Preeclampsia complicates 5–7% of all pregnancies. Preeclampsia occurs with increased frequency among young, nulliparous women. However, the frequency distribution is bimodal, with a second peak occurring in multiparous women greater than 35 years of age. Among daughters of preeclamptic women, the risk of preeclampsia is significantly higher than the population risk. Other predisposing factors for preeclampsia are listed in Table 26–3.
Table 26–3. Risk Factors for Preeclampsia. ||Download (.pdf)
Table 26–3. Risk Factors for Preeclampsia.
|Age <20 years or >35 years|
|Collagen vascular disease|
|Family history of preeclampsia|
Normal pregnancy is associated with decreased maternal sensitivity to endogenous vasopressors. Apparent early in gestation, this effect leads to expansion of the maternal intravascular space and a decline in blood pressure throughout the first half of pregnancy, with a nadir at midgestation. Thereafter, continued expansion of intravascular volume leads to a gradual rise in the blood pressure to prepregnancy levels by term. Women destined to develop preeclampsia do not exhibit normal refractoriness to endogenous vasopressors. As a result, normal expansion of the intravascular space does not occur, and the normal decline in blood pressure during the first half of pregnancy may be absent or attenuated. Despite normal to elevated blood pressure, intravascular volume is reduced.
The etiology of preeclampsia is not known; however, a growing body of evidence suggests that maternal vascular endothelial injury plays a central role in the disorder. Some reports suggest that endothelial damage in preeclampsia results in decreased endothelial production of prostaglandin I2 (prostacyclin), a potent vasodilator and inhibitor of platelet aggregation. Endothelial cell injury exposes subendothelial collagen and can trigger platelet aggregation, activation, and release of platelet-derived thromboxane A2 (TXA2), a potent vasoconstrictor and stimulator of platelet aggregation. Decreased prostacyclin production by dysfunctional endothelial cells and increased TXA2 release by activated platelets and trophoblast may be responsible for reversal of the normal ratio of prostacyclin and TXA2 observed in preeclampsia. The predominance of TXA2 may contribute to the vasoconstriction and hypertension that are central features of the disorder. Elevated intravascular pressure combined with damaged vascular endothelium results in movement of fluid from the intravascular to the extravascular spaces, leading to edema in the brain, retinae, lungs, liver, and subcutaneous tissues. Hypertension and glomerular endothelial damage lead to proteinuria. The resultant decrease in intravascular colloid oncotic pressure contributes to further loss of intravascular fluid. Hemoconcentration is reflected in a rising hematocrit. Consumption of platelets and activation of the clotting cascade at the sites of endothelial damage may lead to thrombocytopenia and disseminated intravascular coagulation (DIC). Soluble fibrin monomers produced by the coagulation cascade may precipitate in the microvasculature, leading to microangiopathic hemolysis and elevation of the serum lactate dehydrogenase level. Cerebral edema, vasoconstriction, and capillary endothelial damage may lead to hyperreflexia, clonus, convulsions, or hemorrhage. Hepatic edema and/or ischemia may lead to hepatocellular injury and elevation of serum transaminases and lactate dehydrogenase levels. The right upper quadrant or epigastric pain observed in severe preeclampsia is thought to be caused by stretching of Glisson's capsule by hepatic edema or hemorrhage. Intravascular fluid loss across damaged capillary endothelium in the lungs may result in pulmonary edema. In the retinae, vasoconstriction and/or edema may lead to visual disturbances, retinal detachment, or blindness. Movement of fluid from the intravascular space into the subcutaneous tissues produces the characteristic nondependent edema of preeclampsia.
