We appreciate the opportunity to expand on the biological foundations of placenta accreta spectrum (PAS) and the translational relevance of this knowledge directly to patient care and surgical strategies for our patients. Robust clinical, pathological, and clinical data have shifted our understanding of PAS from a disorder driven by “aggressive” trophoblast invasion to the consequence of disrupted maternal tissue architecture and cell signaling at the uteroplacental interface. , In normal pregnancy, coordinated decidualization, regulated extravillous trophoblast invasion, spiral artery remodeling, and finely tuned extracellular matrix interactions collectively enable stable implantation and subsequent placental detachment at birth.
The disruption of this system is most often due to previous cesarean deliveries and uterine scarring, which lead to defective decidual formation, dysregulated extracellular remodeling, impaired signaling pathways, and a permissive environment for abnormal anchoring villi and trophoblast adherence into the myometrium. These processes are fundamental elements of both cesarean scar pregnancies and the natural history of PAS pathogenesis and illustrate why histologic absence of decidua and direct apposition of placental villi to myometrium are hallmark features of PAS during prenatal ultrasound, in the operating room, and in the pathology laboratory.
This biological framework is echoed in the natural history of PAS, where there is a loss of the normal physiological regulatory mechanisms within scarred uterine tissue, including cell-cell and cell-matrix signaling disruptions that distort lobular architecture and compromise separation planes. Integrative analyses have highlighted that uterine scar–associated changes in extracellular matrix composition, inflammatory milieu, and trophoblast-decidua interactions collectively redefine the maternal-fetal boundary, yielding aberrant placental adherence.
Understanding the physiology of placentation and the pathophysiology of PAS has direct implications for surgical strategy. Approaches that merely preserve the uterus without addressing the underlying scar defect risk perpetuating the pathologic milieu that predisposes to recurrence and sequelae. In contrast, surgical techniques that entail precise removal of fibrotic, poorly regulated scar tissue and reconstruction with healthy myometrial and stromal elements aim to restore the structural and signaling integrity of the uterine wall. Aligning surgical technique with the biological substrate of disease exemplifies a true translational approach, one in which mechanistic insights inform operative planning, risk stratification, and patient-first counseling and care.
Understanding PAS as a disorder rooted in defective extracellular matrix regulation and disrupted cell communication underscores the importance of combining translational biology with clinical decision-making. Such integration not only refines surgical choice and decreases surgical morbidity but also helps direct research toward regenerative and preventive strategies that target the mediators of abnormal placentation, an increasing common obstetrical problem.
Y.A. is a consultant for Johnson & Johnson MedTech and BilliontoOne and has an investigator-initiated project with Natera unrelated to placenta accreta. The other authors report no conflict of interest.
Y.A. is supported by the Burroughs Wellcome Fund Next Gen Pregnancy Initiative , the David Geffen School of Medicine Physician Scientist Program , and the Society for Maternal-Fetal Medicine Bridge grant related to accreta.
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