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BACKGROUND Pre-eclampsia is a severe pregnancy complication, globally responsible for >60,000 maternal deaths, and 500,000 fetal deaths annually. The only options for prevention are aspirin and possibly calcium. Unfortunately, their effectiveness is moderate at best. Finding better agents that prevent pre-eclampsia could save the lives of many. Metformin is commonly prescribed to treat diabetes during pregnancy. It has an established safety profile in pregnancy and does not cause hypoglycaemia (overly low blood sugar levels). There is now strong evidence to justify a large trial of metformin to prevent pre-eclampsia: 1. Preclinical (laboratory) studies support the concept that metformin could prevent or treat pre-eclampsia. Its actions to mitigate the pathophysiology of pre-eclampsia extend well beyond increasing insulin sensitivity. 2. A meta-analysis of trials comparing metformin administration versus insulin to treat gestational diabetes reported incidental reductions in rates of hypertensive diseases among those receiving metformin. 3. We reported a randomised clinical trial of metformin extended release (XR) to treat women with preterm pre-eclampsia (26-32 weeks’ gestation). Metformin was associated with a prolongation in pregnancy, meaning the baby could be safely delivered at a less preterm gestation (with likely better health outcomes). Hence, metformin may be effective against the pathophysiology of pre-eclampsia. AIM To undertake a multi-centre double-blind randomised clinical trial to evaluate whether 1000 mg of oral metformin XR taken twice a day (commenced between 12+0 to 26+0 weeks gestation until delivery) reduces the risk of pre-eclampsia among women at very high risk. OBJECTIVES Primary objective: To examine whether metformin can decrease the incidence of pre-eclampsia among women with a high risk of developing the condition. Secondary objectives: To examine whether metformin can decrease the incidence of pre-eclampsia before 37 weeks 0 days pre-eclampsia before 34 weeks 0 days all pregnancy related hypertensive diseases Exploratory objectives: To examine whether metformin can decrease the incidence of adverse maternal outcomes can decrease the incidence of adverse perinatal outcomes is associated with adverse maternal side effects is well tolerated If there is a positive outcome, we will perform a health economic evaluation assessing the cost effectiveness of the intervention. METHODS We will perform a double-blind, multi-centre randomised controlled trial. We will include 1548 pregnant women at high risk of pre-eclampsia, defined as chronic hypertension and/or a history of preterm pre-eclampsia and/or any pre-eclampsia in more than one pregnancy. They will be recruited between 12 and 26 weeks' gestation from four high-risk antenatal clinics across South Africa. Participants will be randomised to metformin 1000 mg XR twice daily or placebo (inactive tablet) in a 1:1 ratio. An online stratified randomisation program will be used. Women will be asked to take the medication from randomisation to delivery. Participants will be regularly reviewed across pregnancy by our team of research midwives (during their antenatal visits) where data will be collected, including medication compliance. The outcomes we will examine are listed above. ANTICIPATED OVERALL OUTCOME AND IMPACT If this trial shows metformin prevents pre-eclampsia, it could have a major impact on human health, reducing poor maternal and newborn health outcomes, or even death. Importantly, metformin could be rapidly translated into the clinic in both low-and-middle- and high-income settings. This is because metformin is cheap and safe to use in pregnancy. There is no intellectual property over its use, it is temperature stable and readily available as a tablet.