Preeclampsia and eclampsia revisited.

Abstract: Hypertensive disorders during pregnancy, which account for approximately 15% of pregnancy-related deaths, represent the second-leading cause of morbidity and mortality in the United States. New classifications recommended by the National Institutes of Health's Working Group on High Blood Pressure in Pregnancy have decreased the confusion often associated with these disorders. The cause of preeclampsia-eclampsia still remains elusive, but continued research has provided hope with regard to screening, improved diagnosis, and management. Risk factors that have recently gained attention include inherited thrombophilias, inherited metabolic disorders, and lipid disorders. Treatment and management of the hypertensive disorders of pregnancy have not changed substantially in the past 50 years. Prevention of preeclampsia-eclampsia has been unsuccessful, and recurrence risks remain high. Careful diagnosis, classification, and further investigation of the causes of hypertensive disorders in pregnancy are needed to achieve optimal management of affected women and their fetuses.

Key Words: eclampsia, hypertensive disorders, preeclampsia, pregnancy

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In Volume 2 of the Southern Medical Journal, published in 1909, Maguire (1) discussed the controversial treatment of immediate cesarean section for puerperal eclampsia. More than 90 years later, hypertensive disorders in pregnancy continue to be an area of much attention and research, as well as some controversy. Hypertension in pregnancy is the second-leading cause of morbidity and mortality in the United States, constitutes almost 15% of pregnancy-related deaths, (2) and is a major risk factor fur fetal morbidity and mortality. (2-11)

In recent years, careful classification of these disorders has helped to clarify their course in pregnancy and gain further understanding of their mysterious cause. The most recent classification recommended by the National High Blood Pressure Education Program (12) (Table 1) is as follows: 1) chronic hypertension, which includes preexisting hypertension (essential and secondary); 2) preeclampsia-eclampsia, which is characterized by hypertension and proteinuria (including seizures in the case of eclampsia); 3) preeclampsia superimposed on chronic hypertension; and 4) gestational hypertension, which is hypertension diagnosed for the first time during the pregnancy and does not meet the criteria for preeclampsia. This category is refined 12 weeks postpartum (Table 1). Previous terminology such as pregnancy-induced hypertension has been abandoned.

Blood Pressure and Cardiovascular Adaptations of Normal Pregnancy

During pregnancy, the placenta exerts a significant influence on maternal blood pressure because of the interaction of its various hormones, vasoactive substances, and structure. Maternal cardiac output and local factors also have an effect on uterine and placental perfusion. (13) In normal pregnancy, all fluid compartments expand. Blood volume increases by 40 to 50%. (14,15) Intravascular volume increases primarily as a result of an increase in plasma volume and secondarily by an increase in red cell volume, resulting in physiologic anemia of pregnancy. (15) The increase in intravascular volume results in an increase in left ventricular end diastolic dimension and is responsible for the normal finding of "cardiomegaly" during pregnancy, which is seen on the chest x-rays of pregnant women in the second and third trimesters. (16) Increased heart rate (17) and stroke volume result in a 40% increase in cardiac output (18,19)

Peripheral vascular resistance decreases during normal pregnancy because of peripheral vasodilation. (20) Factors that contribute to the peripheral vasodilation include refractoriness to the pressor effects of angiotensin II and the relaxation of vascular smooth muscles. (21,22) Available research focused on the initiation and control of peripheral vasodilation is ongoing and includes candidates such as nitric oxide, progesterone, prostaglandins, calcium, and decreased response to neurotransmitters. (23-24)

Blood pressure is lower in the pregnant state. As early as 7 weeks' gestation, maternal blood pressure decreases, with a nadir at approximately 16 to 20 weeks' gestation. After 28 weeks, blood pressure increases, reaching nonpregnant values toward the completion of the third trimester. Diastolic blood pressure during pregnancy should be recorded as the complete disappearance of sound (Korotkoff Phase V). Generally, blood pressure greater than 130/80 mm Hg is of concern in pregnancy and warrants close surveillance.

Chronic Hypertension

Chronic hypertension affects approximately 5% of pregnancies but may increase as more women delay childbearing. Among pregnant women with chronic, preexisting hypertension, 95 to 98% have essential hypertension and only 2% have secondary hypertension as a result of renal disease, aldosteronism, Cushing syndrome, renovascular disease, connective tissue disease, or pheochromocytoma. (25)

Many pregnant women with chronic hypertension are being treated with an antihypertensive medication when a pregnancy is discovered. At times, the antihypertensive effects of pregnancy itself allow discontinuation of antihypertensive agents. Reinstitution of antihypertensive medication is considered when blood pressure increases with advancing gestational age, especially after 28 weeks' gestation. If an antihypertensive medication is required during pregnancy, the recommended agent is [alpha]-methyldopa, a centrally acting [alpha]-agonist that has an extensive history of safety during pregnancy. (26,27) Another medication whose safety during pregnancy has been confirmed is labetalol, a [beta]-blocking agent with antagonistic activity at vascular [alpha]-1 receptors. A drawback of labetalol is a potential risk for decreased cardiac output and consequent decreased uterine perfusion, leading to restriction of fetal growth. Angiotensin-converting enzyme inhibitors and angiotensin receptor blocking agents are contraindicated in pregnancy because of their association with fetal congenital malformations, oligohydramnios, renal stcnosis, and fetal death. (28) Diuretic medications generally are not recommended for the treatment of hypertension during pregnancy, because they contract intravascular volume and therefore decrease uterine perfusion.

