Hypertensive Disorders of Pregnancy
Mounira Habli
Baha M. Sibai
Hypertensive disorders are the most common medical complications of pregnancy, affecting 5% to 10% of all pregnancies. These disorders are responsible for approximately 16% of maternal mortality in developed countries. Classification of hypertensive disorders in pregnancy include chronic hypertension and the group of hypertensive disorders unique to pregnancy including gestational hypertension and preeclampsia. Approximately 30% of hypertensive disorders in pregnancy are due to chronic hypertension, and 70% are due to gestational hypertension. The spectrum of disease ranges from mildly elevated blood pressures with minimal clinical significance to severe hypertension and multiorgan dysfunction. The incidence of disease is dependent on many different demographic parameters, including maternal age, race, and associated underlying medical conditions. Understanding the disease process and the impact of hypertensive disorders on pregnancy is of the utmost importance because these disorders remain a major cause of maternal and perinatal morbidity and mortality worldwide.
Definitions and Classifications
Making an appropriate diagnosis can at times be difficult in the gravid patient; however, adhering to the following definitions and classification schemes will help to eliminate confusion. Hypertension is defined as a systolic blood pressure (SBP) of 140 mm Hg or greater or a diastolic blood pressure (DBP) of 90 mm Hg or greater. These measurements must be present on at least two occasions at least 6 hours apart but no more than 1 week apart. In order to reduce inaccurate readings, an appropriate size of cuff should be used (length 1.5 times upper arm circumference or a cuff with a bladder that encircles 80% or more of the arm). Pressure should be taken with the patient in an upright position, after a 10-minute or longer rest period. For patients in the hospital, the blood pressure can be taken with either the patient sitting up or in the left lateral recumbent position with the patient’s arm at the level of the heart. The patient should not use tobacco or caffeine for 30 minutes preceding the measurement. Abnormal proteinuria in pregnancy is defined as the excretion of 300 mg or more of protein in 24 hours. The most accurate measurement of proteinuria is obtained with a 24-hour urine collection. However, in certain instances, semiquantitative dipstick measurement may be the only mode available to assess urinary protein. A value of 1+ or greater correlates with 30 mg/dL. Proteinuria by dipstick is defined as 1+ or more on at least two occasions at least 6 hours apart but no more than 1 week apart. The accuracy of semiquantitative dipstick measurements on spot urine samples as compared with 24-hour urine collections is highly variable. Therefore, should time allow, a 12-hour or 24-hour urine collection should be performed as part of the diagnostic criteria to define proteinuria. When obtaining urine protein measurements, care should be taken to use a clean sample, because blood, vaginal secretions, and bacteria can increase the amount of protein in urine.
Edema is a common finding in the gravid patient, occurring in approximately 50% of women. Lower extremity edema is the most typical form. Pathologic edema is seen in nondependent regions such as the face, hands, or lungs. Excessive, rapid weight gain of 5 pounds or more per week is another sign of fluid retention.
The classification system of hypertension in pregnancy was proposed originally by the American College of Obstetricians and Gynecologists Committee on Terminology in 1972. Further modifications by the National High Blood
Pressure Education Program Working Group in 2000 arrived at the classification scheme used today, which offers simple, concise, and clinically relevant features for each of the four categories. This system recognizes four major categories of hypertension in pregnancy—gestational hypertension, preeclampsia or eclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension. Table 16.1 lists these categories and the features of each.
Pressure Education Program Working Group in 2000 arrived at the classification scheme used today, which offers simple, concise, and clinically relevant features for each of the four categories. This system recognizes four major categories of hypertension in pregnancy—gestational hypertension, preeclampsia or eclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension. Table 16.1 lists these categories and the features of each.
TABLE 16.1 Classification of Hypertension in Pregnancy with Definitions | ||||||||||||||
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Gestational Hypertension
Gestational hypertension is the most frequent cause of hypertension during pregnancy. The rate ranges between 6% and 17% in healthy nulliparous women and between 2% and 4% in multiparous women. It is considered severe if there is sustained SBP to at least 160 mm Hg and/or DBP to at least 110 mm Hg for at least 6 hours without proteinuria. Treatment generally is not warranted, because most patients have mild hypertension. However, approximately 46% of women diagnosed with preterm gestational hypertension will develop proteinuria and progress to preeclampsia. In general, the majority of cases of mild gestational hypertension are diagnosed at or beyond 37 weeks and have a pregnancy outcome similar to term normotensive pregnancies. However, a higher rate of induction and cesarean rate is seen in pregnancies complicated with gestational hypertension.
