Pregnancy-related disorders: molecular mechanisms and management

Abstract Pregnancy-related disorders (PRDs), including preeclampsia (PE), gestational diabetes mellitus (GDM), hyperemesis gravidarum (HG), and intrahepatic cholestasis of pregnancy (ICP), remain major causes of maternal and perinatal morbidity. This review synthesizes their molecular, endocrine, immune, and clinical features. We propose the Placental-Maternal Adaptation Failure Continuum (PMAFC), in which gestational/fetoplacental stress load interacts with maternal adaptive reserve. This load includes placenta-derived signals, the physiological demands of gestation and fetal growth, and secondary maternal or fetal mediators. Placental drive denotes the placenta-derived component, whereas maternal adaptive reserve reflects the capacity of vascular, metabolic, hepatic, neuroendocrine, and immune systems to compensate for pregnancy-related challenges. We distinguish experimentally derived mechanistic hypotheses from findings supported by human studies and consider persistent post-pregnancy changes, termed pregnancy memory, as a potential link to later maternal cardiometabolic risk. We also separate established care from investigational biomarkers and interventions. The soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio can support clinical assessment in selected PE pathways. Cell-free RNA, chromosome 19 microRNA cluster biomarkers, and polygenic risk scores remain investigational. Apheresis has limited human proof-of-concept evidence, whereas sFlt-1 silencing, growth differentiation factor 15 receptor blockade, and strategies to restore hepatobiliary transporter function remain under clinical or preclinical evaluation. PMAFC is an evidence-organizing framework, not a validated predictive or therapeutic algorithm.