Treatment of mild preexisting hypertension is controversial. At present, evidence suggests that treatment of this group does not improve maternal or perinatal outcome and does not decrease the risk of developing superimposed preeclampsia. (29) The goal of therapy is to maintain systolic blood pressure below 160 mm Hg and diastolic pressure below 105 mm Hg. Overly aggressive antihypertensive therapy may cause maternal hypotension and a consequent decrease in uterine perfusion that may affect fetal growth.

Many women with chronic hypertension have uncomplicated pregnancies, but there is risk of poor fetal growth (ie, intrauterine fetal growth restriction) and fetal demise. Women whose plasma volumes do not increase to the same degree as those of normal pregnant women are at greater risk for smaller placentas and growth-restricted infants. Approximately 25% of women with chronic hypertension develop superimposed preeclampsia-eclampsia. (30,31)

Initial management of a pregnant woman with chronic hypertension includes baseline laboratory and radiologic studies (Table 2). If the preexisting diagnosis of hypertension has not been evaluated fully or if blood pressure during early pregnancy is in the severe category, secondary hypertension should be considered. Obstetric management of women with hypertension in the moderate to severe range tends to include antihypertensive medication, blood pressure self-monitoring, home bed rest, frequent prenatal visits, and fetal surveillance. Fetal surveillance involves serial ultrasonographic evaluations for interval fetal growth and amniotic fluid volume, fetal monitoring through nonstress tests or biophysical profiles, and Doppler velocimetry of the umbilical arteries if intrauterine fetal growth restriction is present. In some cases, hospitalization for close surveillance of patient and fetus is warranted.

Preeclampsia-Eclampsia

Preeclampsia affects only pregnant women and is diagnosed when hypertension and proteinuria occur after 20 weeks' gestation. Edema is often seen but is not required to make the diagnosis. If seizures occur as a complication of preeclampsia, the term eclampsia is used. During the past several years, preeclampsia-eclampsia has been the second- or third-leading cause of maternal death (32) and is a common cause of fetal morbidity and wastage.

Preeclampsia affects approximately 4.5 to 11.2% of pregnancies in industrialized countries (33) and occurs more commonly in patients at the extremes of the reproductive age range. It is seen more often in primigravid women than in multiparous women. Recent epidemiologic studies suggest that multiparous women with different partners have a higher risk for preeclampsia than do multiparous women with the same partner, (34,35) perhaps because of a protective effect of repeated exposure to specific antigens.

The cause of preeclampsia remains unknown. Because preeclampsia is a compilation of specific signs and symptoms with different causes, it has been suggested that it is a syndrome rather than a disease. (36) Preeclampsia is more likely to occur in women with multiple gestations, underlying hypertension, and chronic illnesses such as autoimmune disease, diabetes mellitus, and renal disease. Recently, an association of preeclampsia with thrombophilia has been identified, particularly factor V Leiden heterozygote deficiency, (37,38) activated protein C resistance, (39) homocysteinemia, (40) and antiphospholipid syndrome. (41,42) Women who are carriers of certain inherited metabolic disorders seem to be at risk for preeclampsia and other complications of pregnancy. Specifically, women who are heterozygote carriers for [beta]-oxidation disorders, particularly long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, (43) are at risk for preeclampsia and acute fatty liver of pregnancy.

Although the specific cause of preeclampsia remains unknown, several factors contribute to the development of the disease spectrum, including the onset of vasospasm, activation of the coagulation system, oxidative stressors, increased inflammatory response, and ischemia. (44,45) The placenta is considered to be the inciting organ of preeclampsia-eclampsia. A rat model of preeclampsia has recently been developed, which should assist in unraveling these issues. (46) Current theory suggests that incomplete trophoblastic invasion of the uterine vascular endothelium results in thick-walled, muscular vessels rather than saclike, flaccid vessels, which is the normal response to trophoblastic invasion. The abnormally thick-walled vessels have higher resistance and less capacitance and cause a decrease in placental perfusion, leading to hypoxia. (47) Hypoxia in turn directly or indirectly causes several pathophysiologic abnormalities, particularly endothelial damage.

Changes in virtually all organ systems occur in preeclampsia-eclampsia. Intense vasospasm occurs probably in response to the higher sensitivity to all endogenous pressors, particularly angiotensin II. (21) The hypervolemia seen in normal pregnancy does not occur. (48) Decreased intravascular volume and hemoconcentration occur at least in part because of endothelial cell damage that promotes leakage of fluid and protein from the intravascular to the interstitial space. The leakage causes contraction of the intravascular space and expansion of the interstitial space (ie, edema).

Edema of the liver and hepatocellular necrosis results in leakage of aminotransferases and lactate dehydrogenase into the maternal circulation. Bilirubin is rarely increased in preeclampsia. (49) Hepatic hemorrhage, although rare, may manifest as a subcapsular hematoma. Rupture of a hepatic subcapsular hematoma is a life-threatening complication and a surgical emergency.