Preeclampsia and Eclampsia
The rate of preeclampsia ranges between 2% and 7% in healthy nulliparous women. The rate is substantially higher in women with twin gestation (14%) and in those with previous preeclampsia (18%). The symptoms of preeclampsia are headaches, visual changes, and epigastric or right upper quadrant pain plus nausea or vomiting. In the absence of proteinuria, preeclampsia should be considered when gestational hypertension is associated with persistent cerebral symptoms, epigastric or right upper quadrant pain with nausea or vomiting, fetal growth restriction, or thrombocytopenia and abnormal liver enzymes.
Preeclampsia may be subdivided further into mild and severe forms. The distinction between the two is made on the basis of the degree of hypertension and proteinuria as well as the involvement of other organ systems. The criteria for mild preeclampsia and severe preeclampsia are presented in Tables 16.2 and 16.3, respectively. Close surveillance of patients with either mild preeclampsia or gestational hypertension is warranted, because they may progress to fulminant disease. A particularly severe form of preeclampsia is the HELLP syndrome, which is an acronym for hemolysis, elevated liver enzymes, and low platelet count. This syndrome is manifest by laboratory findings consistent with hemolysis, elevated levels of liver function, and thrombocytopenia. The diagnosis may be deceptive, because hypertension and proteinuria might be absent in 10% to 15% of women who develop HELLP and in 20% to 25% of those who develop eclampsia. A patient
diagnosed with HELLP syndrome is automatically classified as having severe preeclampsia. Another severe form of preeclampsia is eclampsia, which is the occurrence of seizures not attributable to other causes.
diagnosed with HELLP syndrome is automatically classified as having severe preeclampsia. Another severe form of preeclampsia is eclampsia, which is the occurrence of seizures not attributable to other causes.
TABLE 16.2 Criteria for the Diagnosis of Mild Preeclampsia | ||
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TABLE 16.3 Criteria for the Diagnosis of Severe Preeclampsia | ||
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Chronic Hypertension
Hypertension that complicates pregnancy is considered chronic if a patient is diagnosed with hypertension before pregnancy, if hypertension is present prior to 20 weeks gestation, or if it persists longer than 12 weeks after delivery.
Chronic Hypertension with Superimposed Preeclampsia
Women with chronic hypertension are at risk of developing superimposed preeclampsia, with the reported rate of superimposed preeclampsia ranging from 10% to 25%. Superimposed preeclampsia is defined as an exacerbation of hypertension with new onset of proteinuria or symptoms of headache or epigastric pain or laboratory abnormalities such as elevated liver enzymes. Exacerbation of hypertension is confirmed if there is an increase in blood pressure to the severe range (SBP of 160 mm Hg or more; DBP of 110 mm Hg or more) in a woman whose hypertension has been well controlled.
Preeclampsia
Preeclampsia is a multisystem disorder of unknown cause that is unique to human pregnancy. The incidence is reported to be between 2% and 7%, depending on the population. Preeclampsia occurs more frequently in primigravidas. The reported rate ranges from 6% to 7% in primigravidas and from 3% to 4% in multiparous patients. Several risk factors for preeclampsia have been identified and are listed in Table 16.4. Generally, preeclampsia is regarded as a disease of first pregnancy. Advanced maternal age (>35 years) is another risk factor, especially if conception was secondary to assisted reproductive technology. Obesity is another important factor. An overall increased rate of thrombopilia has been seen in women with preeclampsia compared with controls.
TABLE 16.4 Risk Factors for Preeclampsia | |
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Etiology
The etiologic agent responsible for the development of preeclampsia remains unknown. The syndrome is characterized by vasospasm; hemoconcentration; and ischemic changes in the placenta, kidney, liver, and brain. These abnormalities usually are seen in women with severe preeclampsia. Theories as to the causative mechanisms include placental origin, immunologic origin, and genetic predisposition, among others. A list of etiologic theories is shown in Table 16.5. A great deal of research is dedicated to solving the etiologic enigma of preeclampsia. Without a definitive etiology, predicting patients at risk for the development of preeclampsia and effecting a treatment for this morbid disease remain difficult.