Endothelial damage appears to be capable of triggering a cascade of events culminating in the multiorgan system dysfunction observed in preeclampsia. However, the mechanism of endothelial injury remains speculative. In one theory, decreased placental oxygenation triggers the placenta to release an unknown factor into the maternal circulation. This circulating factor is capable of damaging or altering the function of maternal endothelial cells and triggering the cascade of events described. In support of this theory, cultured trophoblasts exposed to a hypoxic environment release a variety of potentially vasoactive factors, including thromboxane, interleukin-1, and tumor necrosis factor. Moreover, serum from preeclamptic women, when applied to human endothelial cell cultures, alters the release of a variety of procoagulant, vasoactive, and mitogenic factors, including endothelin, nitric oxide, and prostacyclin. Serum from the same woman 6 weeks after delivery does not produce this effect. Likewise, serum from a nonpreeclamptic woman at the same gestational age fails to trigger these endothelial changes. In many cases, reduced placental oxygenation may be explained by maternal vasculopathy (chronic hypertension, renal disease, collagen vascular disease) and in others by abnormal placental mass (multiple gestation, diabetes, hydatidiform mole). In another subset of patients, reduced placental oxygenation late in pregnancy may be the result of abnormal endovascular trophoblast invasion early in pregnancy. In the first trimester of a normal pregnancy, proliferating trophoblast invades the decidual segments of the maternal spiral arteries, replacing endothelium and destroying the medial elastic and muscular tissue of the arterial wall. The arterial wall is replaced by fibrinoid material. During the second trimester, a second wave of endovascular trophoblastic invasion extends down the lumen of the spiral arteries deeper in the myometrium. The endothelium and musculoelastic architecture of the spiral arteries are destroyed, resulting in dilated, thin-walled, funnel-shaped vessels that are passive conduits of the increased uteroplacental blood flow of pregnancy. In some women destined to develop preeclampsia, the first wave of endovascular trophoblastic invasion may be incomplete, and the second wave does not occur. As a result, the deeper segments of the spiral arteries are not remodeled but instead retain their musculoelastic architecture and their ability to respond to endogenous vasoconstrictors, reducing maternal perfusion of the placenta and predisposing to relative placental hypoxia later in pregnancy. In addition, myometrial portions of the spiral arteries exhibit a unique abnormality characterized by vessel wall damage, fibrinoid necrosis, lipid deposition, and macrophage and mononuclear cell infiltration of vessel walls and surrounding tissues. These changes, histologically similar to those observed in atherosclerosis, are referred to as acute atherosis and may lead to vascular lumen obliteration and placental infarction. Importantly, these changes are attributed to abnormal endovascular trophoblastic invasion during the second trimester of pregnancy, predisposing the fetus to suboptimal placental perfusion early in gestation. Interestingly, the clinical manifestations are observed most often in the third trimester, possibly due to increasing fetal and placental oxygen demands with advancing gestation.
The reason that endovascular trophoblastic invasion progresses normally in most pregnancies but abnormally in others is unclear. One theory maintains that maternal antibodies directed against paternal antigens on invading trophoblasts are necessary to shield those antigens from recognition by decidual natural killer cells, protecting the invading trophoblast from attack and rejection by the cellular arm of the maternal immune system. Supporting this theory is the observation that preeclampsia appears to be associated with primi-paternity and the presumed lack of previous maternal exposure and sensitization to paternal trophoblast antigens in a previous pregnancy. Additional support for this theory is provided by the observation that preeclampsia is more common among women using barrier contraception than among those using nonbarrier forms of contraception before pregnancy. This suggests that maternal exposure (and presumably sensitization) to paternal antigens on sperm is protective against preeclampsia. The observed inverse relationship between duration of cohabitation before pregnancy and the incidence of preeclampsia provides further evidence that maternal sensitization to paternal antigens is protective against preeclampsia. The interplay between immunology and genetics is underscored by the observation that preeclampsia may be more common in pregnancies in which the father was the product of a preeclamptic pregnancy. Applied to the theory under discussion, this suggests that some genetically determined paternal antigens are less antigenic than others and therefore less likely to provoke an antibody response in an exposed mother, decreasing maternal production of “blocking” antibodies and increasing the likelihood of abnormal placental invasion and preeclampsia. Alternatively, paternally inherited genes may code for altered fetal production of insulin-like growth factor-2, an insulin homologue related to placental invasion. Other genes that may be inherited from the father and play a role in the development of preeclampsia include genes coding for angiotensinogen, methylenetetrahydrofolate reductase, and the factor V Leiden mutation.
