INTRODUCTION
Preeclampsia (PE) is a disorder of the placental vasculature, affecting 5% to 8% of all pregnancies worldwide. It still remains a leading cause of maternal and fetal mortality , accounting for 42% of all maternal deaths and 15% of preterm deliveries . It is characterized by diffused endothelial dysfunction, increased peripheral vascular resistance, hypertension, proteinuria, and dysregulated coagulation. The pathogenesis of PE is complex as it progresses from asymptomatic stage in the first trimester to a symptomatic stage late in gestation. Although its etiologies remain largely unknown, mounting evidence has revealed that placental dysfunction is integral to the development of PE . Pathophysiological perturbations of placental development cause incomplete remodeling of the uterine spiral arteries and poor invasion of trophoblasts into placental cells, which induces persistent placental oxidative stress and hypoxia, such as PE . From a clinical perspective, early prediction of preeclampsia (i.e., within the first 16 weeks of gestion) is of critical importance as it would allow for early treatment of high-risk women, which has been proposed to reduce the occurrence of preeclampsia. Gestational interventions such as steroids to accelerate fetal lung maturity , magnesium for seizure prophylaxis , aspirin treatment, and antihypertensive therapy are effective in reducing both maternal and fetal mortality in populations with high risks of developing PE .
However, the early prediction of PE remains challenging. Traditional risk factors such as a prior history of PE, first pregnancy, multiple gestation, and obesity have insufficient sensitivity and specificity (less than 60%) for the prediction of PE . An imbalance of angiogenic and anti-angiogenic factors during pregnancy was found to disrupt the developmental homeostasis of the placenta . Two placental-derived factors, angiogenic soluble fms-like tyrosine kinase (sFlt-1) and anti-angiogenic placental growth factor (PlGF), were associated with the pathophysiology of PE . A multicenter trial demonstrated that the sFlt-1/PlGF ratio in maternal sera significantly differentiates pregnant PE from normal pregnant women after 24 wks’ of gestation . Later studies discovered that this ratio had limited value in predicting the development of PE when examined during the first or early second trimesters . Thus, there is an unmet need to identify sensitive and specific markers to predict PE early in gestation.
Previous studies have suggested that PE is a pregnancy complication that is associated with changes of multiple systems and encompasses genetic, proteomic, and metabolic factors . Recent multi-omics studies identified a number of molecular-level candidates associated with PE . One of these candidates is leptin (Lep), a secreted adipokine that affects the central regulation of energy homeostasis, neuroendocrine function, and cytoplasmic metabolism . Lep can be expressed by both adipose and non-adipose tissues, which, during pregnancy, not only mediates the gestational energy homeostasis , but also modulates various physiological events, such as implantation, placentation, and immune adaption, that are essential for fetal development . Our previous findings have demonstrated elevations of Lep in early gestation in PE patients . Other have also reported that sphingolipid metabolism, particularly via ceramide (Cer), acts downstream to the anorectic actions of central Lep, and played an important role in Lep-induced hypothalamic control of feeding . Furthermore, our recent findings have also illustrated the regulatory role of Cer as a metabolic messenger for the homeostatic development of normal pregnancy along gestation , and placental changes in cytoplasmic amount of Cer in trophoblast cells have been shown to be implicated in the pathogenesis of PE .
In this study, we employed a multi-omics approach to identify Lep and Cer as potential biomarker candidates for risk of impending PE. This initial omics-based discovery led to the generation of our hypothesis that the gestational profiles of Lep and Cer differ in maternal serum from women without PE compared with those with PE. We further hypothesized that the ratio of Lep and Cer can serve as a serological marker capable of predicting impending PE early in gestation. We therefore characterized the serological profiles of circulating Lep and Cer longitudinally and investigated their potential utility in predicting impending PE early in pregnancy and biological insights.