Pre-eclampsia: pathogenesis, novel diagnostics and therapies

Abstract

Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

Fig. 1 ∣. The pathogenesis of pre-eclampsia.

Genetic factors, maternal factors and immunological factors may cause placental dysfunction (stage I), which in turn leads to the release of antiangiogenic factors (such as soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin (sENG)) and other inflammatory mediators that induce preeclampsia (stage II). AT1, angiotensin II type I receptor; dNK, decidual natural killer; ER, endoplasmic reticulum; HELLP, haemolysis, elevated liver enzymes and low platelet count; PlGF, placental growth factor; SNP, single-nucleotide polymorphism; T_reg, regulatory T cell; VEGF, vascular endothelial growth factor.

Fig. 2 ∣. Decidual vasculopathy in a pre-eclamptic placenta.

Image showing a sample of the placental bed of the uterus from a patient with decidual vasculopathy in the third trimester that is stained with haematoxylin and eosin. The vessels show chronic injury with endothelial fragmentation and detachment (arrow) as well as fibrinoid necrosis (**) and remodelling (*) of the vessel wall. Adapted from REF.: The pathology of eclampsia: an autopsy series, Hecht, J. L. et al., Hypertension in Pregnancy, 2017, by permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com).

Fig. 3 ∣. Glomerular endotheliosis.

Electron micrograph showing glomerular endotheliosis with occlusion of the capillary lumen by swollen endothelial cells in a pregnant women with new-onset hypertension and proteinuria (3.7 g per day). Podocytes show protein resorption granules with preservation of their foot processes. Original magnification ×8,000. Image courtesy of I. Stillman, Beth Israel Deaconess Medical Center, USA.

Fig. 4 ∣. The role of sFLT1 in endothelial dysfunction in pre-eclampsia.

a ∣ During normal pregnancy, vascular homeostasis is maintained by physiological levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) signalling in the vasculature by binding to its receptor fms-like tyrosine kinase 1 (FLT1) and other signalling receptors. b ∣ In pre-eclampsia, excess soluble FLT1 (sFLT1) is secreted by the placenta and binds local and circulating VEGF and PlGF, resulting in inhibition of VEGF and PlGF signalling in the vasculature. This inhibition results in endothelial cell dysfunction, including reduced production of prostacyclin and nitric oxide and the release of procoagulant proteins.

Fig. 5 ∣. Dextran-sulfate apheresis enables prolongation of pregnancy in women with pre-eclampsia.

Pretreatment soluble fms-like tyrosine kinase 1 (sFLT1):placental growth factor (PlGF) ratios and pregnancy prolongation in women with pre-eclampsia who were treated with apheresis and untreated contemporaneous controls. Pregnancy continued for 8 days (range 2–11) and 15 days (range 11–21) in women treated once (n = 6) and multiple times (n = 5), respectively, compared with 3 days (range 0–14) in untreated contemporaneous women with pre-eclampsia (n = 22). Republished with permission of American Society of Nephrology, from Thadani et al., Removal of soluble fms-like tyrosine kinase 1 by dextran sulfate apheresis in preeclampsia. Journal of the American Society of Nephrology 27 (2016) (REF.).