Researchers from University College London in England have created the most comprehensive molecular map to date of severe preeclampsia, uncovering distinct fetal and maternal drivers of the disease that could lead to more targeted therapies and earlier intervention.
The study, published in Science Advances, combined single-cell RNA sequencing with spatial transcriptomics across the entire fetal-maternal interface and found that severe preeclampsia is not solely a placental disorder. Instead, the disease involves coordinated dysfunction across multiple maternal and fetal tissues, with different molecular programs emerging in early- versus late-onset disease.
Preeclampsia affects 2% to 4% of pregnancies worldwide and remains a leading cause of maternal and fetal illness and death. Although it is traditionally viewed as a placental disease, the mechanisms responsible for widespread maternal inflammation and endothelial dysfunction have remained unclear.
To better define those mechanisms, investigators analyzed tissues from 20 pregnancies, including 10 women with severe preeclampsia and 10 gestational age-matched controls between 25 and 37 weeks of gestation. By matching pregnancies by gestational age rather than comparing preterm cases with healthy term pregnancies, the researchers were able to distinguish disease-related molecular changes from normal developmental differences.
The analysis revealed extensive placental abnormalities, including molecular signatures of hypoxia, angiogenic imbalance, fibrosis, and altered metabolism. The team also confirmed impaired invasion of fetal extravillous trophoblasts into the maternal uterus, a hallmark of preeclampsia that contributes to defective remodeling of maternal blood vessels.
Beyond the placenta, however, the study identified previously unrecognized maternal immune abnormalities extending into the myometrium and chorioamniotic membranes. These included widespread mitochondrial dysfunction, activation of type I interferon signaling, and altered macrophage responses, providing a potential explanation for the systemic inflammation and endothelial injury that characterize severe disease.
The findings point to several potential therapeutic targets. Leptin (LEP), which was strongly upregulated in placental cells throughout both early and late disease, may contribute to oxidative stress and vascular dysfunction. The researchers suggest that leptin antagonists, already under investigation for autoimmune diseases, warrant exploration as placental-targeted therapies.
The study also highlights type I interferon signaling as a promising target. Elevated interferon activity, detected in maternal immune cells and peripheral blood, could potentially serve as both a biomarker and a therapeutic target for anti-interferon or antioxidant treatments.
“IFN-I in peripheral blood promises better screening of patients that might benefit from anti-IFN or antioxidant therapeutics,” the authors concluded.
Perhaps most importantly, the molecular abnormalities were substantially more pronounced in early-onset disease, suggesting that intervention before clinical deterioration may offer the greatest benefit.
“Given the severity of molecular dysfunctions in early disease, compared to its late presentation, timely intervention during gestation is likely beneficial and could change the extremely poor prognosis of severe PE,” the authors wrote.
The post Molecular Atlas of Severe Preeclampsia Reveals New Therapeutic Targets appeared first on Inside Precision Medicine.