Pathophysiology of Preeclampsia

Incidence and Risk Factors

Preeclampsia complicates 3% to 6% of all pregnancies throughout the world. Rates of severe preeclampsia are steadily increasing in the United States, likely related to increasing obesity and invitro fertilization. In developed countries, maternal lives are saved at the cost of premature delivery of the neonate. There are disproportionately higher rates of preeclampsia with morbidity and mortality among African American women, even after controlling for confounders; however, the reasons for this racial disparity remain unclear. ^, In countries where access to health care is limited, preeclampsia is a leading cause of maternal mortality, with estimates of greater than 60,000 maternal deaths/year.

The epidemiology of preeclampsia provides hints about its pathophysiology that are still being deciphered. Although there are several risk factors for preeclampsia, most cases of preeclampsia occur in healthy nulliparous women. Associations between preeclampsia and nulliparity, change in paternity from a previous pregnancy, short or long interpregnancy interval (less than 2 years or more than 10 years), ^, use of barrier contraception, and assisted reproductive technologies implicate a possible immunogenic exposure to paternal antigen as a predisposing factor. Genetic factors may also contribute, because both a maternal and paternal family history of the disease predisposes to preeclampsia. A woman’s risk for severe preeclampsia is increased two- to four-fold if she has a first-degree relative with a history of preeclampsia. There is a seven-fold risk of recurrence of preeclampsia for women who have had the condition in a previous pregnancy. Genome-wide association study of neonates from 4380 cases of preeclampsia and 310,238 controls found a genome-wide susceptibility locus near the FMS-like tyrosine kinase 1 (FLT1) gene, the protein product of which is a well-established pathogenetic factor in preeclampsia. Multiple gestation is an additional risk factor, with triplet gestation carrying a greater risk than twin gestation; this suggests that increased placental mass may play a role. Other risk factors include advanced maternal age, insulin resistance, obesity, systemic inflammation, and chronic hypertension. The only known factor that is associated with reduced risk for preeclampsia is, paradoxically, cigarette smoking, which is directly associated with fetal growth restriction.

Clinical Features

Preeclampsia is not only a hypertensive disorder but a multisystem disease. In addition to the vascular system and kidney involvement, preeclampsia includes dysfunction of the liver, hemolysis and thrombocytopenia, an increased risk of abruption, and eclamptic seizures. One feature of the disorder is how rapidly it can evolve when a seemingly stable patient with mild hypertension and minimal proteinuria suddenly develops marked liver involvement and extreme hemolysis with thrombocytopenia (HELLP syndrome [ H emolysis E levated L iver enzymes and L ow P latelets]). Other aspects of the preeclampsia’s spectrum includes cardiac dysfunction described as subtle diastolic dysfunction ^, or frank heart failure and cardiomyopathy, ^, thrombotic microangiopathy leading to disseminated intravascular coagulopathy, and a variety of forms of liver dysfunction including subcapsular hematomas. The cerebral effects in addition to severe headache include cerebral edema, intracranial hemorrhage, and even blindness. Magnetic resonance imaging (MRI) studies have revealed that the cerebral edema is often localized to the posterior cerebrum and has been labeled as posterior reversible encephalopathy syndrome (PRES). This is believed to be a result of endothelial damage and loss of myogenic tone in the cerebral vasculature. Severe preeclampsia is associated with intrauterine growth restriction (IUGR) of the fetus and oligohydramnios. ^, Neonatal morbidity is most often due to the sequelae of prematurity and low birth weight, including prolonged neonatal intensive care unit stays, respiratory distress, necrotizing enterocolitis, intraventricular hemorrhage, sepsis, and death.

The exact diagnostic criteria for preeclampsia are not agreed upon worldwide in part due to a plethora of national guidelines. In United States, we adhere mainly to the American College of Obstetrics task force criteria that included appearance of hypertension (systolic or diastolic at or above 140 and 90 mm Hg, respectively) and new-onset proteinuria (at or greater than 300 mg/24 hours of protein, or a protein to creatinine ratio in a spot urine of 0.3 [mg/dL] after 20 weeks of gestation). ^, In the absence of proteinuria the diagnosis should be made when any other of the multisystem aspects are present, such as new-onset thrombocytopenia, liver function abnormalities, pulmonary edema, and cerebral and visual system abnormalities ( Table 170.1 ). ^, The task force also maintained as a classification gestational hypertension, a designation when hypertension alone appeared de novo after mid-pregnancy without proteinuria or any severe features. However, such patients contain a mixture of different pathologies. In some it is chronic previously undiagnosed hypertension masked by the normal decrease in blood pressure that occurs in early gestation. In others it may be subclinical preeclampsia that may progress to full-blown disease with advancing gestational age.

Management of Preeclampsia

The most reliable treatment of preeclampsia is delivery. Removal of the placenta usually results in prompt improvement, although in a few cases, in which the disease has been explosive, symptoms may progress for several days even after delivery. By 6 weeks after delivery, hypertension and proteinuria have usually disappeared, but in unusual cases, this may take 3 or 4 months. The hypertension of preeclampsia usually responds to pharmacologic treatment. Prompt lowering of the blood pressure is important to reduce the risk of cerebral edema, cerebral hemorrhage, and eclampsia. Although proteinuria may lessen as the blood pressure decreases, renal function may not improve and the levels of creatinine, urea, and uric acid in the serum continue to increase slowly even after delivery. The mother remains at risk for development of the HELLP syndrome and the fetus for intrauterine death or placental abruption. Infusions of magnesium sulfate are effective in preventing epileptic seizures. At high concentrations, magnesium ions depress all neural activity, including that of the respiratory center, and infusions of magnesium should not be given if the deep tendon reflexes (e.g., patellar reflex) cannot be elicited or if magnesium levels in the serum are greater than 9 mg/dL. Women with decreased renal function are at increased risk of magnesium toxicity, and it should be used with caution in those patients. Preterm delivery and IUGR are the two most common problems for infants who deliver to women with preeclampsia. Appropriate timing of delivery is a difficult decision, with the goal of balancing the infant’s risk for complications related to prematurity versus maternal morbidity and mortality with continued pregnancy. Although several strategies to prevent preeclampsia have been proposed, none have been proven to be unequivocally effective.