Understanding Preeclampsia: Integrating Placental Dysfunction, Immune Dysregulation and microRNA-Mediated Epigenetic Regulation

Preeclampsia is a pregnancy-specific multisystem disorder and a major cause of maternal and perinatal morbidity and mortality worldwide. This narrative review summarizes current evidence on the principal risk factors and pathophysiological mechanisms involved in its development. The disease is best explained by the two-stage model: in stage 1, inadequate trophoblast invasion and incomplete spiral artery remodeling lead to placental hypoperfusion, hypoxia, and oxidative stress; in stage 2, the hypoxic placenta releases anti-angiogenic and pro-inflammatory factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which trigger systemic endothelial dysfunction and the maternal clinical syndrome. The review highlights the central role of angiogenic imbalance, immune dysregulation, and chronic inflammation in disease progression. Particular emphasis is placed on maternal risk factors such as primiparity, advanced maternal age, obesity, diabetes mellitus, chronic hypertension, multiple pregnancy, prior preeclampsia, genetic susceptibility, and epigenetic regulation. We also emphasize the contribution of microRNAs in relation to placental hypoxia, trophoblast invasion, angiogenesis, endothelial injury and microchimerism to the development of preeclampsia. The review also examines the role of T helper 1 (Th1)/Th2/Th17/regulatory T cells (Treg) imbalance and uterine natural killer cell dysfunction at the maternal–fetal interface. Improved understanding of these interconnected mechanisms may support earlier diagnosis, better risk stratification, and the development of targeted preventive and therapeutic strategies.