for treatment of gestational diabetes (GDM) by national bodies in countries including UK, US, and New Zealand. Metformin has also been trialled for other indications during pregnancy, for example maternal obesity and polycystic ovaries. With risk factors for GDM (for example obesity and maternal age) increasing globally, the proportion of pregnant women prescribed metformin is likely to rise. Moreover, new trials of metformin in pregnancy are planned in low-resource settings, particularly in Asia and Africa. Trials show that metformin limits maternal weight gain during pregnancy and stabilises blood sugar. However it is not known how metformin could affect placental function or impact on the baby's growth in the longer term. Our meta-analysis of trials of metformin treatment for GDM shows that babies are born smaller after metformin compared to insulin treatment but then catch-up in growth after birth, suggesting that metformin may restrict fetal growth during pregnancy. During late pregnancy, the growth of the fetus is highly dependent on the placenta. The placenta has key roles in nutrient-sensing, energy regulation, and metabolism, all of which are crucial for a normal pattern of fetal growth and development. In this project we will investigate the impact of metformin on placental function in human pregnancy, which has potential important consequences for long-term fetal growth and cardio-metabolic outcomes. We will use placentas donated from two previous landmark human studies where mothers were treated with metformin during pregnancy. We will assess markers of cellular ageing (for example measuring telomere length, ageing-associated gene expression, and oxidative stress) in placentas treated with metformin compared to controls to determine whether metformin causes the normal placental ageing process to accelerate. We will also measure placental processing and transfer of key nutrients. We will look for differences in the profiles of metabolic products and lipids in metformin-exposed compared to control placentas, which could have critical long-term effects on fetal growth.We will also test how placental cells from normal healthy pregnancies respond directly to physiologically-relevant concentrations of metformin. We will examine how efficiently metformin-exposed placental cells produce energy via mitochondria compared to controls. We will also measure placental oxygen utilisation and assess the leakage of potentially damaging free radicals. We hypothesise that placental cells exposed to metformin will have inefficient energy production compared to the same cells without added metformin. This experiment will test whether metformin has direct effects on the placental cells themselves (rather than acting indirectly via an effect on the mother's physiology) and also whether energy production might account for the differences that we see in the growth patterns of babies whose mothers are treated with metformin during pregnancy. If metformin adversely impacts on the human placenta, then this study will provide crucial information for pregnant women and their doctors in decision-making regarding metformin treatment in pregnancy. These results are also likely to be of interest to public health policy-makers, particularly as UK NICE guidelines currently recommend metformin as a first-line drug treatment for GDM. The impact of metformin on the placenta will also be of interest and relevance to reproductive biologists, placental physiologists, and other scientists in the field of fetal growth and developmental programming. If these results are reassuring regarding the impact of metformin-exposure on the placenta, then our study will be useful in adding to the body of evidence regarding metformin safety during pregnancy.