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.