Preeclampsia occurs in about 6% of the general population; the incidence varies with geographic location. Predisposing factors are nulliparity, black race, maternal age below 20 or over 35 years, low socioeconomic status, multiple gestation, hydatidiform mole, polyhydramnios, nonimmune fetal hydrops, twins, obesity, diabetes, chronic hypertension, and underlying renal disease. Classification There are 2 categories of preeclampsia, mild and severe. Severe preeclampsia is defined as the following: (1) blood pressure greater than 160 mm Hg systolic or 110 mm Hg diastolic on 2 occasions 6 hours apart; (2) proteinuria exceeding 2 g in a 24-hour period or 2–4+ on dipstick testing; (3) increased serum creatinine (> 1.2 mg/dL unless known to be elevated previously); (4) oliguria  500 mL/24 h; (5) cerebral or visual disturbances; (6) epigastric pain; (7) elevated liver enzymes; (8) thrombocytopenia (platelet count < 100,000/mm3); (9) retinal hemorrhages, exudates, or papilledema; and (10) pulmonary edema. Pathogenesis Preeclampsia has been described as a disease of theories, because the cause is unknown. Some theories include (1) endothelial cell injury, (2) rejection phenomenon (insufficient production of blocking antibodies), (3) compromised placental perfusion, (4) altered vascular reactivity, (5) imbalance between prostacyclin and thromboxane, (6) decreased glomerular filtration rate with retention of salt and water, (7) decreased intravascular volume, (8) increased central nervous system irritability, (9) disseminated intravascular coagulation, (10) uterine muscle stretch (ischemia), (11) dietary factors, and (12) genetic factors. The relatively new theory of endothelial injury explains many of the clinical findings in preeclampsia. The theory emphasizes that there is more to preeclampsia than hypertension. The vascular endothelium produces a number of important substances including endothelial-derived relaxing factor or nitric oxide, endothelin-1, prostacyclin, and tissue plasminogen activator. Thus, endothelial cells modify the contractile response of the underlying smooth muscle cells, prevent intravascular coagulation, and maintain the integrity of the intravascular compartment. Several findings suggest endothelial injury in preeclampsia. The characteristic renal lesion of preeclampsia "glomeruloendotheliosis" is manifested primarily by swelling of the glomerular capillary endothelial cells. The hematologic changes of preeclampsia, ie, thrombocytopenia and microangiopathic hemolytic anemia, are similar to those found in thrombotic thrombocytopenic purpura or hemolytic uremic syndrome—disorders in which endothelial dysfunction is thought to be important. Activation of the clotting cascade and increased sensitivity to pressors are compatible with endothelial cell dysfunction. Biochemical evidence includes an imbalance in the prostacyclin:thromboxane ratio and high circulating concentrations of von Willebrand factor, endothelin, and cellular fibronectin. Serum from preeclamptic women, when applied to human umbilical vein endothelial cell cultures, produces no morphologic abnormalities in the cells but releases procoagulants, vasoconstrictors, and mitogens. In summary, the current hypothesis for the pathogenesis of preeclampsia is that an immunologic disturbance causes abnormal placental implantation resulting in decreased placental perfusion. The abnormal perfusion stimulates the production of substances in the blood that activate or injure endothelial cells. The vascular endothelium provides a single target for these blood-borne products, which explains the multiple organ system involvement in preeclampsia. Pathophysiology Central Nervous System Tissues are capable of regulating their own blood flow; this process is known as autoregulation. Cerebral perfusion is maintained by autoregulation at a constant level of about 55 mL/min/100 g at a wide range of blood pressures (Fig 19–1). However, blood pressure may rise to levels at which autoregulation cannot function. When this occurs, the endothelial tight junctions open, causing plasma and red blood cells to leak into the extravascular space. This may result in petechial hemorrhage or gross intracranial hemorrhage. The upper limit of autoregulation varies from one person to another; eg, chronic hypertension may cause medial hypertrophy of the cerebral vessels, resulting in a shift of the curve to the right (Fig 19–1). This explains the paradox of 2 patients with equally severe hypertension who have markedly different clinical presentations. The young primigravida whose blood pressure is normally 110/70 mm Hg may convulse with a blood pressure of 180/120 mm Hg, while a chronic hypertensive may be asymptomatic or have only a headache at the same pressure. | | Figure 19–1. Representation of the relationship between cerebral blood flow and mean arterial blood pressure. Cerebral blood flow normally remains constant at mean arterial pressures of 60–140 mm Hg. In chronically hypertensive patients, medial hypertrophy causes the lower and upper limits of autoregulation to be shifted to higher blood pressure values. (Modified and reproduced, with permission, from Donaldson JO: Neurology of Pregnancy. Saunders, 1978.) |
