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Pre-eclampsia


Pre-eclampsia
Clinical spectrum of pre-eclampsia
Pre-eclampsia is a unique disorder found only in human pregnancies. Historically, pre-eclampsia has been defined as the triad of hypertension, proteinuria and edema in a pregnant woman. Eclampsia is the occurrence of seizures that cannot be attributed to another cause in a patient with pre-eclampsia. Pre-eclampsia typically occurs in the third trimester of pregnancy, although some cases manifest earlier. Although many patients with pre-eclampsia demonstrate the classic triad, it is now clear that the disorder is really a spectrum of clinical signs and symptoms that accompany microvascular changes in multiple organ systems (Fig. 38.1). The disorder has so many presentations that it has been called the “great imitator.” Central nervous system involvement can result in severe headaches, visual changes, seizures, stroke and blindness. Renal involvement is almost always present and can manifest as proteinuria, oliguria or renal failure. Edema can accumulate in many sites, including the feet, hands, face and lungs. Hemoconcentration, thrombocytopenia and intravascular hemolysis are common signs of hematologic involvement. Hepatic dysfunction often accompanies hematologic changes and produces a group of clinical findings known as HELLP syndrome (hemolysis, elevated liver function tests, low platelets). Patients with HELLP will often develop vague epigastric pain resulting from liver involvement which may be mistaken for heartburn, gallbladder disease or the flu by an unsuspecting health care provider.

Pre-eclampsia

The overall incidence of pre-eclampsia in the obstetric population is 5–8%; the absolute number depends on the proportion of patients at increased risk. Risk factors for developing pre-eclampsia include the primigravid state (first pregnancy), multiple gestation, diabetes, pre-existing hypertension, a long interval between pregnancies, pre-eclampsia in a previous pregnancy, a family history of pre-eclampsia, hydatidiform mole, and inherited and acquired clotting disorders (e.g., protein S and protein C deficiencies and antiphospholipid antibodies). There is considerable overlap between the risk factors for pre-eclampsia and those for fetal growth restriction (FGR). Indeed, the presence of FGR may be the first sign of impending pre-eclampsia and women with pre-eclampsia are at risk for delivering a growth-restricted baby.
Left untreated, pre-eclampsia can be a highly morbid and even fatal disease. The ultimate treatment for the condition is delivery of the pregnancy. This is so effective a therapy that all deranged physiology will revert to normal after delivery provided that no permanent tissue damage has occurred. If the mother is medically supported through a timely delivery and postpartum recovery, her kidneys will begin to make urine again, blood will clot and seizures will stop. In spite of its potential for a 100% cure with proper diagnosis and treatment, pre-eclampsia remains one of the leading causes of maternal death in both developed and developing countries.


Potential mechanisms in pre-eclampsia pathogenesis
It is clear that placental abnormalities are central to the pathogenesis of pre-eclampsia. Delivery cures pre-eclampsia and hydatidiform mole, a form of gestational trophoblast disease characterized by pla- cental overgrowth but no fetal development (Chapter 45), predisposes to the disease. It was originally thought that the placenta secreted a toxin that caused pre-eclampsia and the disorder was appropriately called “toxemia.” While no unique toxins have been identified in the circulation of patients with pre-eclampsia, abnormal concentrations of specific metabolites are found in many of these patients. Circulating thromboxane, a vasoconstricting prostaglandin, is elevated while nitric oxide production is subnormal. A number of other factors, including a soluble form of a vascular endothelial growth factor (VEGF) receptor (sVEGFR-1 or sFlt-1), placental growth factor (PLGF) and soluble endoglin (sENG), a circulating receptor for transforming growth factor β (TGF-β), have been shown to be markedly different in the serum of pregnant women weeks or months before the symptoms of pre-eclampsia manifest. Unfortunately, the test accuracies of these markers are inadequate to predict pre-eclampsia in clinical practice.
There are many unproven but enticing theories about the etiology and pathogenesis of pre-eclampsia. It is likely that there are several initiators of the disease that ultimately converge in a final common pathway. Examination of the small blood vessels in the uteri of women with pre-eclampsia often reveals a failure of the invading trophoblast to remodel the spiral arteries (Fig. 38.2). There are several explanations for why the cytotrophoblast might fail to invade these vessels including abnormal immune activation or genetic predisposition. Cytotrophoblast differentiation into an invasive phenotype is accompanied by increased production of VEGF and PLGF, both proangiogenic factors. Placentas from pre-eclamptic pregnancies secrete increased amounts of sFlt-1, the soluble antagonist to VEGF,  and sENG; both are antiangiogenic factors.
Abnormal immune activation that inhibits trophoblast invasion of maternal blood vessels could explain why pre-eclampsia is most common when a woman is exposed to paternal antigens for the first time: a first pregnancy or, in a multigravid woman, the initial pregnancy with a new partner. Loss of immune tolerance over time would also explain why a long interval between pregnancies is a risk factor for developing pre-eclampsia. Abnormal activation of the immune system underlies other autoimmune diseases, such as systemic lupus erythematosus, that carry an increased risk for pre-eclampsia. Some women with pre-eclampsia have activating autoantibodies to the angiotensin II receptor that inhibit trophoblast invasiveness in vitro.
Specific genetic abnormalities may be involved in the pathophysiology of pre-eclampsia. Women who carry a mutation in the complement receptor CR-1 have an increased risk for pre-eclampsia as do women carrying a specific polymorphism for plasminogen activator inhibitor type 1. Pre-existing insulin resistance confers an increased risk. The fact that a family history of pre-eclampsia increases a woman’s risk for the disease indicates that there may be many additional genetic predispositions to the disease.
A mismatch between fetal and placental demands and the maternal ability to meet them may also cause pre-eclampsia and would explain risk factors such as multiple gestation, maternal vascular disease and hypercoagulable states. Proponents of this theory propose that the undernourished fetus sends signals to the mother to increase perfusion of the placenta. If the mother cannot compensate in response to these initial signals, the fetus sends more urgent signals. Pre-eclampsia would theoretically result from the effects of excessive signals. As an example, hypoxia has been shown to increase the production of sFlt-1 by tro- phoblast cells. Increased sFlt-1 may be part of the pathogenesis of pre-eclampsia.
While the initiating placental abnormality is unclear, the final common pathway for pre-eclampsia is known to be endothelial dysfunction and injury. The vascular endothelium normally functions to prevent microcoagulation and to modulate vascular tone. Vascular injury results in coagulation and alters the response of the underlying vascular smooth muscle to vasoactive substances. Often, substances that act as vasodilators on an intact endothelium will cause vasoconstriction of damaged endothelium. In preeclampsia, endothelial dysfunction can solely explain the basic triad: hypertension (vasospasm), edema (capillary leak) and proteinuria (renal cell damage secondary to hypoperfusion). Experiments in animal models indicate that excess sFlt-1 can directly produce some of the organ dysfunction seen in pre-eclampsia. What remains inexplicable is why only a few, but not all, of the signs and symptoms of pre-eclampsia will appear in any given patient.