A Randomized Double-Blinded Placebo-Controlled Trial of Esomeprazole for the Prevention of Preeclampsia in Moderate- and High-Risk Women: The ESOPOP Trial

Preeclampsia, one of the hypertensive disorders of pregnancy, remains a leading cause of maternal death worldwide, with the majority of deaths occurring in developing countries. Preeclampsia is a multi-organ syndrome of pregnancy that manifests after 20 weeks' gestation with new-onset hypertension alongside maternal end-organ dysfunction and/or fetal growth restriction. Importantly, preeclampsia poses serious health risks for the baby, implicated in 12% of cases of fetal growth restriction, and is a known antecedent in up to 19% of preterm births. There is currently no effective treatment for preeclampsia except delivery of the baby, and as such, it remains a significant burden of disease for both mothers and their babies worldwide. Screening for women at risk of preeclampsia is an important part of antenatal care. Once women are identified as high risk, they can be targeted for more intensive antenatal surveillance and prophylactic interventions. Most current strategies for risk assessment are based on obstetric and medical history and clinical examination. However, there is surprisingly little reliable evidence on the actual risk associated with individual factors and how they might interact. Risk factors with a particularly high association with preeclampsia (more than one in ten risks) include maternal diabetes, chronic hypertension, and renal disease. Thrombophilia and autoimmune disease have a strong association with severe early-onset preeclampsia. Obstetric factors associated with high risk are multiple pregnancies, history of preeclampsia in a previous pregnancy especially if severe or early onset, and a current hydropic pregnancy. Other factors linked with preeclampsia but associated with a somewhat lower risk include first pregnancies, age less than 20 or more than 35 years, a family history of preeclampsia, and obesity. Proton pump inhibitors such as esomeprazole have long-term safety data about the treatment of gastric reflux in pregnancy. In vitro studies show proton pump inhibitors decrease soluble fems like tyrosine kinase -1 (sFlt-1) and soluble endoglin and improve markers of endothelial dysfunction . while esomeprazole reduces blood pressure in a preeclampsia transgenic mouse model that overexpresses sFlt-1.