The hypothalamic-neurohypophyseal system in preeclampsia: a systematic review with a subgroup meta-analysis of copeptin levels worldwide

Literature has reported elevated concentrations of copeptin (CPP), a marker of arginine vasopressin (AVP) secretion, preceding the clinical features of the life-threatening condition, preeclampsia (PE). Those findings pointed to a possible role for the hypothalamic-neurohypophyseal system (HNS) in its pathophysiology. This systematic review and meta-analysis reports CPP levels in women with PE, exploring the AVP system not as a primary driver of the disease, but as a dynamic physiological feature associated with its clinical progression. The search terms used were “preeclampsia-AND-vasopressin-OR-copeptin-OR-oxytocin” in five databases: Google Scholar, Embase, Scopus, PubMed, and Semantic Scholar. Study quality was assessed using the Newcastle-Ottawa Scale. A Gaussian Mixture Model (GMM) algorithm was applied to blind predict the preeclamptic or healthy normotensive pregnancies by the CPP concentration, after performing a Kernel Principal Component Analysis (kPCA). Thirty-nine registries were selected, of which twenty were observational studies documenting CPP concentrations across all three trimesters, encompassing 1025 cases in 2446 pregnancies. Observational and experimental studies have associated the development of PE with circulating CPP levels and pharmacological manipulations involving AVP. Such an association was not found for oxytocin. Continental comparisons reveal a potential gene-environment link, showing a greater effect of higher concentrations of CPP on preeclamptic cases in Asian and African people. Furthermore, gestational hypertension has been associated with single nucleotide polymorphisms (SNPs) in the AVP and ERAP2 genes. Notably, ERAP2 encodes an endopeptidase that cleaves and inactivates AVP. It is essential to improve the early detection of this condition by understanding how genetic and geographic factors influence PE causes. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251111755.