Women with preeclampsia have a decrease in glomerular filtration and renal blood flow. This is thought to be a result of vasospasm and glomerular capillary endothelial edema (ie, glomerular endotheliosis) that renders many glomeruli nonfunctional. Glomerular endotheliosis has been described as the classic pathologic renal lesion of preeclamptic women. (50) An increase in the blood uric acid level due to decreased renal perfusion or to increased production by poorly perfused tissue (51) has long been recognized as a consistent feature of preeclampsia. (52) Proteinuria, primarily due to increased glomerular permeability and damage, (53) is an integral part of the diagnosis of preeclampsia. Oliguria, defined as <500 ml/24 h, may occur secondary to hemoconcentration and decreased renal perfusion. Persistent oliguria may indicate acute tubular necrosis, the most common type of acute renal failure seen in preeclampsia. (54)

Cerebral edema, cerebral hemorrhage, temporary blindness, and seizures are some of the neurologic complications associated with preeclampsia and eclampsia. Other central nervous system manifestations include persistent headache, blurred vision, scotomata, and hyperreflexia.

Thrombocytopenia is the most common hematologic abnormality of severe preeclampsia. Microangiopathic hemolytic anemia may also occur. Changes in the coagulation cascade and in the fibrinolytic system may result in the syndrome of disseminated intravascular coagulopathy. The cause of these changes remains uncertain, but a hypothesis involves vascular endothelial damage that causes activation of platelets and the coagulation cascade. (55)

Maternal morbidity associated with preeclampsia is related to the multiorgan involvement of the disease. Maternal death is largely a result of complications from abruptio placentae, hepatic rupture, and eclampsia. Maternal mortality rates associated with preeclampsia range from 0 to 14%. (56,57)

Fetal morbidity and mortality in preeclamptic women can be substantial. Preeclamptic hypertension, similar to preexisting hypertension in pregnancy, is a risk factor for placental abruption and restriction of fetal growth. As one would expect, the rate of fetal complications parallels the severity of the disease. (58) Delivery of the fetus is more likely to be preterm if preeclampsia is severe and diagnosed early in the pregnancy. The sequelae of prematurity, particularly extreme prematurity (24-28 gestational weeks) may include respiratory distress syndrome, chronic lung disease, intraventricular hemorrhage, cerebral palsy, sepsis, necrotizing enterocolitis, and failure to thrive.

The diagnosis of preeclampsia has traditionally been made when a pregnant woman presents with the triad of hypertension, proteinuria, and edema after 20 weeks' gestation. In rare circumstances, however, preeclampsia has been diagnosed at less than 20 weeks' gestational age in a molar pregnancy. Current diagnostic criteria include only the presence of hypertension (in a woman with previously normal blood pressure) and proteinuria (Table 1). Edema is no longer included as one of the diagnostic criteria, because of its wide spectrum of prevalence in normal pregnant women and because a small subset of women with preeclampsia-eclampsia have minimal edema. It is notable that women with occult or undiagnosed renal disease may present with apparently new-onset hypertension and proteinuria in pregnancy that may mimic preeclampsia. Obtaining a careful history, physical examination, and laboratory evaluation may clarify the diagnosis. In rare instances, a renal biopsy may be appropriate. (59)

Blood pressure values required for the diagnosis of preeclampsia include a systolic pressure in excess of 140 mm Hg and/or a diastolic pressure greater than 90 mm Hg (Korotkoff Phase V) recorded on two separate occasions at least 4 hours apart. Urinary protein excretion >300 mg/24 h is also required to make the diagnosis. The following laboratory studies should be performed to aid in evaluation of the severity of the disorder and guide management: a complete blood count with platelet count, liver enzymes, blood urea nitrogen, serum creatinine, and uric acid, as well as a 24-hour urine collection fur protein excretion and creatinine clearance. Liver studies should include at least the transaminases (alanine aminotransferase and aspartate aminotransferase), lactate dehydrogenase, bilirubin, and albumin (Table 2). Of note, in normal pregnancy, an increase in alkaline phosphatase is seen as a result of the presence of the placental isoform, and plasma albumin seems to decrease because of hemodilution. If the preeclamptic woman has bleeding, abruptio placentae, or microangiopathic hemolytic anemia, then her fibrinogen levels, prothrombin time, activated partial thromboplastin time, and fibrin degradation products also should be obtained. (60)

Preeclampsia has been classified as mild and severe. Severe preeclampsia consists of systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 110 mm Hg as well as significant proteinuria (>5.0 g/d), with or without evidence of effects on other organ systems. The following signs and symptoms, although variable in presence, are associated with severe preeclampsia: headache, visual disturbances, confusion, right upper quadrant or epigastric pain, impaired liver function, proteinuria, oliguria, pulmonary edema, microangiopathic hemolytic anemia, thrombocytopenia, and fetal intrauterine growth restriction. Preeclampsia is considered mild if hypertension and proteinuria as previously defined are present but not in the severe range and there is no evidence of other organ dysfunction.

Eclampsia is the occurrence of seizure activity not secondary to other convulsive disorders in women with signs and symptoms of preeclampsia. Convulsions may occur antepartum, intrapartum, or postpartum. The mechanisms leading to the development of convulsions in women with eclampsia may include cerebral edema, ischemia, hemorrhage, or transient vasospasm. Although eclampsia most often occurs in the setting of severe preeclampsia, it can occur in women with mild preeclampsia. There are no recognized clinical determinants of remote prediction of which women with preeclampsia will experience seizures. Severe headache and hyperreflexia, however, are common clinical precursors of eclamptic seizures. (61)

The combination of hemolysis, elevated liver function, and low platelets (HELLP) is a syndrome that is a variant of severe preeclampsia. (62) The complete spectrum of HELLP syndrome is seen in approximately 15% of women with preeclampsia-eclampsia. (63) It is generally agreed that pregnancies complicated by preeclampsia and HELLP syndrome are at even higher risk for maternal and/or fetal complications. (64)

The treatment and management of preeclampsia-eclampsia varies according to severity and gestational age at diagnosis. The definitive cure for preeclampsia is delivery of the fetus. Although optimal for the mother, however, preterm delivery may not be ideal for the fetus. Women suspected of having preeclampsia should be evaluated promptly and hospitalized at the time of diagnosis. Laboratory studies (Table 2) should be obtained to determine the severity of the disease.