The mechanism of the cerebral damage in eclampsia is unclear. The pathologic findings are similar to those of hypertensive encephalopathy. These abnormalities include fibrinoid necrosis and thrombosis of arterioles, microinfarcts, and petechial hemorrhages. In both hypertensive encephalopathy and eclampsia, the lesions are widely distributed throughout the brain, but the brainstem is more severely affected in the former, while the cortex is more severely affected in the latter. Other differences in the two conditions are that eclampsia may be seen in the absence of hypertension and that retinal hemorrhages and infarcts are rare in eclampsia. Two theories have been proposed to explain the pathogenesis of hypertensive encephalopathy, vasospasm, and forced dilation. In the first, vasospasm causes local ischemia, arteriolar necrosis, and disruption of the blood-brain barrier. According to the second, as blood pressure rises above the limit of autoregulation, cerebral vasodilation occurs. Initially, some vessel segments dilate, and some remain constricted. Overdistention of the dilated segments results in necrosis of the medial muscle fibers and damage to the vessel wall. It is possible that both mechanisms are operant. The presence of cerebral edema in preeclampsia-eclampsia is controversial. One set of researchers stated that cerebral edema was not present in eclamptic patients when autopsy was performed within 1 hour of death and that such edema was a late postmortem change. In contrast, some others found generalized cerebral edema in some autopsy specimens and confirmed increased intracranial pressure in eclamptics with prolonged coma (> 6 hours). Early studies of cerebrospinal fluid opening pressure showed elevated pressures; however, more recent studies have failed to confirm this. Head computed tomographic (CT) scans in women with eclampsia have shown abnormalities in about one-third. By using fourth-generation equipment and with a short interval from seizure to CT scan, abnormalities may be detected in half the patients. The main findings are focal hypodensities in the white matter in the posterior half of the cerebral hemispheres with occasional lesions in the gray matter, temporal lobes, and brainstem. One researcher suggested that these areas of radiographic hypodensity represented petechial hemorrhages accompanied by local edema. Subarachnoid or intraventricular hemorrhages may be seen in the most severe cases. Magnetic resonance imaging (MRI) is more sensitive at demonstrating abnormalities than CT scan, but it is not as widely available. T2-weighed MRI scans show high signal in the cortical and subcortical white matter. Most of the abnormalities lie in the occipital and parietal areas in watershed areas where the anterior, middle, and posterior circulations meet. Basal ganglia and brainstem abnormalities occur in more critically ill patients. Cerebral angiography has been performed in a few patients with eclampsia, revealing diffuse arterial vasoconstriction. Electroencephalograms (EEGs) show nonspecific abnormalities in about 75% of patients after eclamptic seizures. The pattern is usually a diffuse slowing of activity (theta or delta waves), sometimes with focal slow activity and occasional paroxysmal spike activity. These abnormalities may be seen in other conditions, such as hypoxia, renal disease, polycythemia, hypocalcemia, and water intoxication. The electroencephalographic pattern is unaffected by magnesium sulfate. It gradually returns to normal 6–8 weeks postpartum. Uncomplicated eclampsia causes no permanent neurologic deficit. Eyes Both serous retinal detachment and cortical blindness may occur. Pulmonary System Pulmonary edema may occur with severe preeclampsia or eclampsia. It may be cardiogenic or noncardiogenic and usually occurs postpartum. In some cases it may be related to excessive fluid administration or to delayed mobilization of extravascular fluid. It may also be related to decreased plasma colloid oncotic pressure from proteinuria, use of crystalloids to replace blood loss, and decreased hepatic synthesis of albumin. Pulmonary edema is particularly common in patients with underlying chronic hypertension and hypertensive heart disease, which may be manifested by systolic dysfunction, diastolic dysfunction, or both. Aspiration of gastric contents is one of the most dreaded complications of eclamptic seizures. This may result in death because of asphyxia from particulate matter plugging major airways or in chemical pneumonitis from aspirated gastric acid. Aspiration