The Interplay between Pathophysiological Pathways in Early-Onset Severe Preeclampsia Unveiled by Metabolomics.

Lina Youssef,Marta Palomo,Josep Maria Campistol,Héctor García-Calderó,Fatima Crispi,Virginia Hernandez-Gea,Jezid Miranda,Olga Tura-Ceide,Francesca Crovetto,Cristina Paules,Eduard Gratacos,Joan Carles Garcia-Pagan,Pol Herrero,Ana Paula Dantas,Miquel Blasco,Núria Canela,Maribel Diaz-Ricart,Rui Vasco Simoes

doi:10.3390/life12010086

Abstract

Introduction: Preeclampsia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality. The precise pathogenesis of this complex disorder is still unrevealed. Methods: We examined the pathophysiological pathways involved in early-onset preeclampsia, a specific subgroup representing its most severe presentation, using LC-MS/MS metabolomic analysis based on multi-level extraction of lipids and small metabolites from maternal blood samples, collected at the time of diagnosis from 14 preeclamptic and six matched healthy pregnancies. Statistical analysis comprised multivariate and univariate approaches with the application of over representation analysis to identify differential pathways. Results: A clear difference between preeclamptic and control pregnancies was observed in principal component analysis. Supervised multivariate analysis using orthogonal partial least square discriminant analysis provided a robust model with goodness of fit (R2X = 0.91, p = 0.002) and predictive ability (Q2Y = 0.72, p < 0.001). Finally, univariate analysis followed by 5% false discovery rate correction indicated 82 metabolites significantly altered, corresponding to six overrepresented pathways: (1) aminoacyl-tRNA biosynthesis; (2) arginine biosynthesis; (3) alanine, aspartate and glutamate metabolism; (4) D-glutamine and D-glutamate metabolism; (5) arginine and proline metabolism; and (6) histidine metabolism. Conclusion: Metabolomic analysis focusing specifically on the early-onset severe form of preeclampsia reveals the interplay between pathophysiological pathways involved in this form. Future studies are required to explore new therapeutic approaches targeting these altered metabolic pathways in early-onset preeclampsia.

Highlights

Preeclampsia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality
We analyzed blood metabolomic profiles of mothers and fetuses at delivery using nuclear magnetic resonance approach and demonstrated that cases of preeclampsia with fetal growth restriction exhibit the most disturbed metabolomic profiles [16]. To further explore these complex alterations and pathophysiological pathways involved, we have studied a well-defined subgroup of early-onset severe preeclampsia, typically associated with fetal growth restriction, using liquid chromatography tandem mass spectrometry (LC-MS/MS) metabolomics–a highly sensitive technique performed with multi-level extraction of lipids and small metabolites from maternal blood samples
Average gestational age at the time of delivery was 32 weeks, up to 80% of deliveries were achieved through cesarean sections and all neonates were admitted to the neonatal intensive care unit, exhibiting subsequently one case of neonatal mortality

Summary

Introduction

Preeclampsia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality. Preeclampsia is a multi-system disorder unique to pregnancy characterized by newonset elevated blood pressure associated with proteinuria occurring after 20 weeks of gestation [1] This complex disease affects 2–5% of pregnancies and is a major cause of maternal and perinatal morbidity and mortality [2,3]. Abnormal placentation is known to play a central role especially in severe cases of preeclampsia [4,5], it is assumed that preeclampsia is a spectral disorder with different underlying etiologies, all converging into a seemingly identical clinical presentation that affects maternal health [6] This heterogeneity strongly limits our understanding of the underlying etiology and the identification of therapeutic targets. Understanding the pathophysiology of early-onset severe preeclampsia is paramount for improving its clinical management, as well as detecting potential therapeutic targets for this subtype of preeclampsia

Methods

Results

Discussion

Conclusion