Delivery is indicated when preeclampsia is diagnosed at or beyond 38 weeks of pregnancy, regardless of the severity of the disease. However, individualized management of patients with mild preeclampsia at term when the cervix is not favorable for inducing labor is an alternative option that requires close observation and delivery at no later than 40 weeks' gestation (Table 3).

When mild preeclampsia is diagnosed in a preterm pregnancy, hospital bed rest until delivery with close maternal and fetal surveillance (ie, expectant management) is recommended. In these premature gestations, consideration may be given to antenatal glucocorticoid therapy to accelerate fetal lung maturation (Table 3). During the course of hospitalization, the woman with mild preeclampsia is monitored closely for signs and symptoms of severe preeclampsia or impending eclampsia (eg, persistent headache, hyperreflexia). Blood pressure measurements are usually recorded every 4 hours, and maternal weight should be assessed daily to detect excessive weight gain due to edema. Laboratory tests (Table 2) should be obtained twice weekly or more frequently if signs or symptoms suggest progression of disease. Fetal surveillance is instituted in the form of daily fetal movement count, nonstress tests, and serial ultrasonographic evaluation of fetal growth and amniotic fluid volume to confirm fetal well-being. The optimal frequency of these tests has not been established but should depend on gestational age and the condition of the patient and fetus. More frequent antenatal fetal surveillance is required if the disease process worsens or if there is evidence of poor fetal growth or decreasing amniotic fluid volume. Expectant management usually continues until the pregnancy reaches term, the fetal lung maturity is documented by amniotic fluid studies, or severe preeclampsia or other complications develop.

Delivery is generally recommended for women with severe preeclampsia, even if the fetus is at less than 38 weeks' gestation (Table 3). When severe preeclampsia is diagnosed in a pregnant woman at preterm gestation (usually <32 wk), however, an initial observation period and conservative expectant management in a tertiary care center may be attempted cautiously (Table 3). (65,66) When eclampsia develops, expedient delivery is mandated, regardless of gestational age.

Once it is determined that delivery is required, labor induction should be performed without delay. The goals during the intrapartum period are to prevent seizures, stabilize blood pressure, and promote delivery. During labor and delivery, women with preeclampsia-eclampsia receive IV magnesium sulfate for seizure prophylaxis, usually as a loading dose of 4 to 6 g magnesium sulfate x [sup.7][H.sub.2]O infused for 20 minutes followed by a continuous IV infusion at 2 g/h. Because magnesium is excreted in the urine, blood levels also depend on urine output. Serum blood levels should be monitored. The therapeutic range for magnesium sulfate is generally considered to be 4 to 8 mg/dl. In a patient with elevated creatinine or oliguria, the patient's magnesium level should be followed carefully and the magnesium sulfate infusion adjusted accordingly.

During labor, maternal blood pressure should be evaluated carefully and antihypertensive treatment should be initiated if systolic levels are persistently greater than 160 mm Hg or diastolic levels are consistently greater than 105 mm Hg. The most widely used antihypertensive medication in the intrapartum period for women with preeclampsia-eclampsia is hydralazine. It is best administered by IV bolus every 20 minutes. A starting dose of 5 mg is administered, which may be increased to 10 mg if indicated after 20 minutes of observation. The total dose of IV hydralazine in an acute therapeutic incident should not exceed 20 to 30 mg. An alternative antihypertensive medication used in this clinical setting is labetalol, which is usually administered as an IV bolus injection every 10 minutes at a starting dose of 20 mg, with subsequent dose doubled from the previous dose and the maximum acute total dose not to exceed 220 mg. Care should be taken not to decrease the patient's blood pressure acutely or to diastolic levels less than 80 mm Hg, because suboptimal uterine and placental perfusion may result in abnormal fetal heart rate patterns, such as fetal bradycardia or late deceleration. (67)

Continuous electronic fetal heart rate and uterine activity monitoring should be instituted in all cases. Vaginal delivery is safer than cesarean section in women with preeclampsia-eclampsia and usually should be attempted unless there are other obstetric indications for cesarean delivery. Certain women at preterm gestation with severe preeclampsia or eclampsia in whom the cervix is unfavorable for vaginal delivery may benefit from cesarean section without attempting labor induction.

Regional anesthesia is commonly used in women with preeclampsia. The sympathetic blockade and peripheral vascular dilation caused by local anesthetics used in epidural anesthesia may cause hypotension, however, unless meticulous attention is paid to anesthetic technique and proper gradual volume expansion. (68) When general anesthesia is required, it is crucial to carefully control maternal blood pressure during both the induction of and the recovery from anesthesia.

After delivery, the patient with preeclampsia-eclampsia is kept under close observation, and the magnesium sulfate infusion is continued for seizure prophylaxis. Resolution of the disease process, which manifests most commonly by diuresis, usually begins to occur within 24 hours. Some patients, however, especially those with HELLP syndrome or severe disease in midtrimester, may require intensive monitoring for several days before resolution occurs. Such patients may require magnesium sulfate treatment for more than 24 hours until diuresis occurs.