may cause various types of pneumonia, ranging from patchy pneumonitis to full-blown adult respiratory distress syndrome. Cardiovascular System Plasma volume is reduced in patients with preeclampsia. Normal physiologic volume expansion does not occur, possibly because of generalized vasoconstriction, capillary leak, or some other factor. Because the cause of the reduced volume is unknown, management is controversial. One theory is that the decreased volume is a primary event causing a chronic shocklike state. Hypertension is thought to be the result of release of a pressor substance from the hypoperfused uterus or of compensatory secretion of catecholamines. Proponents of this theory advocate avoidance of diuretics and use of volume expanders. Another theory is that decreased volume is secondary to vasoconstriction. Proponents of this theory advocate the use of vasodilators and warn that volume expanders may aggravate hypertension or cause pulmonary edema. Studies using the Swan-Ganz catheter have demonstrated a spectrum of hemodynamic findings in preeclampsia ranging from a low-output, high-resistance state to a high-output, low-resistance state. One study found a low wedge pressure, low cardiac output, and high systemic vascular resistance in untreated nulliparous preeclamptic women, while patients who received various therapies and were usually referred, a wide range of hemodynamics was found. The conclusion was that the untreated preeclamptic patient was significantly volume-depleted and that the wide spectrum of hemodynamic findings in the treated group resulted from prior therapy and the presence of other variables such as labor, multiparity, and preexisting hypertension. In another study of a heterogeneous population of pretreated and nonpretreated patients, a generally consistent profile emerged. Preeclampsia was in general a high cardiac output state associated with an inappropriately high peripheral resistance. Although the systemic vascular resistance was within the normal range for pregnancy, it was still inappropriately high for the elevated cardiac output. The failure of the circulation to dilate in the setting of increasing cardiac output appeared to be a characteristic feature of preeclampsia. The normal wedge and central venous pressures found in their study suggested venoconstriction with central relocation of intravascular volume if the generally accepted reports of decreased plasma volume in preeclampsia are correct. They postulated splanchnic venoconstriction as the mechanism of this volume shift. Normal pregnant women are resistant to the vasoconstrictor effects of angiotensin II. Pregnant women require about 21/2 times the amount of angiotensin II required by nonpregnant women to raise the diastolic blood pressure 20 mm Hg. Patients who will develop superimposed preeclampsia lose their refractoriness to angiotensin II many weeks before hypertension develops. These patients may be identified as early as 18–24 weeks' gestation by infusion of angiotensin II. Normal pregnant women lose their refractoriness to angiotensin II after treatment with prostaglandin synthetase inhibitors such as aspirin or indomethacin; this suggests that prostaglandin is involved in mediating vascular reactivity to angiotensin II in pregnancy. Refractoriness to angiotensin II can be restored in patients with preeclampsia by the administration of theophylline, a phosphodiesterase inhibitor that increases intracellular levels of cyclic adenosine monophosphate (cAMP). Therefore, prostaglandins synthesized in the arteriole may modulate vascular reactivity to angiotensin II by altering the intracellular level of cAMP in vascular smooth muscle. Liver The spectrum of liver disease in preeclampsia is broad, ranging from subclinical involvement with the only manifestation being fibrin deposition along the hepatic sinusoids to rupture of the liver. Within these extremes lie the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) and hepatic infarction. Kidneys The characteristic lesion of preeclampsia, glomeruloendotheliosis, is a swelling of the glomerular capillary endothelium that causes decreased glomerular perfusion and glomerular filtration rate. Fibrin split products have been found on the basement membrane by some observers, who have suggested that intravascular coagulation may be secondary to thromboplastin released from the placenta. However, the fibrin split products are found infrequently and only in small amounts. Other investigators have detected IgM, IgG, and complement in the glomeruli of some patients and have suggested an immunologic mechanism. Serial renal biopsies have shown that the lesion is totally reversible over about 6 weeks. Blood Most patients with preeclampsia-eclampsia have normal clotting studies. In some, a spectrum of abnormalities may be found, ranging from isolated thrombocytopenia to microangiopathic