TABLE 16.5 Etiologic Theories in Preeclampsia | |
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Pathophysiology
Cardiovascular
The hypertensive changes seen in preeclampsia are attributed to intense vasoconstriction with segmental spasm that occurs particularly in arterioles and is thought to be due to increased vascular reactivity. The underlying mechanism responsible for the increased vascular reactivity is presumed to be alterations in the normal interactions of vasodilatory (prostacyclin, nitric oxide) and vasoconstrictive (thromboxane A2, endothelin) substances. These changes lead to higher arterial blood pressures (afterload). Another vascular hallmark of preeclampsia is hemoconcentration. Patients with preeclampsia have lower intravascular volumes and less tolerance for the blood loss associated with delivery. It is thought that endothelial damage promotes leakage of intravascular fluid and protein into the interstitial space, leading to lower intravascular volume. The heart in a healthy woman with preeclampsia is normal in function and contractility.
Hematologic
Several abnormalities of the coagulation system can occur. The most common hematologic abnormality in preeclampsia is thrombocytopenia (platelet count <100,000/mm3). The suggested pathophysiology likely is vascular endothelial damage or activation and higher levels of thromboxane A2. Another possible hematologic abnormality is microangiopathic hemolysis, as seen in HELLP syndrome, and can be diagnosed by schistocytes seen on peripheral smear and increased lactate dehydrogenase (LDH) levels. Interpretation of the baseline hematocrit in a preeclamptic patient may be difficult. A low hematocrit may signify hemolysis, and a falsely high hematocrit may be due to hemoconcentration.
Renal
Vasospasm in preeclampsia leads to decreased renal perfusion and subsequent decreased glomerular filtration rate (GFR). In normal pregnancy, the GFR is increased up to 50% above prepregancy levels. Because of this, serum creatinine levels in preeclamptic patients rarely rise above normal pregnancy levels (0.8 mg/dL). Close monitoring of urine output is necessary in patients with preeclampsia, because oliguria (defined as <500 cc in 24 hours) may occur due to renal insufficiency. Rarely, profound renal insufficiency may lead to acute tubular necrosis. The pathognomonic renal lesion in preeclampsia is called glomerular capillary endotheliosis, which is swelling of the glomerular capillary endothelial and mesangial cells.
Hepatic
Hepatic damage associated with preeclampsia can range from mildly elevated liver enzyme levels to subcapsular liver hematomas and hepatic rupture. The latter usually are associated with HELLP syndrome. Approximately 20% of maternal mortality in preeclampsia is related to hepatic complications. The pathologic liver lesions seen on autopsy are periportal hemorrhages, hepatocellular necrosis, ischemic lesions, intracellular fatty changes, and fibrin deposition.
Central Nervous System
Eclamptic convulsions are perhaps the most disturbing central nervous system (CNS) manifestation of preeclampsia and remain a major cause of maternal mortality in the Third World. The exact etiology of eclampsia is unknown but is thought to be attributed to coagulopathy, fibrin deposition, and vasospasm. The most common finding in the brain is edema, which likely is due to vascular autoregulation dysfunction. Radiologic studies may show evidence of cerebral edema and hemorrhagic lesions, particularly in the posterior hemispheres, which may explain the visual disturbances seen in preeclampsia. Other CNS abnormalities include headaches and visual disturbances such as scotomata; blurred vision; and rarely, temporary blindness.
Fetus and Placenta
The hallmark placental lesion in preeclampsia is acute atherosis of decidual arteries. This is due in part to the abnormal adaptation of the spiral artery–cytotrophoblast interface and results in poor perfusion. This may lead to poor placental perfusion, resulting in oligohydramnios; intrauterine growth restriction; placental abruption; fetal distress; and ultimately, fetal demise.
Prediction
No good screening test exists for the prediction of preeclampsia. Several methods have been proposed but have not been found to be cost-effective or reliable (Table 16.6). Given that nulliparity has a 5% to 7% risk of preeclampsia
and multiparity carries only a 3% risk, an accurate and thorough maternal history with identification of risk factors is the most cost-effective screening method available. Doppler ultrasonography is a useful method to assess the velocity of uterine blood flow in the second trimester. Abnormal velocity waveform is characterized by a high resistance index or an early diastolic notch (unilateral or bilateral). Data still do not support this test for routine screening. Recently, investigators have begun to examine soluble FMS-like tyrosine kinase-1 receptors (sFlt-1) and placental growth factor as early markers for preeclampsia. Future studies using proteomic and other markers such as soluble endoglin and FMS-like tyrosine kinase receptors (sFlt) are still ongoing.
and multiparity carries only a 3% risk, an accurate and thorough maternal history with identification of risk factors is the most cost-effective screening method available. Doppler ultrasonography is a useful method to assess the velocity of uterine blood flow in the second trimester. Abnormal velocity waveform is characterized by a high resistance index or an early diastolic notch (unilateral or bilateral). Data still do not support this test for routine screening. Recently, investigators have begun to examine soluble FMS-like tyrosine kinase-1 receptors (sFlt-1) and placental growth factor as early markers for preeclampsia. Future studies using proteomic and other markers such as soluble endoglin and FMS-like tyrosine kinase receptors (sFlt) are still ongoing.