Preeclampsia Superimposed on Chronic Hypertension

Approximately 25% of women with preexisting hypertension who become pregnant develop superimposed preeclampsia. (69) Superimposed preeclampsia is especially increased in women with chronic severe hypertension and in women with preexisting cardiovascular or renal disease. (70) The diagnosis of superimposed preeclampsia may be difficult in women with preexisting proteinuria as a result of renal disease. This diagnosis should be suspected if there is a sudden increase in proteinuria or hypertension, thrombocytopenia develops, or liver enzyme levels are abnormal in women with chronic hypertension after 20 weeks" gestation. Women with preeclampsia superimposed on chronic hypertension are at higher risk for poor perinatal outcome and placental abruption. (71,72) Underlying end organ disease such as left ventricular hypertrophy or cardiac dysfunction predisposes them to more frequent and more serious complications.

Prevention and Recurrence of Preeclampsia-Eclampsia

Recent investigations in preeclampsia have centered on prevention. Low-dose aspirin (50-150 mg), (73-75) oral calcium supplementation, (76,77) garlic tablets, (78) fish oils, (79) and magnesium supplementation (80) have generally been found to be ineffective in preventing preeclampsia. The search for preventive measures continues, however, and initial studies of antioxidants such as vitamins C and E are promising. (81)

Recurrence of preeclampsia is influenced by many factors, including the certainty and severity of the disorder in the affected pregnancy, the presence of underlying illness, genetic tendencies, and change of partners. Young, otherwise healthy women with severe preeclampsia or eclampsia in the first pregnancy were found to have a 19.5% risk for developing mild preeclampsia, a 25.9% risk for severe preeclampsia, and a 1.4% risk for eclampsia in the subsequent pregnancy. (82) Women with preeclampsia-eclampsia that occurred in the late second or early third trimester are particularly at risk. (83) Women with preeclampsia may be at increased risk for chronic hypertension later in life (84) and possibly undiagnosed renal disease. (85) Women who have had severe preeclampsia at less than 34 weeks' gestation should be evaluated for antiphospholipid syndrome (86) and possibly for inherited thrombophilias.

Despite considerable research in recent years, hypertensive disorders of pregnancy are still devastating for both mother and fetus. Careful diagnosis, classification, and further investigation of their causes will help in their management and, ultimately, in their prevention.

Key Points

* Hypertensive disorders in pregnancy have a major impact on maternal and fetal outcomes.

* The National Institutes of Health has recommended a new classification system for hypertensive disorders in pregnancy.

* The causes of preeclampsia-eclampsia are still unknown, but the disease seems to begin at implantation, well before clinical manifestations allow the diagnosis to be made.

* Management of preeclampsia-eclampsia has not changed considerably in the past 50 years, and the definitive cure remains delivery of the fetus and placenta.

Table 1. Classification of hypertensive disorders in pregnancy (a)

Disorder                                     Definition

Chronic hypertension         Hypertension present before pregnancy or
                               first diagnosed before 20 weeks'
                               gestation
Preeclampsia-eclampsia       New-onset hypertension (>140 mm Hg systo-
                               lic or >90 mm ltg diastolic pressure)
                               and proteinuria (excretion >0.3 g in 24
                               h) after 20 weeks' gestation in a pre-
                               viously normotensive woman
                             Eclampsia if seizures also occur (both can
                               occur before 20 weeks' gestation in
                               molar pregnancies)
Preeclampsia superimposed    New-onset or acutely worse proteinuria,
  on chronic hypertension      sudden increase in blood pressure,
                               thrombocytopenia, or elevated liver
                               enzymes after 20 weeks' gestation in
                               women with preexisting hypertension
Gestational hypertension     Increased blood pressure (>140 min Hg
                               systolic or >90 nun Hg diastolic pres-
                               sure) first diagnosed after 20 weeks'
                               gestation and not accompanied by
                               proteinuria
  Transient hypertension     Hypertension resolves by 12 weeks post-
                               partum
  Chronic hypertension       Hypertension does not resolve by 12 weeks
                               postpartum

(a) Adapted from NIH Working Group Report on High Blood Pressure in
Pregnancy. (2)

Table 2. Testing in pregnant women with hypertensive disorders of
pregnancy (a)

Examination                       Parameters measured

Laboratory (b,c)    Serum electrolytes, BUN, creatinine, uric acid,
                      transaminases (AST, ALT), lactic acid dehydro-
                      genase, albumin
                    CBC with platelet count and blood smear
                    24-h urine collection for protein excretion and
                      creatinine clearance
                    Coagulation studies: fibrinogen level, PT, aPTT,
                      and fibrin degradation products (d)
Radiology (e)       Chest x-ray
Cardiology (e)      Electrocardiogram, echocardiogram

(a) BUN, blood urea nitrogen: AST, aspartate aminotransrferase: ALT
alanine aminotransferase; CBC, complete blood count; PT prothrombin
time; aPTT, activated partial thromboplastin time.

(b) Obtained in women with chronic hypertention to assess end organ
disease and as baseline to aid in the latter diagnosis of superimposed
preeclampsia.

(c) Obtained to aid in diagnosis or to monitor progression of
preeelampsia.

(d) Obtained if bleeding, abruptio placentae, or microangiopathic
hemolytic anemia.

(e) Obtained in women with chronic hrpertension; often omitted in women
with mild preexisting chronic hypertnsion.

