Maternal Plasma Cell-Free RNA as a Predictor of Early and Late-Onset Preeclampsia Throughout Pregnancy

Early-onset (EOPE) and late-onset preeclampsia (LOPE) pose significant challenges to maternal and child health, highlighting the need for early, non-invasive risk identification. In this prospective longitudinal study, we followed 9,586 pregnant women, collecting blood samples each trimester: 9-14 weeks (T1), 18-28 weeks (T2), and after 28 weeks or at preeclampsia diagnosis (T3). Plasma cell-free RNA (cfRNA) signatures were analyzed in women who developed EOPE (n=42) or LOPE (n=43) and compared to matched normotensive controls (n=75). Mapping cfRNA origins and performing differential abundance analysis provided insights into multi-organ impacts, revealing distinct transcriptional features of EOPE and LOPE. We developed a first-trimester EOPE predictive model using 36 transcripts, achieving 83% sensitivity, 88% specificity, and an AUC of 0.85, detecting risk 18.0 weeks before onset. A second-trimester model based on 87 cfRNA transcripts, predicted EOPE 8.5 weeks prior to onset with 87% sensitivity, 84% specificity, and an AUC of 0.85. For LOPE model, detecting risk 14.9 weeks before onset, used 92 cfRNAs, with 86% sensitivity, 89% specificity, and an AUC of 0.88. EOPE models were enriched for decidua-associated transcripts, highlighting the maternal involvement in this subtype, while LOPE models showed diverse tissue responses, paving the way for improved subtype differentiation and tailored interventions to mitigate preeclampsia risks.