hemolytic anemia to disseminated intravascular coagulation (DIC). Thrombocytopenia is the most common abnormality; a count of less than 150,000/ L is found in 15–20% of patients. Fibrinogen levels are actually elevated in preeclamptic women as compared with normotensive patients. Low fibrinogen levels in preeclampsia-eclampsia are usually associated with abruptio placentae or fetal demise. Elevated fibrin split products are seen in 20% of patients (usually in the range of 10–40 L/mL). Microangiopathic hemolytic anemia without other signs of DIC may be seen in about 5% of patients, and evidence of DIC is also present in about 5%. In the past, DIC was thought to be the cause of preeclampsia; now it is regarded as a sequela of the disease. The HELLP syndrome describes patients with hemolytic anemia, elevated liver enzymes, and low platelet count. Criteria for the diagnosis at the authors' institution are schistocytes on the peripheral blood smear, lactic dehydrogenase > 600 U/L, total bilirubin > 1.2 mg/dL, aspartate aminotransferase > 70 U/L, and platelet count < 100,000/mm3. This syndrome is present in about 10% of patients with severe preeclampsia-eclampsia. It is frequently seen in Caucasian patients with delay in diagnosis or delivery and in patients with abruptio placentae. The syndrome may occur remote from term (eg, at 31 weeks) and with no elevation of blood pressure. The syndrome is frequently misdiagnosed as hepatitis, gallbladder disease, idiopathic thrombocytopenic purpura, or thrombotic thrombocytopenic purpura. Most hematologic abnormalities return to normal within 2–3 days after delivery, but thrombocytopenia may persist for a week. Endocrine System The role of the renin-angiotensin-aldosterone system in the regulation of blood pressure during normal and hypertensive pregnancy has not been clearly defined. In normal pregnancy, estrogen's effect on the liver markedly increases production of renin substrate. This increases plasma renin activity, plasma renin concentration, and angiotensin II levels. Plasma aldosterone levels rise even higher than can be accounted for by the prevailing plasma renin activity. Despite the high plasma concentration of aldosterone, there is no blood pressure increase or hypokalemia in normal pregnancy; indeed, blood pressure falls in the midtrimester. This may be due to counterregulatory factors such as the natriuretic effect of progesterone or activation of vasodepressor systems such as kinins or prostaglandins. Interpreting renin, angiotensin, and aldosterone levels in studies of preeclampsia is difficult because of differences in the definition of preeclampsia (parity, degree of proteinuria, early- or late-onset disease), differences in taking of blood samples (values may be affected by bed rest, sodium intake, labor, etc), and differences in assay techniques. In the majority of studies, renin, angiotensin, and aldosterone are all suppressed in preeclampsia, but they are still above nonpregnant levels. The available evidence suggests that the renin-angiotensin system is only secondarily involved in preeclampsia. Atrial natriuretic peptide (ANP) is a volume regulatory hormone synthesized by cardiac myocytes, which has potent natriuretic, diuretic, and vasorelaxant properties. ANP secretion is stimulated by increased atrial pressure and alterations in sodium balance. Elevated concentrations of ANP accompany pathologic states characterized by fluid overload such as cirrhosis, congestive heart failure, and chronic renal failure. However, ANP is elevated in preeclampsia, a disorder supposedly characterized by hypovolemia. It is even elevated in the second trimester before the onset of clinical evidence of preeclampsia. The mechanism for the elevation is unknown. It may be that endothelin or another vasoactive peptide is stimulating release of ANP. It may also be that the widely accepted concept of central hypovolemia in preeclampsia is incorrect. Catecholamines Urinary and blood catecholamine levels are the same in normotensive pregnant women, women with preeclampsia, and nonpregnant controls. However, it cannot be ruled out that sympathetic activity is of pathogenetic importance for initiation or maintenance of hypertension in patients with preeclampsia. Catecholamine levels increase during labor, presumably owing to stress. The vascular refractoriness to catecholamines is lacking in preeclampsia, as is the refractoriness to other endogenous vasopressors such as antidiuretic hormone and angiotensin II. Prostacyclin Prostacyclin is a prostaglandin discovered in 1976. It increases intracellular cAMP in smooth muscle cells and platelets resulting in vasodilator and platelet antiaggregatory effects. Its half-life is about 3 minutes, breaking down in plasma to 6-keto-PGF1 , which is stable and can be measured as an indication of prostacyclin levels. These plasma levels are