Prediction and Identification of Cerebral Complications in Preeclampsia– A Translational Journey from Mothers to Rats

Abstract

Severe complications of preeclampsia, particularly cerebral manifestations such as eclampsia, are a major cause of maternal mortality. Prediction of women at high risk as well as the pathways leading to eclampsia remain poorly understood. This thesis aims to evaluate current approaches for predicting severe complications, to elucidate underlying mechanisms of cerebral complications, and to identify potential targets for neuroprotective interventions. Study I, a systematic review and meta-analysis of predictive tests for maternal and perinatal outcomes in hypertensive disorders of pregnancy, revealed significant heterogeneity across the included studies due to differences of population, predictors and outcomes. For maternal outcomes, only the fullPIERS model could be pooled showing moderate performance with high heterogeneity. Meta-analyses of perinatal outcomes were limited by low study quality. These findings highlight the need for future studies to use standardized definitions and robust external validation of promising predictors. Using a translational approach in studies II and III, we identified elevated levels of blood-brain barrier injury, neuroinflammatory and neurodegenerative markers in the cerebrospinal fluid of women with eclampsia and preeclampsia. These findings indicate significant cerebral involvement comparable to that observed in other severe neurological conditions such as traumatic brain injury. Consistent with these findings, the preeclampsia-like RUPP rat model demonstrated increased blood–brain barrier disruption and endothelial dysfunction. These alterations were associated with astrocyte reactivity and impaired glutamate homeostasis, which may contribute to region-specific changes in neuronal transmission as observed in the rat model. Although apoptotic pathways were upregulated in the cortex, no histological evidence of tissue scaring process was observed. Together, these findings provide novel insights into cerebral involvement in preeclampsia, even in the absence of overt neurological symptoms such as eclamptic seizures. This improved understanding may contribute to the identification of novel therapeutic targets and the development of more accurate predictors for eclampsia.