Evidence-Based Revised View of the Pathophysiology of Preeclampsia

Abstract

Preeclampsia is a life-threatening vascular disorder of pregnancy due to a failing stressed placenta. Millions of women risk death to give birth each year and globally each year, almost 300,000 lose their life in this process and over 500,000 babies die as a consequence of preeclampsia. Despite decades of research, we lack pharmacological agents to treat it. Maternal endothelial oxidative stress is a central phenomenon responsible for the preeclampsia phenotype of high maternal blood pressure and proteinuria. In 1997, it was proposed that preeclampsia arises due to the loss of VEGF activity, possibly due to elevation in anti-angiogenic factor, soluble Flt-1 (sFlt-1). Researchers showed that high sFlt-1 and soluble endoglin (sEng) elicit the severe preeclampsia phenotype in pregnant rodents. We demonstrated that heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway prevents placental stress and suppresses sFlt-1 and sEng release. Likewise, hydrogen sulphide (HS)/cystathionine-γ-lyase (Cth) systems limit sFlt-1 and sEng and protect against the preeclampsia phenotype in mice. Importantly, HS restores placental vasculature, and in doing so improves lagging fetal growth. These molecules act as the inhibitor systems in pregnancy and when they fail, preeclampsia is triggered. In this review, we discuss what are the hypotheses and models for the pathophysiology of preeclampsia on the basis of Bradford Hill causation criteria for disease causation and how further in vivo experimentation is needed to establish 'proof of principle'. Hypotheses that fail to meet the Bradford Hill causation criteria include abnormal spiral artery remodelling and inflammation and should be considered associated or consequential to the disorder. In contrast, the protection against cellular stress hypothesis that states that the protective pathways mitigate cellular stress by limiting elevation of anti-angiogenic factors or oxidative stress and the subsequent clinical signs of preeclampsia appear to fulfil most of Bradford Hill causation criteria. Identifying the candidates on the roadmap to this pathway is essential in developing diagnostics and therapeutics to target the pathogenesis of preeclampsia.

Risk Factors for Pregnancy-Associated Stroke in Women With Preeclampsia

“…Infections may also provoke cardiac arrhythmias or dehydration-induced thrombosis; in one study, infections tripled the odds of peripartum cerebral venous thrombosis. 23 The pathophysiology of PEC remains incompletely understood, 1 although imbalance of pro- and anti-angiogenic factors and an increase in pro-inflammatory cytokines appear to play roles. 24 Animal models of PEC have demonstrated impaired cerebral autoregulation, increased blood-brain barrier permeability, and neuronal hyperexcitability, mediated by elevated levels of tumor necrosis factor- alpha .…”

“…1 Approximately 36% of women with pregnancy-associated strokes (PAS) have comorbid PEC, 2 and PEC increases stroke risk during the puerperium up to 6-fold. 3 Among women with PAS, women with PEC are at increased risk of complications and death.…”

Preeclampsia: Pathophysiology and the Maternal-Fetal Risk

“…However, there are several theories that have been put forth that may explain most of the abnormalities seen in this disease process [6].…”

“…Eclampsia complicates 2-3% of women diagnosed with preeclampsia with severe features who are not receiving anti-seizure prophylaxis (magnesium sulfate) and up to 0.6% of women diagnosed with preeclampsia without severe features [6]. Eclampsia may lead to significant maternal morbidity and even mortality.…”

Disturbed Maternal Immune Milieu Early in Pregnancy Could Predict Later Development of Pre-Eclampsia and Differentiate Its Severity Grades.

“…Worldwide, PE affects 2-8% of all pregnancies (1) . PE is a life-threatening vascular disorder of pregnancy due to a failing stressed placenta (3) and represents a significant health risk to both pregnant women and their unborn children (4) .…”