Cariprazine as a transdiagnostic treatment for symptoms of depression across different disorders.

Preeclampsia is a serious hypertensive pregnancy condition that is a leading cause of maternal and fetal morbidity and mortality, and estimated to occur in 2–8% of pregnancies globally (; ; ). The contributing factors to preeclampsia are multifactorial (maternal morbidities, genetics, etc.) although poor or reduced placental perfusion and its downstream consequences are thought to underly the most severe forms of preeclampsia (; ). Preeclampsia is often clinically separated into early-onset (EOPE) and late-onset (LOPE), depending on whether the onset occurred before or after 34-week gestation (). Although this distinction is not clear-cut, in EOPE maternal symptoms are generally more severe, neonate outcomes are worse, and placental pathology is typically present (; ). In contrast, LOPE does not have as clear associations with placental pathology (; ). Numerous groups have studied molecular associations in the placenta using transcriptomic, genomic, and epigenomic data (; ; ; ; ) in an attempt to explore deeper into the pathophysiology underlying preeclampsia. There is a tendency to lower methylation in placentas from preeclamptic relative to non-preeclamptic pregnancies, and there are more changes in the placental methylome associated with EOPE than LOPE (13–15). However, there have been few studies linking such molecular changes directly to placental histopathology findings. Maternal vascular malperfusion (MVM) is the most common placental pathology observed in placentas from pregnancies with EOPE, being present in 70–95% of cases (; ; ). MVM represents a broad category of placental pathology defined by damage to utero-placental vasculature resulting in impaired maternal blood flow to the placenta, and is characterized by lesions to the chorionic villi that can include placental infarction, retroplacental hemorrhage, accelerated villous maturation, and distal villous hypoplasia (). While MVM is associated with preeclampsia, it is also prevalent in cases of fetal growth restriction and preterm birth (; ), and is even relatively common in placentas from uncomplicated pregnancies (12–36%) (; ). If the molecular signatures associated with EOPE are also linked to MVM, it could provide insight into the mechanisms underlying EOPE as well as other MVM-related pregnancy outcomes. DNA methylation (DNAme) is one molecular tool that has been widely used to study EOPE in the placenta post-delivery (; ; ; ; ; ). Recently, Boyano et al. () developed , a machine learning-based classification tool that utilizes DNAme at 45 CpGs to score a placental DNA methylome from zero to one, corresponding to the probability of the placenta coming from pregnancy with EOPE. eoPRED was initially developed with the idea to use DNAme to improve identification of an EOPE or “placental preeclampsia” phenotype. However, the eoPRED tool was trained using the clinical diagnosis of EOPE and has not yet been evaluated in relationship to placental histopathology findings. We hypothesized that the eoPRED score may reflect molecular changes associated with MVM and would therefore correlate with the severity of MVM pathology. If so, this could offer an approach to quantify an aspect of EOPE associated placental pathology, independent of the presence of a clinical diagnosis of EOPE. Thus, our objective was to explore associations between eoPRED score and placental histopathology.