TABLE 16.6 Proposed Methods of Prediction of Preeclampsia | ||
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TABLE 16.7 Methods to Prevent Preeclampsia | ||||||||||||||||||||||||||||||
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Prevention
Preventive interventions for preeclampsia could impact maternal and perinatal morbidity and mortality worldwide. As a result, during the past decade, several randomized trials reported several methods to reduce the rate and/or severity of preeclampsia. Several trials assessed protein or low-salt diets, diuretics, bed rest, zinc, magnesium, fish oil, or vitamin C and E supplementation and heparin to prevent preeclampsia in women, but results showed minimal to no effect (Table 16.7). Recently, the results of two large randomized clinic trials using vitamin C and E in both healthy women and women at high risk showed no reduction in the risk of preeclampsia, intrauterine growth restriction, or the risk of death or other serious outcomes in their infants. Furthermore, the World Health Organization (WHO) conducted a randomized trial of calcium supplementation among low-calcium-intake pregnant women. The study showed that 1.5 g per day of calcium does not prevent preeclampsia but did reduce its severity, maternal morbidity, and neonatal mortality. On the other hand, a new evidence-based review of the available scientific evidence in regard to calcium intake and hypertensive disorder in pregnancies did not support a benefit.
Maternal and Perinatal Outcome
Maternal and neonatal outcome in patients with preeclampsia relates largely to one or more of the following factors: the gestational age at delivery, severity of disease, quality of management, and presence of preexisting disease. Perinatal mortalities are increased in those who develop the disease at <34 weeks gestation. Risk to the mother can be significant and includes the possible development of disseminated intravascular coagulation (DIC), intracranial hemorrhage, renal failure, retinal detachment, pulmonary edema, liver rupture, abruptio placentae, and death (Table 16.8). Therefore, experienced clinicians should be caring for women with preeclampsia.
Mild Preeclampsia
Diagnosis of Mild Preeclampsia and Gestational Hypertension
The diagnosis of mild preeclampsia requires the presence of hypertension and proteinuria in pregnancy. Once the diagnosis is made, treatment is delivery. The decision for active management versus expectant management depends on several factors: severity of disease, gestational age, fetal and
maternal status, presence of labor, and the wishes of the mother. Because the spectrum of disease in preeclampsia is variable, it is important to monitor patients for the development of severe preeclampsia. Patients with mild preeclampsia are at risk of developing eclampsia, potentially suddenly, without warning, and with minimal blood pressure elevations. Another risk is abruptio placentae. However, both of these risks are less than 1%.
maternal status, presence of labor, and the wishes of the mother. Because the spectrum of disease in preeclampsia is variable, it is important to monitor patients for the development of severe preeclampsia. Patients with mild preeclampsia are at risk of developing eclampsia, potentially suddenly, without warning, and with minimal blood pressure elevations. Another risk is abruptio placentae. However, both of these risks are less than 1%.
TABLE 16.8 Maternal and Fetal Complications in Severe Preeclampsia | ||
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Management of Mild Preeclampsia
Ideally, a patient who has preeclampsia should be hospitalized at the time of diagnosis. Management of the patient with mild preeclampsia should include baseline laboratory evaluation, including a 24-hour urine collection for protein, hematocrit, platelet count, serum creatinine value, and aspartate aminotransferase (AST) level. At the time of diagnosis, ultrasonography should be performed to evaluate amniotic fluid volume and estimated fetal weight and to confirm gestational age.
The only definitive cure for preeclampsia is delivery. The main objective of management of preeclampsia must always be the safety of the mother and a mature newborn who will not require intensive and prolonged neonatal care. In patients diagnosed with mild preeclampsia at term (>37 weeks), the general consensus is delivery especially since perinatal outcome is similar to normotensive pregnancy. For the patient who is preterm (<37 weeks), controversy arises regarding management with respect to level of activity, diet, antihypertensive medications, and delivery. Usually, these patients do not require immediate delivery, and expectant management is warranted. Hence, the clinical decision making in patients with mild preeclampsia is twofold. If expectant management is chosen, the second question then becomes where to manage the patient—in the hospital or at home?