low, indicating that prostacyclin acts physiologically at the local level rather than as a circulating hormone. Prostacyclin is made primarily in the endothelial cell from arachidonic acid, catalyzed by the enzyme cyclooxygenase. Cyclooxygenase can be inhibited by aspirin-like drugs. Mechanical or chemical perturbation of the endothelial cell membrane stimulates formation and release of prostacyclin. For example, pulsatile pressure or chemicals such as bradykinin or thrombin stimulate prostacyclin generation in the vessel wall. Thromboxane A2 generated by platelets from arachidonic acid via cyclooxygenase induces vasoconstriction and platelet aggregation. Thus, prostacyclin and thromboxane have opposing roles in regulating platelet-vessel wall interaction. Aspirin irreversibly inhibits cyclooxygenase. Cyclooxygenase must be produced continuously by endothelial cells, because they recover their ability to synthesize prostacyclin within a few hours after a dose of aspirin. On the other hand, platelets do not have a nucleus and therefore cannot make fresh cyclooxygenase. Thromboxane synthesis recovers only as new platelets enter the circulation. Platelet life span is about 1 week. Thus, daily treatment with low-dose aspirin results in chronic inhibition of thromboxane metabolites and decreased excretion of prostacyclin metabolites in preeclamptic patients. Low-dose aspirin therapy is aimed at restoring the presumed thromboxane-prostacyclin imbalance in preeclampsia. Nitric Oxide Nitric oxide (NO) is an endogenous vasodilator and inhibitor of platelet aggregation and acts synergistically with prostacyclin. It is produced by endothelial cells from L-arginine. Synthesis can be inhibited by arginine analogs such as NG-monomethyl-L-arginine and NG-nitro-L-arginine. Intravenous injection of one of these inhibitors into rats, rabbits, or guinea pigs causes an immediate rise in blood pressure that is reversed by L-arginine. This indicates that continual basal release of NO from endothelial cells keeps the vasculature in a dilated state. NO acts only in the immediate vicinity of the cell that releases it. Any that escapes into the bloodstream decays chemically to form nitrite or is immediately inactivated by hemoglobin. NO plays an important role in several pathologic processes. It is one of the mediators of hypotension in septic shock. A deficiency of NO contributes to the cause of hypertension and atherosclerosis. Currently it is thought that the NO system may be more important than the prostaglandins in the pathogenesis of preeclampsia. Chronic blockade of the endogenous NO system produces a model of hypertension and renal damage in pregnant and nonpregnant rats. Some studies have shown that there is decreased excretion of NO in the urine of pregnant preeclamptic women, but whether NO plays an important pathophysiologic role in the development of preeclampsia remains unknown. Endothelin-1 In addition to the relaxing factors prostacyclin and NO, the vascular endothelium releases vasoconstrictor substances. The vasoconstrictor endothelin was discovered in 1988. There are 3 different isopeptides: endothelin 1, 2, and 3. Endothelin-1 is the only endothelin manufactured by endothelial cells. Endothelins are also synthesized by kidney cells and nervous tissue. There are widespread endothelin-binding sites including those in the brain, lung, kidney, adrenal, spleen, intestine, and placenta. It is thought that endothelins act as endogenous agonists of dihydropyridine-sensitive calcium channels. The most striking property of endothelin-1 is its long-lasting vasoconstrictor action. It is 10 times more potent than angiotensin II. Endothelin may play a role in constriction of placental vessels after delivery and may regulate closure of the ductus arteriosus in the newborn. The mitogenic effects of endothelin-1 may cause vascular wall hypertrophy in atherosclerosis and hypertension. Endothelin-1 may play a role in renal vasoconstriction in acute renal failure. A 3-fold elevation of plasma endothelin 1 and 2 has been found in women with preeclampsia compared with gestation-matched controls. One hypothesis is that prostacyclin is an antiplatelet and vasodilator mechanism held in reserve to reinforce the NO system when endothelial damage occurs. Lack of NO may be a causative factor in hypertension. Endothelin-1 is released by endothelial cells to constrict the underlying smooth muscle in an emergency such as laceration. Excess endothelin-1 may also be involved in the genesis of hypertension. Placenta In normal pregnancy, the proliferating trophoblast invades the decidua and the adjacent myometrium in 2 forms: interstitial and endovascular. The role of the interstitial form is not clear but it may serve to anchor the placenta. The endovascular trophoblastic cells invade the maternal spiral arteries, where they replace the endothelium and destroy the medial