Some studies have demonstrated that invading trophoblastic cells in normal pregnancy undergo an “antigenic shift” to resemble vascular endothelial antigens, masking them from recognition and rejection by decidual natural killer cells. Invading trophoblasts in preeclamptic pregnancies may fail to make this antigenic shift, exposing them to recognition by natural killer cells and halting normal invasion.
Recent work has demonstrated that soluble fms-like tyrosine kinase-1 (sFlt-1) is increased in the placenta and serum of women with preeclampsia. This protein adheres to placental growth factor and vascular endothelial growth factor (VEGF), preventing their interaction with endothelial receptors and causing endothelial dysfunction. Interrupted angiogenesis may contribute to faulty placental invasion early in pregnancy and subsequent risk for placental hypoxia–ischemia and preeclampsia. Unbound placental growth factor and VEGF have been found in decreased concentration during and even before the development of clinical preeclampsia.
Genetic, immunologic, and other factors govern the complex interaction between the maternal host and the invading trophoblast. Detailed discussion of these and other possible etiologies of the entity of preeclampsia are beyond the scope of this chapter. Regardless of the etiology, thorough familiarity with the clinical aspects of the disorder can help guide thoughtful and coherent management.
Preeclampsia exerts an effect on many different maternal organ systems:
Pathologic findings in preeclampsia-induced cerebral injury include fibrinoid necrosis, thrombosis, microinfarcts, and petechial hemorrhages, primarily in the cerebral cortex. Cerebral edema may be observed. Head computed tomographic findings include focal white matter hypodensities in the posterior cerebral hemispheres, temporal lobes, and brain stem, possibly reflecting petechial hemorrhage with resultant local edema. Magnetic resonance imaging may reveal occipital and parietal abnormalities in the watershed distribution of the major cerebral arteries, as well as lesions in the brain stem and basal ganglia. Subarachnoid or intraventricular hemorrhage may occur in severe cases.
Preeclampsia is characterized by the absence of normal intravascular volume expansion, a reduction in normal circulating blood volume, and a loss of normal refractoriness to endogenous vasopressors, including angiotensin II. Invasive hemodynamic monitoring in preeclamptic patients has yielded conflicting information. Depending on disease severity, effects of previous therapy, and other factors, preeclampsia has been described variously as a state of abnormally high cardiac output and low systemic vascular resistance, a state of abnormally low cardiac output and high systemic vascular resistance, or a state of high cardiac output and high systemic vascular resistance. These divergent observations underscore the complexity of the disorder.
Alterations in colloid oncotic pressure, capillary endothelial integrity, and intravascular hydrostatic pressure in preeclampsia predispose to noncardiogenic pulmonary edema. In women with preeclampsia superimposed on chronic hypertension, preexisting hypertensive cardiac disease may exacerbate the situation, superimposing cardiogenic pulmonary edema on noncardiogenic, preeclampsia-related pulmonary edema. Excessive administration of intravenous (IV) fluid and postpartum mobilization of accumulated extravascular fluid also increase the risk of pulmonary edema. In eclampsia, pulmonary injury may result from aspiration of gastric contents, leading to pneumonia, pneumonitis, or adult respiratory distress syndrome.
Histologic lesions in the liver are characterized by sinusoidal fibrin deposition in the periportal areas with surrounding hemorrhage and portal capillary thrombi. Centrilobular necrosis may result from reduced perfusion. Inflammation is not characteristic. Subcapsular hematomas may develop. In severe cases involving hepatocellular necrosis and DIC, intrahepatic hematomas may progress to liver rupture. Right upper quadrant pain or epigastric pain are classic symptoms attributed to stretching of Glisson's capsule. Elevation of serum transaminases is a hallmark of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome.
Distinct histologic changes have been described in the kidneys of women with preeclampsia. The classic renal lesion of preeclampsia, glomeruloendotheliosis, is characterized by swelling and enlargement of glomerular capillary endothelial cells, leading to narrowing of the capillary lumen. There is an increased amount of cytoplasm containing lipid-filled vacuoles. Mesangial cells may be swollen as well. Immunoglobulins, complement, fibrin, and fibrin degradation products have been observed in the glomeruli, but their presence is variable.
