Maternal Plasma Cell-Free RNA as a Dynamic Liquid Biopsy of Placental Dysfunction: A Systematic Review of Precision Prediction of Preeclampsia, Preterm Birth, and Adverse Pregnancy Outcomes

Abstract

Maternal plasma cell-free RNA (cfRNA) offers a noninvasive view of biological activity across pregnancy, but its predictive value for placental dysfunction remains uncertain because the literature spans different specimens, RNA classes, platforms, and clinical outcomes. We conducted this preliminary systematic review to collect, organize, and critically map the available evidence before larger validation efforts. The review used predefined systematic-review methods and was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020. Searches identified 976 records; 32 publications formed the final evidence corpus. Primary human studies evaluating maternal circulating RNA were distinguished from placental-tissue transcriptomics, whole-blood mRNA, circulating microRNA, multi-omic studies, reviews, commentaries, and conventional non-RNA biomarker literature, which were used only for mechanistic or clinical context. Among primary studies, plasma cfRNA signatures showed the clearest predictive evidence for preeclampsia and spontaneous preterm birth. For preeclampsia, reported discrimination varied substantially between model development and independent validation: one study reported an area under the receiver operating characteristic curve of 0.99 in discovery and 0.71–0.74 across validation cohorts, whereas another reported externally validated area under the curve of 0.87 and 0.81 for early-onset preeclampsia in the first and second trimesters, respectively. cfRNA profiles also captured gestational timing and pathways related to trophoblast stress, angiogenic imbalance, inflammation, immune regulation, and endothelial dysfunction. These findings support cfRNA as a biologically informative candidate liquid biopsy, rather than a clinically established test. Evidence remains heterogeneous, and differences in sampling, assays, outcomes, modeling, and validation preclude pooled accuracy estimates. Prospective multicenter validation, analytical standardization, and evidence of clinical utility are required before cfRNA-guided obstetric care can be recommended in practice.