Biology and Pathophysiology of Placenta Accreta Spectrum Disorder.

Placenta accreta spectrum (PAS) disorders present a significant clinical challenge, characterized by abnormal placental adherence to the uterine wall secondary to uterine scarring. With the rising global cesarean delivery rates, the incidence of this iatrogenic disorder has increased, underscoring the critical need for an understanding of its pathophysiology to inform management and prevention strategies. Normal placentation depends on tightly regulated extravillous trophoblast invasion into the decidua, spiral artery remodeling, interactions with the extracellular matrix, and immune modulation. Uterine scarring disrupts this balance, creating an environment deficient in key regulatory signals required for coordinated implantation and decidualization. In PAS, the loss of inhibitory decidual cues and deficient boundary limits permits unrestrained trophoblast into the abnormal decidual environment. Dysregulated signaling, along with an inflammatory milieu in scarred tissues, exacerbates abnormal placental development. Current prenatal imaging focuses on the appearance of excessive fibrinoid deposition, extracellular matrix remodeling, and incomplete spiral artery transformation as surrogates of PAS risk stratification. Emerging single-cell RNA sequencing and proteomic profiling offer insights into biomarkers and pathways that enable targeted interventions. Preventive efforts should prioritize reducing cesarean delivery rates to limit uterine scarring. Advances in regenerative medicine and bioengineering, including extracellular matrix-modulating biomaterials, growth factor therapies, and antifibrotic interventions, hold promise for improving scar healing and reducing PAS risk. This review bridges foundational science and clinical application, emphasizing the importance of the underlying placental biology and pathophysiology to make a clinical difference in detecting, treating, and preventing PAS. Addressing drivers of abnormal placentation is critical for improving maternal and neonatal outcomes with this increasingly prevalent iatrogenic condition.