Retinal vasospasm, retinal edema, serous retinal detachment, and cortical blindness may occur in the setting of preeclampsia. Blindness is uncommon and usually transient, resolving within hours to days of delivery.
The observed alteration in the ratio of vasoconstrictive and vasodilatory prostaglandins in preeclampsia led investigators to study the effectiveness of prostaglandin synthesis inhibitors in preventing the disorder. Several small trials of low-dose aspirin reported significant reductions in the incidence of preeclampsia in high-risk populations. However, in 1994 the Collaborative Low-Dose Aspirin Study in Pregnancy (CLASP) Collaborative Group reported a large randomized trial comparing low-dose aspirin with placebo in more than 9300 high-risk patients. Low-dose aspirin did not reduce the incidence of preeclampsia in this high-risk population. Because the risks of the regimen are few, some physicians may reasonably choose to use it.
Calcium is essential in the synthesis of nitric oxide, a potent vasodilator believed to contribute to the maintenance of reduced vascular tone in pregnancy. Calcium supplementation during pregnancy has been proposed as a means to prevent preeclampsia. Although individual studies have demonstrated mixed results regarding the efficacy of calcium supplementation, a meta-analysis concluded that calcium supplementation of at least 1 gram daily during pregnancy appears to reduce the risk of preeclampsia by approximately 50%.
A diagnosis of preeclampsia is made based on 2 criteria: (1) elevated maternal blood pressure of ≥140 mm Hg systolic or ≥90 mm Hg diastolic on 2 occasions 6 hours apart, and (2) proteinuria ≥300 mg in a 24-hour urine specimen. In the past, the classic diagnostic triad included hypertension, proteinuria, and edema. Recently, the National High Blood Pressure Education Working Group recommended eliminating edema as a diagnostic criterion because it is too frequent an observation during normal pregnancy to be useful in diagnosing preeclampsia. In addition to the classic findings of hypertension and proteinuria, women with preeclampsia may complain of scotomata, blurred vision, or pain in the epigastrium or right upper quadrant. Examination often reveals brisk patellar reflexes and clonus. Laboratory abnormalities include elevated levels of hematocrit, lactate dehydrogenase, serum transaminases and uric acid, and thrombocytopenia. Although biochemical evidence of DIC may be detected with increased fibrin degradation products, hypofibrinogenemia and prolongation of the prothrombin time and activated partial thromboplastin time usually are seen only in cases complicated by abruption or multiple organ failure.
Preeclampsia is classified into mild or severe based on the degree of hypertension and proteinuria and the presence of other findings (Table 26–4). The HELLP syndrome is a variant of preeclampsia that is characterized by hemolysis, elevated liver enzymes, and low platelets. It complicates 10% of cases of severe preeclampsia and up to 50% of cases of eclampsia. Right upper quadrant pain, nausea, vomiting, and malaise are common. Hypertension and proteinuria are variable. The hallmark of the disorder is microangiopathic hemolysis leading to elevation of serum lactate dehydrogenase level and fragmented red blood cells on peripheral smear. Transaminase levels are elevated, thrombocytopenia is present, and DIC may be evident. Management is similar to that of severe preeclampsia. (See Chapter 29, Gastrointestinal Disorders in Pregnancy, for a more extensive review of HELLP syndrome.)
Table 26–4. Classification of Preeclampsia. ||Download (.pdf)
Table 26–4. Classification of Preeclampsia.
|Mild Preeclampsia||Severe Preeclampsia|
|Blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic but <160/110 mm Hg||Blood pressure ≥160 mm Hg systolic or ≥110 mm Hg diastolic on 2 occasions at least 6 hours apart while the patient is on bed rest|
|Proteinuria ≥300 mg/24 h but <5 g/24 h||Proteinuria of 5 g or higher in 24-hour urine specimen or 3+ or greater on 2 random urine samples collected at least 4 hours apart|
|Asymptomatic||Oliguria <500 mL in 24 hours|
|Cerebral or visual disturbances|
|Pulmonary edema or cyanosis|
|Epigastric or right upper quadrant pain|
|Impaired liver function|
|Fetal growth restriction|
Complications related to preeclampsia include preterm birth, intrauterine fetal growth restriction, placental abruption, maternal pulmonary edema, and eclampsia. The estimated incidence of eclampsia is 1–3 per 1000 preeclamptic patients. Eclampsia is defined as one or more generalized convulsions in the setting of preeclampsia.