Table 3. Management of preeclampsia-eclampsia according to severity

                       Gestational age
Severity                 at diagnosis                 Management

Mild pre-         <38 wk without maternal
  eclampsia         or fetal compromise (a)    Hospitalization for bed
                                                 rest and close obser-
                                                 vation
                                               Maternal glucocorticoid
                                                 therapy at 24-34 wk
                                                 for fetal lung
                                                 maturation
                  [greater than or equal to]
                    38 wk without maternal
                    or fetal compromise        Delivery
                                               Magnesium sulfate
                                                 seizure prophylaxis
                                                 intrapartum and post-
                                                 partum
                                               Delivery may be delayed
                                                 to 40 weeks' gestation
                                                 if cervix is unfavo-
                                                 rable for labor induc-
                                                 tion
Severe pre-       <32 wk                       Hospitalization with
  eclampsia (b)                                  close maternal and
                                                 fetal surveillance,
                                                 ideally in a tertiary
                                                 care center
                                               Maternal glucocorticoid
                                                 therapy for fetal lung
                                                 maturation if [greater
                                                 than or equal to] 24
                                                 weeks
                                               Delivery if maternal or
                                                 fetal compromise
                  32-36 wk                     Delivery
                                               Magnesium sulfate
                                                 seizure prophylaxis
                                                 intrapartum and post-
                                                 partum
                                               Antihypertensive therapy
                                               Maternal glucocorticoid
                                                 therapy for fetal lung
                                                 maturation if <34
                                                 weeks
                                               In selected women,
                                                 cautious delay in
                                                 delivery until fetal
                                                 lung maturity is docu-
                                                 mented by amniocente-
                                                 sis
                  [greater than or equal to]
                    36 wk                      Delivery
                                               Magnesium sulfate sei-
                                                 zure prophylaxis
                                                 intrapartum and
                                                 postpartum
                                               Antihypertensive
                                                 therapy
Eclampsia         [greater than or equal to]
                    20 wk                      Stabilization and expe-
                                                 dient delivery
                                               Magnesium sulfate
                                                 seizure prophylaxis
                                                 intrapartum and
                                                 postpartum
                                               Antihypertensive therapy

(a) Maternal compromise includes progression to severe preeclampsia,
severe headache, right upper quadrant pain, visual disturbances,
thrombocytopenia, elevated liver enzymes; fetal compromise includes
poor fetal growth, low amniotic fluid volume, and abnormalities of the
fetal heart rate tracing or biophysical profile.

(b) Systolic blood pressure >160 mm Hg or diastolic blood pressure >110
mm Hg, proteinuria >5.0 g/24 h.

References

(1.) Maguire DL. The treatment of puerperal eclampsia by caesarian section. South Med J 1909;2:1076-1079.

(2.) Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1-S22.

(3.) Cunningham FG, Lindheimer MD. Hypertension in pregnancy. N Engl J Med 1992;326:927-931.

(4.) MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol 2001;97:533-538.

(5.) Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. ACOG technical bulletin: Hypertension in pregnancy--Number 219: January 1996 (replaces no. 91, February 1986). Int J Gynaecol Obstet 1996;53:175-183.

(6.) Garovic VD. Hypertension in pregnancy: Diagnosis and treatment. Mayo Clin Proc 2000;75:1071-1076.

(7.) Saftlas AF, Olson DR, Franks AL, et al. Epidemiology of preeclampsia and eclampsia in the United States, 1979-1986. Ant J Obstet Gynecol 1990;163:460-465.

(8.) Lindheimer MD. Hypertension in pregnancy. Hypertension 1993;22: 127-137.

(9.) Ceron-Mireles P, Harlow SD, Sanchez-Carrillo CI, et al. Risk factors for pre-eclampsia/eclampsia among working women in Mexico City. Paediatr Perinat Epidemiol 2001;15:40-46.

(10.) Burrows RF, Burrows EA. The feasibility of a control population for a randomized controlled trial of seizure prophylaxis in the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1995;173:929-935.

(11.) Cunningham FG, Gant NF, Leveno KJ, et al. Hypertensive disorders in pregnancy, in Williams Obstetrics. New York, McGraw-Hill Health Professions Division, 2001, ed 21, pp 567-618.

(12.) National High Blood Pressure Education Program. Working Group Report on High Blood Pressure in Pregnancy (NIH Publication No, 003029). Bethesda, MD, National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, revised July 2000. Available at: http://www.nhlbi.nih.gov/ health/prof/heart/hbp/hbp_preg.pdf Accessed June 24, 2003.

(13.) Pridjian G. Placental transfer, fetomaternal interaction: Placental physiology and its role as go between, in Avery GB, Fletcher MA, MacDonald MG (eds): Neonatology; Pathophysiology and Management of the Newborn. Philadelphia, Lippincott Williams & Wilkins, 1999, ed 5, pp 125-131.

(14.) Pirani BB. Campbell DM, MacGillivray I. Plasma volume in normal first pregnancy. J Obstet Gynaecol Br Commonw 1973;80:884-887.

(15.) Scott DE. Anemia during pregnancy. Obstet Gynecol Annu 1972;1:219-244.

(16.) Hunter S, Robson SC. Adaptation of the maternal heart in pregnancy. Br Heart J 1992;68:540-543.

(17.) Clapp JF III, Capeless E. Cardiovascular function before, during, and after the first and subsequent pregnancies. Am J Cardiol 1997;80:1469-1473.

(18.) Lang RM, Pridjian G, Feldman T, et al. Left ventricular mechanics in preeclampsia. Am Heart J 1991;121:1768-1775.

