Basic Science for Clinicians Preeclampsia, a Disease of the Maternal Endothelium The Role of Antiangiogenic Factors and Implications for Later Cardiovascular Disease

Preeclampsia is a clinical syndrome defined as the new onset of hypertension and proteinuria during the second half of pregnancy.1 It afflicts 3% to 5% of pregnancies and is a leading cause of maternal mortality, especially in developing countries.2,3 Because the only known remedy is delivery of the placenta, in developed countries preeclampsia is an important cause of premature delivery, usually medically indicated for the benefit of the mother. This results in infant morbidity and substantial healthcare expenditure.4 Despite the considerable morbidity and mortality, the cause of preeclampsia has remained enigmatic. Both hypertension and proteinuria implicate the endothelium as the target of the disease. The hypertension of preeclampsia is characterized by peripheral vasoconstriction and decreased arterial compliance.5,6 The proteinuria of preeclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost.7,8 Podocyturia has been recently associated with preeclampsia during clinical disease9; however, whether this is the cause or effect of proteinuria is unknown. The glomerular filtration rate is decreased compared with normotensive pregnant women; in rare cases, acute renal failure may develop. Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers. When the liver is involved, women may present with abdominal pain, nausea, vomiting, and elevated liver enzymes. Pathological examination of the liver reveals periportal and sinusoidal fibrin deposition and, in more extreme cases, hemorrhage and necrosis.10 The severe preeclampsia variant HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurs in 20% of women with severe preeclampsia,11 and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops.12 Approximately 20% of women with HELLP syndrome develop disseminated intravascular coagulation, which carries a poor prognosis for both mother and fetus.11 Placental abruption, ascites, hepatic infarction, hepatic rupture, intra-abdominal bleeding, pulmonary edema, and acute renal failure are all severe clinical manifestations associated with preeclampsia that can result in maternal death.13 Perhaps the most feared complication of preeclampsia is eclampsia itself, defined by the presence of seizures, for which women with severe preeclampsia are often treated with magnesium sulfate prophylaxis.1 The brain injury in eclampsia is associated with cerebral edema and characteristic white matter changes of reversible posterior leukoencephalopathy syndrome, which is similar to findings noted in hypertensive encephalopathy and with cytotoxic immunosuppressive therapies.14 Cerebrovascular complications, including stroke and cerebral hemorrhage, are responsible for the majority of eclampsia-related deaths.15 Complications affecting the developing fetus include indicated prematurity,16 intrauterine fetal growth restriction, oligohydramnios, bronchopulmonary dysplasia,17 and increased risk of perinatal death.18 The risk factors for preeclampsia are varied and unique to this condition. Genetic factors are at least partially responsible, because both a maternal and a paternal family history of the disease predispose to preeclampsia.19 There is a 7-fold risk of recurrence for women who have had the disease in a previous pregnancy.20 Multiple gestation is an additional risk factor, and triplet gestation carries a greater risk than twin, suggesting that increased placental mass plays some role.20 Associations between preeclampsia and nulliparity,20 change in paternity from a previous pregnancy,21 increased interpregnancy interval,22 use of barrier contraception,23 and conception by intracytoplasmic sperm injection24 implicate limited recent exposure to paternal antigen as a predisposing factor. Notably, classic cardiovascular risk factors are associated with preeclampsia: Maternal age 40 years, insulin resistance, obesity, and systemic inflammation and preexisting hypertension, diabetes mellitus, or renal disease all increase the risk.20,25,26 Consistent with this, women with a history of preeclampsia have an elevated risk for cardiovascular disease later in life (see discussion later in this review). Surprisingly, smoking during pregnancy protects against preeclampsia.27