Abstract
Preeclampsia (PE) is a heterogeneous disease for which the current clinical classification system is based on the presence or absence of specific clinical features. PE-associated placentas also show heterogeneous findings on pathologic examination, suggesting that further subclassification is possible. We combined clinical, pathologic, immunohistochemical, and transcriptomic profiling of placentas to develop integrated signatures for multiple subclasses of PE. In total, 303 PE and 1388 nonhypertensive control placentas were included. We found that maternal vascular malperfusion (MVM) in the placenta was associated with preterm PE with severe features and with small-for-gestational-age neonates. Interestingly, PE placentas with either MVM or no histologic pattern of injury showed a linear decrease in proliferative (p63+) cytotrophoblast per villous area with increasing gestational age, similar to placentas obtained from the nonhypertensive patient cohort; however, PE placentas with fetal vascular malperfusion or villitis of unknown etiology lost this phenotype. This is mainly because of cases of fetal vascular malperfusion in placentas of patients with preterm PE and villitis of unknown etiology in placentas of patients with term PE, which are associated with a decrease or increase, respectively, in the cytotrophoblast per villous area. Finally, a transcriptomic analysis identified pathways associated with hypoxia, inflammation, and reduced cell proliferation in PE-MVM placentas and further subclassified this group into extravillous trophoblast-high and extravillous trophoblast-low PE, confirmed using an immunohistochemical analysis of trophoblast lineage-specific markers. Our findings suggest that within specific histopathologic patterns of placental injury, PE can be subclassified based on specific cellular and molecular defects, allowing the identification of pathways that may be targeted for diagnostic and therapeutic purposes.