Decoding the Genomic Architecture of Placenta Accreta Spectrum: Integrative Multi-Omics, Trophoblast Invasion Biology, and Precision Prediction

Placenta accreta spectrum (PAS) has emerged as one of the most consequential complications in contemporary obstetrics, yet the biological mechanisms underlying abnormal placental attachment remain incompletely resolved. Much of the existing literature has focused on surgical management and imaging diagnosis, while the genomic and molecular architecture of PAS has received comparatively less integrative attention. Over the past decade, however, rapid advances in high-resolution molecular technologies – including single-cell transcriptomics, spatial transcriptomics, proteomics, and circulating biomarker profiling – have begun to reveal a far more complex biological landscape than previously appreciated. The present systematic review was therefore undertaken to synthesize current evidence on the genomic, epigenetic, and multi-omics determinants of pathological trophoblast invasion that characterize PAS. A comprehensive literature search was conducted across major biomedical databases, with study identification, screening, and eligibility assessment performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance. After sequential filtering of records through predefined inclusion criteria and risk-of-bias evaluation, forty-three studies were included in the final qualitative synthesis. Across these studies, converging lines of evidence suggest that PAS reflects a convergence of several molecular disturbances rather than a single pathway defect. Altered trophoblast differentiation programs, dysregulated signaling networks – including Wingless-related Integration Site, NOTCH, Phosphoinositide 3-Kinase/AKT, and transforming growth factor-β – and disruption of the decidual immune microenvironment consistently appear as central elements. In parallel, emerging biomarker research highlights the potential clinical relevance of circulating proteins, exosomal microRNAs, and cell-free placental DNA as early indicators of abnormal placentation. Taken together, the literature indicates that PAS may be better understood as a systems-level disorder of placental invasion governed by interconnected genomic and microenvironmental processes. Integrating multi-omics discovery with translational biomarker development may ultimately enable earlier risk prediction and more individualized clinical management of PAS.