(19.) Robson SC, Hunter S, Boys RJ, et al. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol 1989; 256:H1060-H1065.

(20.) Chapman AB, Abraham WT, Zamudio S, et al. Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Kidney Int 1998;54:2056-2063.

(21.) Gant NF, Chand S, Whalley PJ, et al. The nature of pressor responsiveness to angiotensin II in human pregnancy. Obstet Gynecol 1974;43: 854-860.

(22.) Chesley LC, Talledo OE, Bohler CS, et al. Vascular reactivity to angiotensin II and norepinephrine in pregnant and nonpregnant women. Am J Obstet Gynecol 1965;91:837-841.

(23.) Lopez-Jaramillo P. Calcium, nitric oxide, and preeclampsia. Semin Perinatol 2000;24:33-36.

(24.) Nisell H, Hjemdahl P, Linde B, et al. Sympathoadrenal and cardiovascular reactivity in pregnancy-induced hypertension: Part II--Responses to tilting. Am J Obstet Gynecol 1985;152:554-560.

(25.) August P, Lindheimer MD. Chronic hypertension and pregnancy, in Lindheimer MD, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy. New York, McGraw-Hill Health Professions Division, 1999, ed 2, pp 615-616.

(26.) Cockburn J, Moar VA, Ounsted M, et al. Final report of study on hypertension during pregnancy: The effects of specific treatment on the growth and development of the children. Lancet 1982;1:647-649.

(27.) Redman CW. Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet 1976;2:753-756.

(28.) Buttar HS. An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development. Mol Cell Biochem 1997; 176:61-71.

(29.) Sibai BM, Mabie WC, Shamsa F, et al. A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am J Obstet Gynecol 1990;162:960-967.

(30.) Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;67:197-205.

(31.) Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 1994;171:410-416.

(32.) Centers for Disease Control and Prevention. Maternal mortality: United States, 1982-1996. MMWR Morb Mortal Wkly Rep 1998;47:705-707.

(33.) U.S. Department of Health, Education, and Welfare. The Collaborative Perinatal Study of the National Institute of Neurological Diseases and Stroke: The Women and their Pregnancies (DHEW Publication No. (NIH) 73-379). Bethesda, MD, U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, 1972.

(34.) Li DK, Wi S. Changing paternity and the risk of preeclampsia/eclampsia in the subsequent pregnancy. Am J Epidemiol 2000;151:57-62.

(35.) Trupin LS, Simon LP, Eskenazi B. Change in paternity: A risk factor for preeclampsia in multiparas. Epidemiology 1996;7:240-244.

(36.) Barron WM. The syndrome of preeclampsia. Gastroenterol Clin North Am 1992;21:851-872.

(37.) Bozzo M, Carpani G, Leo L, et al. HELLP syndrome and factor V Leiden. Eur J Obstet Gynecol Reprod Biol 2001;95:55-58.

(38.) Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9-13.

(39.) van Pampus MG, Dekker GA, Wolf H, et al. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 1999;180:1146-1150.

(40.) Powers RW, Evans RW, Majors AK, et al. Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation. Am J Obstet Gynecol 1998;179:1605-1611.

(41.) Alsulyman OM, Castro MA, Zuckerman E, et al. Preeclampsia and liver infarction in early pregnancy associated with the antiphospholipid syndrome. Obstet Gynecol 1996;88:644-646.

(42.) Shehata HA, Nelson-Piercy C, Khamashta MA. Management of pregnancy in antiphospholipid syndrome. Rheum Dis Clin North Am 2001; 27:643-659.

(43.) Tyni T, Ekholm E, Pihko H. Pregnancy complications are frequent in long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Obstet Gynecol 1998;178:603-608.

(44.) Pridjian G, Puschett JB. Preeclampsia: Part 2--Experimental and genetic considerations. Obstet Gynecol Surv 2002;57:619-640.

(45.) Pridjian G, Puschett JB. Preeclampsia: Part 1--Clinical and pathophysiologic considerations. Obstet Gynecol Surv 2002;57:598-618.

(46.) Pridjian G, Ianosi MY, Williams J, et al. Volume expansion as a proximate cause of preeclampsia in a rat model, in Abstracts of the 13th World Congress of the International Society for the Study of Hypertension in Pregnancy, June 2-4, 2002, Toronto, ON, Canada.

(47.) Cross JC, Werb Z, Fisher SJ. Implantation and the placenta: Key pieces of the development puzzle. Science 1994;266:1508-1518.

(48.) Gallery ED, Lindheimer MD. Pathology and pathophysiology of preeclampsia: Alterations in volume homeostasis, in Lindheimer MD, Roberts JM, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy. New York, McGraw-Hill Health Professions Division, 1999, ed 2, pp 327-347.

(49.) Knox TA. Olans LB. Liver disease in pregnancy. N Engl J Med 1996; 335:569-576.

(50.) Morris RH, Vassalli P, Beller PK, et al. Immunofluorescent studies of renal biopsies in the diagnosis of toxemia of pregnancy. Obstet Gynecol 1964;24:32-46.

(51.) Parks DA, Granger DN. Xanthine oxidase: Biochemistry, distribution and physiology. Acta Physiol Scand Suppl 1986;548:87-99.

(52.) Hayashi TT. The effect of Benemid on uric acid excretion in normal pregnancy and in preeclampsia, Am J Obstet Gynecol 1957;73:17-22.

(53.) Katz M, Berlyne GM. Differential renal protein clearance in toxaemia of pregnancy. Nephron 1974;13:212-220.

