Pre-eclampsia part 1: current understanding of its pathophysiology

Abstract

Pre-eclampsia is characterized by new-onset hypertension and proteinuria at ≥20 weeks of gestation. In the absence of proteinuria, hypertension together with evidence of systemic disease (such as thrombocytopenia or elevated levels of liver transaminases) is required for diagnosis. This multisystemic disorder targets several organs, including the kidneys, liver and brain, and is a leading cause of maternal and perinatal morbidity and mortality. Glomeruloendotheliosis is considered to be a characteristic lesion of pre-eclampsia, but can also occur in healthy pregnant women. The placenta has an essential role in development of this disorder. Pathogenetic mechanisms implicated in pre-eclampsia include defective deep placentation, oxidative and endoplasmic reticulum stress, autoantibodies to type-1 angiotensin II receptor, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and the presence of an antiangiogenic state, among which an imbalance of angiogenesis has emerged as one of the most important factors. However, this imbalance is not specific to pre-eclampsia, as it also occurs in intrauterine growth restriction, fetal death, spontaneous preterm labour and maternal floor infarction (massive perivillous fibrin deposition). The severity and timing of the angiogenic imbalance, together with maternal susceptibility, might determine the clinical presentation of pre-eclampsia. This Review discusses the diagnosis, classification, clinical manifestations and putative pathogenetic mechanisms of pre-eclampsia.

Figure 1. An experiment supporting the concept that hypertension in pregnancy represents a uteroplacental response to ischaemia

A. In the Goldblatt model of renovascular hypertension, clamping the renal artery leads to development of hypertension through renal ischaemia in nonpregnant animals. B. By contrast, clamping the aorta below the renal arteries does not induce hypertension in nonpregnant animals. C. Aortic clamping in pregnant animals leads to hypertension. D. After hysterectomy, however, hypertension can no longer be elicited by aortic clamping, suggesting that the ischaemic pregnant uterus is the source of signals that lead to maternal systemic hypertension. Permission obtained from Semin. Perinatol. 12, Romero, R. et al. Toxemia: new concepts in an old disease, 302–323 © Elsevier (1988).

Figure 2. Failure of physiological transformation of the spiral arteries is implicated in pre-eclampsia

A. In a normal pregnancy, physiological transformation of the myometrial segment of the spiral artery occurs. Trophoblast cells extend to both the decidual segment and one-third of the myometrial segment of the spiral artery. Both the arterial media and endothelium are destroyed by trophoblasts, converting the arteries into wide-calibre vessels and increasing the delivery of blood to the intervillous space. B. In pregnancies affected by pre-eclampsia, a key feature associated with the failure of physiological transformation of the spiral arteries is lack of invasion of the trophoblasts into the myometrial segment of the spiral artery. The resulting lack of transformation of blood vessels results in narrow spiral arteries, a disturbed pattern of blood flow and reduced uteroplacental perfusion. Permission obtained from Nature Publishing Group © Moffett-King, A. et al. Nat. Rev. Immunol. 2, 656–663 (2002).

Figure 3. Transformed and nontransformed spiral arteries in the myometrium

A. Transformed spiral arteries are characterized by the presence of intramural trophoblasts (arrowheads) and fibrinoid degeneration (arrows) of the arterial wall. B. Nontransformed spiral arteries lack intramural trophoblasts and fibrinoid degeneration, and retain intact arterial contours. Arrowheads indicate the presence of trophoblasts in myometrium, but not in the wall of the spiral artery. Both images stained with cytokeratin 7 (brown) and periodic acid–Schiff (pink), magnification ×200. Permission obtained from the NIH © Espinoza, J. et al. J. Perinat. Med. 34, 447–458 (2006).

Figure 4. Integrated model of the complex pathophysiology of pre-eclampsia

Genetic (including maternal–fetal genotype incompatibility) and environmental (preconception exposure to paternal antigens) factors disrupt pregnancy-induced immunomodulation, leading to trophoblast and decidual pathology, shallow endometrial invasion and failure of physiological transformation of the spiral arteries (a disorder of deep placentation). The degree of uterine ischaemia is determined by the severity of the placentation defect and fetal demand on the blood supply. Obstetric disorders occur when these two factors are mismatched. The timing and extent of the mismatch determines the clinical presentation (fetal death, pre-eclampsia with IUGR, IUGR alone and late pre-eclampsia). Pre-eclampsia occurs as a result of adaptive responses involving the release of inflammatory cytokines, anti-AT₁ autoantibodies, angiogenic and antiangiogenic factors and syncytiotrophoblast-derived particles into the maternal circulation. Collectively, these factors induce leukocyte activation, intravascular inflammation, endothelial cell dysfunction and excessive thrombin generation. The multiorgan features of pre-eclampsia result from the consequences of these processes in different target organs. Abbreviations: AT₁, type-1 angiotensin II receptor; ER, endoplasmic reticulum; ICH, intracerebral haemorrhage; IUGR, intrauterine growth restriction; PlGF, placental growth factor; ROS, reactive oxygen species; s, soluble; VEGF, vascular endothelial growth factor; VEGFR-1, vascular endothelial growth factor receptor 1.