Rethinking preeclampsia: six paradigm shifts in placental pathophysiology for maternal-foetal medicine.

Preeclampsia affects 2-4% of pregnancies worldwide and remains a leading contributor to maternal and perinatal morbidity and mortality. The prevailing framework, anchored in defective second-trimester spiral-artery remodelling, placental hypoxia, and antiangiogenic imbalance, continues to guide screening, prediction, and prevention. Evidence accumulated over the past 5 years, however, indicates that several pillars of this framework may require revision. This narrative review synthesises six inter-related paradigm shifts emerging principally from the research programme of the Huppertz group at the Medical University of Graz between 2020 and 2026, and situates them against contemporaneous mainstream formulations. The six shifts addressed are: first-trimester villous origins rather than second-trimester deep-placentation failure; intervillous hyperoxia rather than placental hypoxia in early-onset disease; metabolic and glycocalyx-based pathogenesis rather than pure angiogenic imbalance; the placenta as an endogenous exposome via extracellular vesicles; steroid imbalance coupled with alternative renin-angiotensin-leptin signalling; and reduced immune tolerance together with dynamic