elastic and muscular tissue of the arterial wall. The arterial wall is replaced by fibrinoid material. This process is complete by the end of the first trimester, at which time it extends to the deciduomyometrial junction. There appears to be a resting phase in the process until 14 to 16 weeks' gestation, when a second wave of trophoblastic invasion extends down the lumen of the spiral arteries to their origin from the radial arteries deep in the myometrium. The same process is then repeated, ie, replacement of the endothelium, destruction of the medial musculoelastic tissue, and fibrinoid change in the vessel wall. The end result is that the thin-walled, muscular spiral arteries are converted to saclike, flaccid uteroplacental vessels, which passively dilate to accommodate the greatly augmented blood flow required in pregnancy (Fig 19–2). | | Figure 19–2. The placental bed in normal and preeclamptic pregnancy. In preeclampsia, the physiologic changes in the uteroplacental arteries do not extend beyond the deciduomyometrial junction, leaving a constricting segment between the radial artery and the decidual portions. (Reproduced, with permission, from Brosens IA: Morphological changes in the uteroplacental bed in pregnancy hypertension. Clin Obstet Gynaecol 1977;4:573.) |
Preeclampsia develops following a partial failure in the process of placentation. First, not all the spiral arteries of the placental bed are invaded by trophoblast. Second, in those arteries that are invaded, the first phase of trophoblastic invasion occurs normally, but the second phase does not occur, and the myometrial portions of the spiral arteries retain their reactive musculoelastic walls. In addition, acute atherosis (a lesion similar to atherosclerosis) develops in the myometrial segments of the spiral arteries of patients with preeclampsia. The lesion is characterized by fibrinoid necrosis of the arterial wall, the presence of lipid and lipophages in the damaged wall, and a mononuclear cell infiltrate around the damaged vessel. Acute atherosis may progress to vessel obliteration with corresponding areas of placental infarction. Thus, in preeclampsia there is an area of vascular resistance in the spiral artery because of failure of the second wave of trophoblastic invasion. In addition, acute atherosis further compromises the vascular lumen. Consequently, the fetus is subjected to poor intervillous blood flow from the time of early gestation; this may result in intrauterine growth retardation or stillbirth. Antihypertensive therapy may be detrimental because peripheral vasodilatation may further reduce the already compromised placental blood flow. Clinical Findings Symptoms and Signs Hypertension Hypertension is the most important criterion for the diagnosis of preeclampsia, and it may occur suddenly. Many young primigravidas have blood pressure readings of 100–110/60–70 mm Hg during the second trimester. An increase of 15 mm Hg in the diastolic or 30 mm Hg in the systolic pressure should be considered ominous. Thus, in these patients, blood pressures of 120/80 mm Hg may be relative hypertension. The blood pressure is often quite labile. It usually falls during sleep in patients with mild preeclampsia and chronic hypertension, but in patients with severe preeclampsia, blood pressure may increase during sleep, eg, the most severe hypertension may occur at 2:00 AM. Proteinuria Proteinuria is the last sign to develop. Eclampsia may occur without proteinuria. One set of researchers found no proteinuria in 29% of one series of eclamptic patients. Most patients with proteinuria will have glomeruloendotheliosis on kidney biopsy. Proteinuria in preeclampsia is an indicator of fetal jeopardy. The incidence of small for gestational age (SGA) infants and perinatal mortality is markedly increased in patients with proteinuric preeclampsia. Edema Previously a weight gain of more than 2 lb/wk or a sudden weight gain over 1 to 2 days was considered worrisome. However, edema is a common occurrence in women with normal pregnancy, and preeclampsia may occur in women with no edema. The use of edema as a defining criterion for preeclampsia is controversial, and most recent reports omit it from the definition. Differing Clinical Picture in Preeclamptic Crises Preeclampsia-eclampsia is a multisystem disease with varying clinical presentations. One patient may present with eclamptic seizures, another with liver dysfunction and intrauterine growth retardation, another with pulmonary edema, still another with abruptio placentae and renal failure, and another with ascites and anasarca. Laboratory Findings The hemoglobin and hematocrit may be elevated due to hemoconcentration, or in more severe cases, there may be anemia secondary to hemolysis. Thrombocytopenia is often present. Fibrin split products and decreased coagulation factors may be detected. Uric acid is usually