Placental malaria and preeclampsia: shared pathways and translational perspectives in endemic regions

Placental malaria (PM), driven by sequestration of Plasmodium falciparum-infected erythrocytes within the placental intervillous space, remains a major contributor to adverse maternal and fetal outcomes in endemic regions. Increasing evidence suggests that PM may also contribute to the development of preeclampsia (PE), a leading cause of maternal and perinatal morbidity and mortality worldwide. Although PM and PE arise from distinct initiating events, Plasmodium falciparum sequestration in PM and defective spiral artery remodeling in PE, both conditions converge on shared placental and systemic biological pathways. In PM, P. falciparum-infected red blood cells (iRBCs) sequester within the placental intervillous space through binding of parasite-expressed variant surface antigen 2-chondroitin sulfate A (VAR2CSA) adhesion to chondroitin sulfate A (CSA) on the syncytiotrophoblast. This sequestration, together with the accumulation of parasite derived products such as hemozoin, promotes local inflammation, syncytiotrophoblast stress, and disruption of placental vascular homeostasis. In PE, placental hypoperfusion and ischemia-reperfusion injury induce oxidative stress and abnormal trophoblast turnover. Despite these different origins, both conditions produce some overlapping patterns of placental injury including angiogenic dysregulation, characterized by elevated anti-angiogenic factors and reduced pro-angiogenic mediators. This convergence is further marked by activation of inflammatory signalling through NF-κB and inflammasome pathways, oxidative injury, complement activation, and systemic endothelial dysfunction. This review synthesizes current evidence on the shared biological pathways linking PM and PE and explores how malaria-induced placental injury may increase susceptibility to PE. We also examine the implications of overlapping biomarker signatures for diagnosis and risk stratification in malaria-endemic settings. Key knowledge gaps are highlighted, and priorities for future research are proposed to inform integrated strategies for malaria control and improved clinical management of PE in malaria-endemic settings.