TABLE 16.9 Criteria for Home Management of Mild Preeclampsia | ||
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In the past, once diagnosed with mild preeclampsia, a woman was either delivered immediately or managed in the hospital for the remainder of the pregnancy. Several studies have shown that a management plan including immediate delivery may not be justified. Sibai and colleagues studied 200 women with preeclampsia who were managed as inpatients with unrestricted activity, and they were randomized to receive labetalol or no medications. The mean pregnancy prolongation was 21 days. The rate of placental abruption was 1.1%, and the perinatal mortality rate was 5.4 per 1,000. Another study by Matthews and colleagues evaluated the effect on preeclampsia of bed rest versus unlimited activity. They also found no significant difference in maternal or fetal outcomes.
At-home management of these patients or use of a day care setting is appropriate in most cases, provided the patient is compliant, has readily available transportation, and is reliable with follow-up (Table 16.9). These women are instructed to restrict their activity and to follow a low-salt diet. The authors do not recommend the use of antihypertensive medications in order not to mask the potential diagnosis of severe preeclampsia. Using this approach, it is important to educate patients regarding the signs and symptoms to report (Table 16.10). They should be advised to return immediately to the hospital if any of these arise. If the disease progresses from mild to severe or if there is any indication
of fetal compromise—including nonreassuring fetal heart rate test results, oligohydramnios, or growth restriction—the patient should be hospitalized and evaluated for delivery. Serial laboratory evaluation of platelet counts and liver enzyme values should be performed every 3 to 7 days to monitor for worsening disease. Significant abnormalities in any of these laboratory criteria warrant hospitalization. Antenatal surveillance should include at least twice weekly nonstress tests (Table 16.11).
of fetal compromise—including nonreassuring fetal heart rate test results, oligohydramnios, or growth restriction—the patient should be hospitalized and evaluated for delivery. Serial laboratory evaluation of platelet counts and liver enzyme values should be performed every 3 to 7 days to monitor for worsening disease. Significant abnormalities in any of these laboratory criteria warrant hospitalization. Antenatal surveillance should include at least twice weekly nonstress tests (Table 16.11).
TABLE 16.10 Signs and Symptoms of Preeclampsia That Warrant Prompt Evaluation | |
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TABLE 16.11 Maternal and Fetal Evaluation in Mild Preeclampsia | |
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Optimal timing of delivery is dependent on maternal and fetal status. In the preterm pregnancy, the sole benefit of expectant management is for the fetus. Once a pregnancy reaches term, the plan should be for delivery. Induction of labor is indicated in those patients with a favorable cervix (Fig. 16.1). At 37 weeks or beyond, if the cervix is unfavorable, there are two options: either cervical ripening and delivery or continued expectant management with maternal and fetal evaluation. The preferred mode of delivery remains vaginal. A cesarean section should be performed for obstetric indications only.
In the past, while in labor, patients with mild preeclampsia received intravenous magnesium sulfate (MgSO4) for seizure prophylaxis. A regimen for MgSO4 administration is presented later in this chapter. The exact point in labor at which to start MgSO4 remains unknown. There is no support in the literature for the need or the optimal timing to begin the MgSO4 infusion, and this should be left to the discretion of the physician. There are only two double-blind, placebo-controlled trials evaluating the use of MgSO4 in patients with mild preeclampsia. In both trials, patients with well-defined mild preeclampsia were randomized during labor or postpartum, and there was no difference in the percentage of women who progressed to severe preeclampsia (12.5% vs. 13.8%; relative risk [RR] 0.90; 95% confidence interval [CI] 0.52 to 1.54). There were no instances of eclampsia among 181 patients assigned to placebo. Thus, the authors recommend to individualize each case for the use of MgSO4.
Pain management in labor should be individualized as well. Intravenous narcotics and regional anesthesia are both appropriate options. Close monitoring of blood pressure intrapartum is necessary. Antihypertensive medications may be needed in order to keep blood pressure values below 160 mm Hg systolic and below 110 mm Hg diastolic. The most commonly used intravenous medications for this purpose are labetalol and hydralazine. The recommended dosages of medications for the immediate treatment of hypertension are listed in Table 16.12
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