elevated above 6 mg/dL. Serum creatinine is most often normal (0.6–0.8 mg/dL) but may be elevated in severe preeclampsia. Although hepatic abnormalities occur in about 10% of patients, the bilirubin is usually below 5 mg/dL and the aspartate aminotransferase (AST) below 500 IU. Alkaline phosphatase may increase 2- to 3-fold. Lactate dehydrogenase may be quite high (because of hemolysis or liver injury). Blood glucose and electrolytes are normal. Urinalysis reveals proteinuria and occasional hyaline casts. Differential Diagnosis See Table 19–1. Complications Preeclampsia may be associated with early delivery and fetal complications due to prematurity. Fetal risks include acute and chronic uteroplacental insufficiency. In the most severe cases, this may result in intrapartum fetal distress or stillbirth. Chronic uteroplacental insufficiency increases the risk of intrauterine growth retardation and oligohydramnios. Prevention More than 100 clinical, biophysical, and biochemical tests have been reported to predict preeclampsia. Unfortunately, most suffer from poor sensitivity, and none are suitable for routine use as a screening test in clinical practice. As a result, most studies of prevention have used patients with various risk factors for preeclampsia. Calcium Supplementation Several authors have reported reduced urinary excretion of calcium during preeclampsia and for several weeks prior to the onset of clinically apparent disease. In addition, abnormal intracellular calcium metabolism in platelets and red blood cells has been demonstrated in women with preeclampsia as compared with normotensive pregnant women. However, there are no data suggesting that calcium supplementation prevents preeclampsia in women with low-risk pregnancies. The National Institutes of Health studied 4589 healthy nulliparous women by randomly assigning them to receive 2 g elemental calcium or placebo daily at 13 to 21 weeks' gestation. In this study there was no decrease in the incidence or severity of preeclampsia in the group receiving calcium. However, randomized trials on women considered to be at high risk for developing preeclampsia have suggested a reduction in the incidence of the disease among women receiving supplemental calcium. Aspirin There is evidence to suggest that thromboxane A2 production is markedly increased, while prostacyclin production is reduced in women with well-established preeclampsia and prior to the onset of preeclampsia. In addition, placental infarcts and thrombosis of the spiral arteries have been demonstrated in pregnancies complicated by preeclampsia, particularly in those with severe fetal growth retardation or fetal demise. As a result of these findings, several authors have used various antithrombotic agents in an attempt to prevent preeclampsia. Today the prevailing opinion is that aspirin prophylaxis does not benefit most women in the prevention of preeclampsia. Eight large studies have been done worldwide to investigate this treatment. All demonstrated minimal to no reduction in the incidence of preeclampsia. So the place of aspirin in preeclampsia prevention is uncertain. It may be that the benefits are confined to high-risk women. A further matter of concern is the higher incidence of abruptio placentae found in the aspirin-treated patients in one study. There is currently no proven way to prevent preeclampsia, but good prenatal care and regular visits to the physician will allow for early diagnosis before the condition becomes severe. Pregnant women at high risk for preeclampsia (those with a history of hypertension before conception or in a previous pregnancy, especially before 34 weeks, or multiparity; women with diabetes, collagen vascular disease, or renal disease; and women with multifetal pregnancy) should undergo baseline testing early in the pregnancy. Such tests make it easier later in the pregnancy to determine if preeclampsia is developing. These include hematocrit and hemoglobin, platelet count, serum creatine and uric acid, and 24-hour urine collection for protein and creatinine clearance if 1+ protein is present on dipstick. Women with a preexisting history of hypertension are at increased risk of intrauterine growth retardation and should have early ultrasounds if dating is in question, followed by follow-up scans to monitor growth. The physician must have full knowledge of the patient profile and must maintain a high index of suspicion throughout the pregnancy. Eclampsia cannot always be prevented. Patients may deteriorate suddenly and without warning. Treatment Mild Preeclampsia Treatment of Mother The treatment of preeclampsia is bed rest and delivery. The patient is usually hospitalized upon diagnosis, since this diminishes the possibility of convulsions and enhances the chance of fetal survival. Hospitalization to prevent premature delivery in preeclampsia is far less expensive than