A placental DNA methylation score associated with early-onset preeclampsia and maternal vascular malperfusion pathology

Introduction Early-onset preeclampsia (EOPE) is a severe maternal hypertensive disorder of pregnancy, where placental dysfunction is a component of the pathophysiology. Previously, we developed the eoPRED tool, which is a DNA methylation (DNAme)-based method that estimates the likelihood that a placenta came from a pregnancy complicated by EOPE. We hypothesize that this score may reflect maternal vascular malperfusion (MVM), which is the most common placental pathology observed in early-onset preeclampsia (EOPE), but is also associated with preterm birth and fetal growth restriction. To test this we evaluated whether eoPRED score is associated with the severity of MVM pathology in placentas from both preeclamptic and non-preeclamptic pregnancies. Methods We utilized 493 placentas with both Infinium EPICv1.0 DNA methylation data and histopathologic characterization by a placental pathologist. We evaluated associations between eoPRED score and four major classes of placental pathology: maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), chronic inflammation (CI), and acute inflammation (AI). Results eoPRED score was higher in placentas from pregnancies with EOPE (n = 7) than controls without preeclampsia (n = 402, p < 0.001). Independent of EOPE, eoPRED correlated with the grade of MVM (R = 0.34, p < 0.01), but was not associated with any other pathology class. Discussion eoPRED score can not only be used to identify cases of likely EOPE but is also associated with placental maternal vascular dysfunction in the absence of preeclampsia. This score may thus be useful in placental DNAme datasets lacking pathology information to identify associations between exposures/and or birth outcomes with placental dysfunction.