In the management of preeclampsia, with few exceptions, maternal interests are best served by immediate delivery. However, this approach may not be in the best interest of the fetus. In the case of extreme prematurity, for example, the fetus may benefit from a period of expectant management during which corticosteroids are administered to accelerate fetal maturation. The decision to proceed with immediate delivery versus expectant management is based on several factors, including disease severity, fetal maturity, maternal and fetal condition, and cervical status.
Women with mild preeclampsia are hospitalized for further evaluation and, if indicated, delivery. If mild preeclampsia is confirmed and the gestational age is 40 weeks or greater, delivery is indicated. At gestational ages of 37–40 weeks, cervical status is assessed and, if favorable, induction is initiated. If the cervical status is unfavorable, preinduction cervical ripening agents are used as needed. Occasionally, women with very unfavorable cervical examinations between 37 and 40 weeks may be managed expectantly for a limited time with bed rest, antepartum fetal surveillance, and close monitoring of maternal condition, including blood pressure measurement every 4–6 hours and daily assessment of patellar reflexes, weight gain, proteinuria, and symptoms. A complete blood count and levels of serum transaminases, lactate dehydrogenase, and uric acid should be checked weekly to twice weekly. Delivery is indicated if the cervical status becomes favorable, antepartum testing is abnormal, the gestational age reaches 40 weeks, or evidence of worsening preeclampsia is seen. If expectant management is undertaken after 37 weeks, the patient should understand that the only known benefit is a possible reduction in the rate of caesarean birth.
Women with mild preeclampsia before 37 weeks' gestation are managed expectantly with bed rest, twice-weekly antepartum testing, and maternal evaluation as described. Corticosteroids are administered if the gestational age is <34 weeks; amniocentesis is performed as needed to assess fetal pulmonary maturity. When extended expectant management is undertaken, fetal growth is assessed with ultrasound every 3–4 weeks. Occasionally, outpatient management is reasonable in carefully selected, reliable, asymptomatic patients with minimal proteinuria and normal laboratory test results. This approach includes bed rest at home, daily fetal movement counts, twice-weekly antepartum testing, serial evaluation of fetal growth, and frequent assessment, often by a visiting nurse, of blood pressure, proteinuria, weight gain, patellar reflexes, and symptoms. Any evidence of disease progression constitutes an indication for hospitalization and consideration of delivery. The benefit of prophylactic intrapartum magnesium sulfate in preventing convulsions in patients with mild preeclampsia has not been demonstrated conclusively in the literature.
Severe preeclampsia mandates hospitalization. Delivery is indicated if the gestational age is 34 weeks or greater, fetal pulmonary maturity is confirmed, or evidence of deteriorating maternal or fetal status is seen. Acute blood pressure control may be achieved with hydralazine, labetalol, or nifedipine. The goal of antihypertensive therapy is to achieve a systolic blood pressure <160 mm Hg and a diastolic blood pressure <105 mm Hg. Overly aggressive control of the blood pressure may compromise maternal perfusion of the intervillous space and adversely affect fetal oxygenation. Hydralazine is a peripheral vasodilator that can be given in doses of 5–10 mg administered intravenously (IV). The onset of action is 10–20 minutes, and the dose can be repeated in 20–30 minutes if necessary. Labetalol can be administered in doses of 5–20 mg by slow IV push. The dose can be repeated in 10–20 minutes. Nifedipine is a calcium channel blocker that can be used in doses of 5–10 mg orally. The sublingual route of administration should not be used. The dose can be repeated in 20–30 minutes, as needed.