the cost of caring for a premature infant. Women with mild preeclampsia who can be relied on to follow the physician's instructions may be treated as outpatients. A typical home regimen consists of bed rest, daily urine dipstick measurements of proteinuria, and blood pressure monitoring. Patients are seen at least twice weekly for antepartum fetal heart rate testing and periodic 24-hour urine protein measurements. Patients must be warned of danger signals such as severe headache, epigastric pain, or visual disturbances. The occurrence of these signals, increasing blood pressure, or proteinuria mandates communication with the physician and probable hospitalization. Hospitalized patients are allowed to be up and around as they feel comfortable. The blood pressure is measured every 4 hours, and patients are weighed daily. Urine dipstick testing for protein is performed daily. Twenty-four-hour urine studies for creatinine clearance and total protein are obtained twice weekly. Liver function, uric acid, electrolytes, and serum albumin are determined on admission and weekly. Coagulation studies such as prothrombin clotting time, partial thromboplastin time, fibrinogen, and platelet count should be done in patients with severe preeclampsia. Assessments of gestational age and estimated fetal weight are performed by ultrasonic examination on admission and thereafter as indicated (usually every 2 weeks). Antihypertensive medications are usually withheld unless the diastolic blood pressure exceeds 100 mm Hg and the gestational age is 30 weeks or less. (Long-term antihypertensive therapy is discussed later under Chronic Hypertension.) Sedatives were used in the past but have become disfavored because they interfere with fetal heart rate testing and because one of them—phenobarbital—impaired vitamin K–dependent clotting factors in the fetus. The usual indications for delivery of patients with preeclampsia are summarized in Table 19–2. Assessment of Fetal Status Fetal status is evaluated by twice-weekly nonstress tests and ultrasound assessment of amniotic fluid volume. Nonreactive nonstress tests require further evaluation with either a biophysical profile or an oxytocin challenge test. Amniocentesis to determine the lecithin:sphingomyelin (L:S) ratio is not frequently used in preeclampsia, since early delivery is usually for maternal indications, but it may be useful as the fetus approaches maturity. Corticosteroids should be used to accelerate fetal lung maturity in patients with preeclampsia when there is an immature L:S ratio if it is thought that delivery may occur in the next 2–7 days. With rapidly worsening preeclampsia, fetal monitoring should be continuous because of the risk of abruptio placentae and uteroplacental insufficiency. Severe Preeclampsia The goals of management of severe preeclampsia are (1) prevention of convulsions, (2) control of maternal blood pressure, and (3) initiation of delivery. Delivery is the definitive mode of therapy if severe preeclampsia develops at or beyond 36 weeks' gestation or if there is evidence of fetal lung maturity or fetal jeopardy. If delivery of a preterm infant (< 36 weeks' gestation) is anticipated, maternal transfer to a tertiary care center is advised to ensure proper neonatal intensive care. Management of patients with severe preeclampsia occurring earlier in pregnancy is controversial. Some institutions use antihypertensive drugs to control maternal blood pressure until fetal lung maturity is reached. Corticosteroids should be used to accelerate lung maturity. All women at 40 weeks with mild preeclampsia should be delivered. At 38 weeks, women with mild preeclampsia and a favorable cervix should be induced. Anyone at 32–34 weeks with severe preeclampsia should be considered for delivery, and the fetus may benefit from corticosteroids. In patients 23–32 weeks with severe preeclampsia, delivery may be delayed in an effort to reduce perinatal morbidity and mortality. This should be done only at a tertiary care center. The mother should be placed on magnesium sulfate for a minimum of the first 24 hours while the diagnosis is made. Blood pressure should be controlled with the medications to be discussed. The patient should be given corticosteroids to promote fetal lung maturity. The mother may be closely observed with frequent laboratory evaluations. Indications for delivery include development of symptoms, laboratory evidence of organ damage, and fetal deterioration (Table 19–2). If the gestational age is less than 23 weeks, the patient should be offered induction of labor to terminate the pregnancy. Vaginal delivery is preferable to cesarean section and labor induction should be aggressive. A clear endpoint for delivery should be determined, usually within 24 hours. If delivery is not achieved within the set time frame, cesarean is warranted. Prognosis See below, under Eclampsia. | 