(54.) Cunningham FG, Gant NF, Leveno KJ, et al. Hypertensive disorders in pregnancy, in Williams Obstetrics. New York, McGraw-Hill Health Professions Division, 2001, ed 21, pp 567-618.

(55.) Maynard JR, Dreyer BE, Stemerman MB, et al. Tissue-factor coagulant activity of cultured human endothelial and smooth muscle cells and fibroblasts. Blood 1977;50:387-396.

(56.) Pritchard JA, Pritchard SA. Standardized treatment of 154 consecutive cases of eclampsia. Am J Obstet Gynecol 1975;123:543-552.

(57.) Lopez-Llera M. Complicated eclampsia: Fifteen years' experience in a referral medical center. Am J Obstet Gynecol 1982;142:28-35.

(58.) Ferrazzani S, Caruso A, De Carolis S, et al. Proteinuria and outcome of 444 pregnancies complicated by hypertension. Am J Obstet Gynecol 1990;162:366-371.

(59.) Lindheimer MD, Davison JM. Renal biopsy during pregnancy: "To b ... or not to b ...?" Br J Obstet Gynaecol 1987;94:932-934.

(60.) Barron WM, Heckerling P, Hibbard JU, et al. Reducing unnecessary coagulation testing in hypertensive disorders of pregnancy. Obstet Gynecol 1999;94:364-370.

(61.) Witlin AG, Saade GR, Mattar F, et al. Risk factors for abruptio placentae and eclampsia: Analysis of 445 consecutively managed women with severe preeclampsia and eclampsia. Ant J Obstet Gynecol 1999;180: 1322-1329.

(62.) Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: A severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;142:159-167.

(63.) Crosby ET. Obstetrical anaesthesia for patients with the syndrome of haemolysis, elevated liver enzymes and low platelets. Can J Anaesth 1991;38:227-233.

(64.) Sibai BM, Ramadan MK, Usta I, et al. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol 1993;169:1000-1006.

(65.) Odendaal HJ, Pattinson RC, Bam R, et al. Aggressive or expectant management for patients with severe preeclampsia between 28-34 weeks' gestation: A randomized controlled trial. Obstet Gynecol 1990; 76:1070-1075.

(66.) Sibai BM, Mercer BM, Schiff E, et al. Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks' gestation: A randomized controlled trial. Am J Obstet Gynecol 1994;171:818-822.

(67.) Spinnato JA. Sibai BM. Anderson GD. Fetal distress after hydralazine therapy for severe pregnancy-induced hypertension. South Med J 1986; 79:559-562.

(68.) Clark SL, Cotton DB. Clinical indications for pulmonary artery catheterization in the patient with severe preeclampsia. Am J Obstet Gynecol 1988;158:453-458.

(69.) Sibai BM, Lindheimer M, Hauth J, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;339:667-671.

(70.) Dekker GA. Risk factors for preeclampsia. Clin Obstet Gynecol 1999; 42:422-435.

(71.) Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 1994:171:410-416.

(72.) McCowan LM, Buist RG. North RA, et al. Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 1996;103:123-129.

(73.) Hauth JC, Goldenberg RL, Parker CR Jr, et al. Low-dose aspirin therapy to prevent preeclampsia. Am J Obstet Gynecol 1993;168:1083-1093.

(74.) CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. CLASP: A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet 1994;343:619-629.

(75.) Sibai BM, Caritis SN, Thorn E, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women: The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1993;329:1213-1218.

(76.) Belizan JM, Villar J, Gonzalez L, et al. Calcium supplementation to prevent hypertensive disorders of pregnancy. N Engl J Med 1991;325: 1399-1405.

(77.) Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2000;3:CD001059.

(78.) Ziaei S, Hantoshzadeh S, Rezasoltani P, et al. The effect of garlic tablet on plasma lipids and platelet aggregation in nulliparnus pregnants at high risk of preeclampsia. Eur J Obstet Gynecol Reprod Biol 2001;99: 201-206.

(79.) Laivuori H, Hovatta O, Viinikka L, et al. Dietary supplementation with primrose oil or fish oil does not change urinary excretion of prostacyclin and thromboxane metabolites in pre-eclamptic women. Prostaglandins Leukot Essent Fatty Acids 1993;49:691-694.

(80.) Ehrenberg A. Non-medical prevention of pre-eclampsia. Acta Obstet Gynecol Scand Suppl 1997;i64:108-110.

(81.) Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: A randomised trial. Lancet 1999;354:810-816.

(82.) Sibai BM, el-Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: Subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 1986;155:1011-1016.

(83.) Sibai BM, Mercer B, Sarinoglu C, Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis. Am J Obstet Gynecol 1991;165:1408-1412.

(84.) Sibai BM. Management and counseling of patients with preeclampsia remote from term. Clin Obstet Gynecol 1992;35:426-436.

(85.) Ihle BU, Long P, Oats J. Early onset pre-eclampsia: Recognition of underlying renal disease. Br Med J (Clin Res Ed) 1987;294:79-81.

(86.) Alsulyman OM, Castro MA, Zuckerman E, et al. Preeclampsia and liver infarction in early pregnancy associated with the antiphospholipid syndrome. Obstet Gynecol 1996;88:644-646.

From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Tulane University School of Medicine, New Orleans, LA.

We received no financial support and claim no proprietary interests.

Reprint requests to Gabriella Pridjian, MD, Department of Obstetrics and Gynecology, SL11, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112. Email: [e-mail]

Accepted June 9, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9609-0891