The prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings.

Preeclampsia is a syndromic disease of the mother, fetus, and placenta. The main limitation in early and accurate diagnosis of preeclampsia is rooted in the heterogeneity of this syndrome as reflected by diverse molecular pathways, symptoms, and clinical outcomes. Gaps in our knowledge preclude successful early diagnosis, personalized treatment, and prevention. The advent of “omics” technologies and systems biology approaches addresses this problem by identifying the molecular pathways associated with the underlying mechanisms and clinical phenotypes of preeclampsia. Here, we provide a brief overview on how the field has progressed, focusing on studies utilizing state-of-the-art transcriptomics and proteomics methods. Moreover, we summarize our systems biology studies involving maternal blood proteomics and placental transcriptomics, which identified early maternal and placental disease pathways and showed that their interaction influences the clinical presentation of preeclampsia. We also present an analysis of maternal blood proteomics data which revealed distinct molecular subclasses of preeclampsia and their molecular mechanisms. Maternal and placental disease pathways behind these subclasses are similar to those recently reported in studies on the placental transcriptome. These findings may promote the development of novel diagnostic tools for the distinct subtypes of preeclampsia syndrome, enabling early detection and personalized follow-up and tailored care of patients.

AbstractThe concept of the Great Obstetrical Syndromes was introduced to explain the unique nature of obstetrical disease, which differs fundamentally from disorders in other areas of medicine. These syndromes, including preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm birth, represent clinical endpoints rather than single diseases and share defining characteristics: they arise from multiple etiologies, have a prolonged subclinical phase, involve the fetus as an active participant, are adaptive in nature, and result from complex genetic and environmental interactions between the mother and fetus. Among the diverse mechanisms leading to these syndromes, abnormalities of the maternal supply line to the placenta constitute one major etiology and are often caused by vascular disorders affecting the maternal cardiovascular system and uterine spiral arteries, resulting in placental lesions of maternal vascular malperfusion. The most severe spiral artery lesion is atherosis, which closely resembles atherosclerosis and links obstetrical syndromes to maternal vascular disease. Disorders of deep placentation associated with maternal vascular malperfusion are accompanied by characteristic alterations in angiogenic balance, and the ratio of placental growth factor to soluble fms-like tyrosine kinase-1 in the maternal circulation serves as a biomarker of this pathophysiologic process. Importantly, each obstetrical syndrome is associated with a stereotypic temporal pattern of angiogenic imbalance that reflects differences in disease burden, timing, and clinical expression. While substantial progress has been made in the prediction and prevention of preeclampsia, these concepts extend to other obstetrical syndromes, including fetal growth restriction, fetal death, and spontaneous preterm labor, supporting a unified biologic framework for early risk assessment and personalized prevention.