Multi-Omics Reveals Early Pregnancy Placental Dysfunction Associated With Preterm and Term Preeclampsia

Preeclampsia, a severe pregnancy-induced disorder unique to humans, affects ∼2%-8% of pregnancies globally. Strong evidence supports placental dysfunction as central to preeclampsia; however, there is inadequate understanding of the precise pathogenesis of preeclampsia. In this study, we present a comprehensive multi-omics analysis of early pregnancy placental biopsies (chorionic villus samples) from pregnancies that later developed preterm/term preeclampsia, compared to normotensive controls. Using an integrative multivariate approach, we uncovered distinct molecular signatures associated with preeclampsia. Preterm preeclampsia was strongly associated with dysregulated lipoprotein metabolism, while term preeclampsia exhibited alterations in inflammatory pathways, Notch/Kit signaling, and ribosome assembly. These results challenge the prevailing notion that term preeclampsia is unrelated to early placental pregnancy dysfunction. To validate our findings, we focused on melanophilin, a gene downregulated in the early pregnancy placenta of term preeclampsia. Melanophilin expression was reduced during cytotrophoblast syncytialization; however, excessive loss disrupted syncytiotrophoblast function, triggering the production of factors known to drive preeclampsia. Our study provides critical insights into the early pregnancy aberrations underlying preterm and term preeclampsia, paving the way for the development of predictive biomarkers and targeted preventative treatments. This work represents a significant step toward unraveling the complex etiology of preeclampsia and improving maternal and perinatal health outcomes.