sFLT1-induced preeclampsia and fetal growth restriction – from placental pathology to adverse neurodevelopmental outcome

• Applicants: Professor Dr. Ivo Bendix; Professorin Dr. Alexandra Gellhaus
• Subject Area: Gynaecology and Obstetrics ; Pediatric and Adolescent Medicine
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 491780329

Preeclampsia (PE) is a life-threatening disease, not only affecting mothers and fetuses but also long-term development of the offspring. Within this translational proposal in the field of perinatology that combines expertise from obstetrics/placental pathology research and perinatal neurosciences we aim to unravel consequences of elevated soluble fms-like tyrosine kinase 1 (sFLT1) not only on maternal and placental pathology but also on fetal and postnatal neurodevelopment. PE, mainly defined by hypertension and proteinuria after 20 weeks of gestation, is a complication in approximately 2-8% of all pregnancies in Europe. It is associated with an increased risk of fetal growth restriction (FGR), preterm birth and perinatal morbidity and mortality in mothers and infants. Clinically PE is subdivided in early-onset PE (< 34 weeks) and late-onset PE (> 34 weeks), presenting with different pathologies. Women with early-onset PE display more severe symptoms and higher serum levels of the anti-angiogenic biomarker sFLT1 than women with late-onset PE. Apart from removal of the placenta by preterm delivery, there is no effective routine therapy, leading to an increased frequency of preterm births with adverse neurodevelopmental consequences for the offspring. In this proposal we will make use of innovative translational animal models, mimicking different subtypes of human PE to investigate the role of different levels of the provoking key factor, sFLT1, on placental function and neurodevelopment of the fetus and offspring.Analysis of placenta morphology and function will be accompanied by in depth molecular analysis, focusing on parameters of inflammation, hypoxia and regulation of nutrient transporters. Fetal and postnatal neurodevelopment with a focus on vascularization, neuronal and oligodendrocyte differentiation will be evaluated biochemically, by immunohistochemistry, three-dimensional whole-organ imaging and axonal tract tracing. In addition to forebrain analyses, a specific focus will be on the cerebellum, decisive for development of complex cognitive functions. Long-term outcome in the offspring will be analyzed via neurobehavioral tests for motor-cognitive abilities and sensory filter function followed by assessment of microstructural changes by magnet resonance/diffusion tensor imaging. These complex pre-clinical analyses will be accompanied by an observational clinical study on neonatal morbidity and long-term neurodevelopmental outcome in mother/preterm PE/FGR infant pairs (N=130). This proposal offers the unique possibility to predict whether PE/FGR pathology and postnatal neurodevelopment is dependent on different sFLT1-levels. Our expectation is to identify sFLT1 as a prognostic biomarker not only for PE/FGR but also for long-term outcome in the offspring, which will allow identification of cut-off values for novel therapeutic approaches like sFLT1-apheresis with beneficial effects for mothers and infants.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Co-Investigators: Privatdozentin Dr. Britta Hüning; Professorin Dr. Angela Köninger
• Cooperation Partner: Professor Dr. Stéphane Sizonenko