Uzan et al in multiparas. Moreover, nulliparity and a new partner have been shown to be important risk factors (Table 1).5 Other risk factors have been identified, including a medical history of chronic hypertension, kidney disease, diabetes, obesity, birthplace in Africa, age $35 years, and pregnancy characteristics, such as twin or molar pregnancy, previous pre-eclampsia, or fetal congenital abnormality.6,7 High altitude has also been shown to increase the incidence of pre-eclampsia, and is attributed to greater placental hypoxia, smaller uterine artery diameter, and lower uterine artery blood flow.8 Pre-eclampsia may be life-threatening for both mother and child, increasing both fetal and maternal morbidity and mortality.5 In the mother, pre-eclampsia may cause premature cardiovascular disease, such as chronic hypertension, ischemic heart disease, and stroke, later in life,9 while children born after pre-eclamptic pregnancies and who are relatively small at birth, have an increased risk of stroke, coronary heart disease, and metabolic syndrome in adult life.10–12 The sole curative treatment being delivery, management must continuously balance the risk–benefit ratio of induced preterm delivery and maternal–fetal complications. Screening women at high risk and preventing recurrences are also key issues in the management of pre-eclampsia. Pathophysiology During normal pregnancy, the villous cytotrophoblast invades into the inner third of the myometrium, and spiral arteries lose their endothelium and most of their muscle fibers. These structural modifications are associated with functional alterations, such that spiral arteries become low- resistance vessels, and thus less sensitive, or even insensitive, to vasoconstrictive substances. Pre-eclampsia has a complex pathophysiology, the pri- mary cause being abnormal placentation. Defective invasion of the spiral arteries by cytotrophoblast cells is observed during pre-eclampsia. Recent studies have shown that cytotrophoblast invasion of the uterus is actually a unique differentiation pathway in which the fetal cells adopt cer- tain attributes of the maternal endothelium they normally replace. In pre-eclampsia, this differentiation process goes awry.13 The abnormalities may be related to the nitric oxide pathway, which contributes substantially to the control of vascular tone. Moreover, inhibition of maternal synthesis of nitric oxide prevents embryo implantation.14 Increased uterine arterial resistance induces higher sensitivity to vasoconstriction and thus chronic placental ischemia and oxidative stress. This chronic placental ischemia causes fetal 468 submit your manuscript | www.dovepress.com Dovepress Dovepress complications, including intrauterine growth retardation and intrauterine death. In parallel, oxidative stress induces release into the maternal circulation of substances such as free radicals, oxidized lipids, cytokines, and serum soluble vascular endothelial growth factor 1. These abnormalities are responsible for endothelial dysfunction15 with vascular hyperpermeability, thrombophilia, and hypertension, so as to compensate for the decreased flow in the uterine arteries due to peripheral vasoconstriction. Endothelial dysfunction is responsible for the clinical signs observed in the mother, ie, impairment of the hepatic endothelium contributing to onset of the HELLP (Hemolysis, Elevated Liver enzymes and Low Platelet count) syndrome, impairment of the cerebral endothelium inducing refractory neurological disorders, or even eclampsia. Depletion of vascular endothelial growth factor in the podocytes makes the endotheliosis more able to block the slit diaphragms in the basement membrane, adding to decreased glomerular filtra- tion and causing proteinuria. Finally, endothelial dysfunction promotes microangiopathic hemolytic anemia, and vascular hyperpermeability associated with low serum albumin causes edema, particularly in the lower limbs or lungs. The crucial issue to understand is that the prime mover of pre-eclampsia is abnormal placentation. Two common theories appear to be interlinked, ie, a genetic theory1,16 and an immunological theory.17,18 Several susceptibility genes may exist for pre-eclampsia.16,19 These genes probably interact in the hemostatic and cardiovascular systems, as well as in the inflammatory response. Some have been identified, and in candidate gene studies they have provided evidence of linkage to several genes, including angiotensinogen on 1-q42–43 and eNOS on 7q36; other main important loci are 2p12, 2p25, 9p13, and 10q22.1.16 Pre-eclampsia can be perceived as an impairment of the maternal immune system that prevents it from recognizing the fetoplacental unit. Excessive production of immune cells causes secretion of tumor necrosis factor alpha which induces apoptosis of the extravillous cytotrophoblast.17 The human leukocyte antigen (HLA) system also appears to play a role in the defective invasion of the spiral arter- ies, in that women with pre-eclampsia show reduced levels of HLA-G and HLA-E.18 During normal pregnancies, the interaction between these cells and the trophoblast is due to secretion of vascular endothelial growth factor and pla- cental growth factor by natural killer cells. High levels of soluble fms-like tyrosine kinase 1 (sFlt-1), an antagonist of vascular endothelial growth factor and placental growth factor, have been found in women with pre-eclampsia.17,18 Vascular Health and Risk Management 2011:7