Management of severe preeclampsia before 34 weeks is controversial. In some institutions, delivery is accomplished regardless of fetal maturity. In others, delivery is delayed for a limited period of time to permit the administration of corticosteroids. Four large randomized controlled trials comparing magnesium sulfate with other methods of treatment to prevent convulsions in women with severe preeclampsia have demonstrated that magnesium sulfate is associated with a significantly lower rate of eclampsia than either no treatment or nimodipine. Lucas and colleagues reported no seizures among 1049 preeclamptic women receiving magnesium sulfate prophylaxis. Nonetheless, tonic–clonic convulsions may occur despite magnesium sulfate therapy. Magnesium sulfate is initiated, fetal status is monitored continuously, and antihypertensive agents are used as needed to maintain a systolic blood pressure <160 mm Hg and a diastolic blood pressure <105 mm Hg. Between 33 and 35 weeks, consideration should be given to amniocentesis for pulmonary maturity studies. If mature, immediate delivery is indicated. If immature, corticosteroids are administered and, if possible, delivery is delayed 24–48 hours. Between 24 and 32 weeks, antihypertensive therapy is instituted as indicated, corticosteroids are administered, and extensive maternal counseling is undertaken to clarify the risks and benefits of pregnancy prolongation. Neonatology consultation is helpful to delineate the neonatal risks specific to gestational age and estimated fetal weight. The duration of expectant management is determined on an individual basis, taking into account maternal wishes, estimated fetal weight, gestational age, and maternal and fetal status. Expectant management is contraindicated in the presence of fetal compromise, uncontrollable hypertension, eclampsia, DIC, HELLP syndrome, cerebral edema, pulmonary edema, or evidence of cerebral or hepatic hemorrhage. When severe preeclampsia is diagnosed before 24 weeks of gestation, the likelihood of a favorable outcome is low. Thorough counseling should address realistically the risks and anticipated benefits of expectant management and should include the option of pregnancy termination. If an appropriately informed patient declines the option of pregnancy termination, expectant management should proceed as outlined previously.
Intrapartum Management of Preeclampsia
In women with preeclampsia without contraindications to labor, vaginal delivery is the preferred approach. Cervical ripening agents and oxytocin are used as needed. If magnesium sulfate is used for seizure prophylaxis, it is administered as an IV loading dose of 4–6 g over 20–60 minutes, followed by a maintenance dose of 1–2 g/h. Urine output and serum creatinine level are monitored, and the magnesium dose is adjusted accordingly to prevent hypermagnesemia. Patellar reflexes and respiratory rate should be assessed frequently. In the presence of patellar reflexes, serum magnesium levels usually are unnecessary. Therapeutic magnesium levels range from 4–8 mg/dL. Loss of patellar reflexes is observed at magnesium levels of 10 mg/dL or higher, respiratory paralysis may occur at levels of 15 mg/dL or above, and cardiac arrest is possible with levels in excess of 25 mg/dL. Calcium gluconate (10 mL of 10% solution) should be available in the event of hypermagnesemia. To avoid pulmonary edema, total IV fluids should not exceed 100 mL/h. Pain control is achieved with regional anesthesia or with intramuscular or IV narcotic analgesics. Invasive hemodynamic monitoring is reserved for refractory pulmonary edema, adult respiratory distress syndrome, or oliguria unresponsive to fluid challenge. If caesarean section is required, platelets should be available for possible transfusion for patients with platelet counts <50,000/mm3. Use of other blood products is guided by clinical and laboratory findings.
In most cases eclamptic seizures are self-limited, lasting 1–2 minutes. The first priorities are to ensure that the airway is clear and to prevent injury and aspiration of gastric contents. Diazepam or lorazepam should be used only if seizures are sustained. Nearly all tonic–clonic seizures are accompanied by a prolonged fetal heart rate deceleration that resolves after the seizure has ended. Once the patient has been stabilized, delivery is indicated. If possible, a 10- to 20-minute period of in utero resuscitation should be permitted before delivery. Convulsions alone do not constitute an indication for caesarean section. However, if vaginal birth is not possible within a reasonable period of time, caesarean delivery is performed in most cases. A number of studies suggest that magnesium sulfate is superior to phenytoin, diazepam, and a lytic cocktail at preventing recurrent seizures in women with eclampsia.
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