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Preeclampsia and Eclampsia

WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers.
Educational grant provided by Women's Health and Education Center (WHEC).

Hypertensive disease occurs in approximately 12-22% of pregnancies, and it is directly responsible for 17.6% of maternal deaths in the United States. However, there is confusion about the terminology and classification of these disorders. We hope to provide guidelines for the diagnosis and management of hypertensive disorders unique to pregnancy (preeclampsia and eclampsia), as well as the various associated complications.

The purpose this document is to provide guidelines for the diagnosis and management of hypertensive disorders unique to pregnancy -- preeclampsia and eclampsia. Various associated complications are also discussed. Expectant management should be considered for women remote from term who have mild preeclampsia. For the prevention and treatment of seizures in women with severe preeclampsia or eclampsia magnesium sulfate is the drug of choice. Practitioners should be aware that various laboratory tests may be useful in the management of women with preeclampsia. The differential diagnosis is also discussed. It is important that clinician make the accurate diagnosis when possible because the management and complications from these syndromes may be different.

Introduction:

The National High Blood Pressure Education Program Working Group has recommended that the term "gestational hypertension" replace the term "pregnancy-induced hypertension" to describe cases in which elevated blood pressure without proteinuria develops in a woman after 20 weeks of gestation and blood pressure levels return to normal in postpartum period(1). Hypertension during pregnancy is defined as a systolic blood pressure level of 140 mm Hg or higher or a diastolic blood pressure level of 90 mm Hg or higher that occurs after 40 weeks of gestation in a woman with previously normal blood pressure. As many as one quarter of women with gestational hypertension will develop proteinuria, ie, preeclampsia. Women who demonstrate an elevation of more than 30 mm Hg systolic or more than 15 mm Hg diastolic above baseline warrant close observation.

Preeclampsia: is a pregnancy-specific syndrome that usually occurs after 20 weeks of gestation. Criteria for diagnosis of preeclampsia are:

  • Blood pressure of 140 mm Hg systolic or higher or 90 mm Hg diastolic or higher that occurs after 20 weeks of gestation in a woman with previously normal blood pressure
  • Proteinuria, defined as urinary excretion of 0.3 g protein or higher in a 24-hour urine specimen
  • May be associated with other signs and symptoms, such as edema, visual disturbances, headache, and epigastric pain
  • Laboratory abnormalities may include hemolysis, elevated liver enzymes, and low platelet counts (HELLP syndrome)

Severe Preeclampsia: preeclampsia is considered severe if one or more of the following criteria is present:

  • Blood pressure of 160 mm Hg systolic or higher or 110 mm Hg diastolic or higher on two occasions at least 6 hours apart while the patient is on bed rest
  • Proteinuria of 5 g or higher in a 24-hour urine specimen or 3+ or greater on two random urine samples collected at least 4 hours apart
  • Oliguria of less than 500 ml in 24 hours
  • Cerebral or visual disturbances
  • Pulmonary edema or cyanosis
  • Epigastric or right upper-quadrant pain
  • Impaired liver function
  • Thrombocytopenia
  • Fetal growth restriction

Eclampsia: is defined as the presence of new-onset grand mal seizures in a woman with preeclampsia. Other causes of seizures in addition to eclampsia include a bleeding arteriovenous malformation, ruptured aneurysm, or idiopathic seizure disorder.

Superimposed Preeclampsia: the diagnostic criteria include in a woman with hypertension before 20 weeks of gestation, a sudden increase in proteinuria if already present in early gestation, a sudden increase in hypertension, or the development of HELLP syndrome. Women with chronic hypertension who develop headache, scotomata, or epigastric pain also may have superimposed preeclampsia.

Risk Factors:

The exact incidence of preeclampsia is unknown but it has been reported to be approximately 5-8%. Preeclampsia is primarily a disorder of first pregnancies. Other risk factors include multifetal gestations, preeclampsia in previous pregnancy, chronic hypertension, pregestational diabetes, vascular and connective tissue disease, nephropathy, antiphospholipid antibody syndrome, obesity, age 35 years or older, and African -American race. Women with thrombophilias may have a genetic predisposition to preeclampsia.

Pathophysiology:

The etiology of preeclampsia is unknown, although much of the literature has focused on the degree of trophoblastic invasion by the placenta. In cases of preeclampsia, invasion by the trophoblast appears to be incomplete. Moreover, the severity of hypertension may be related to the degree of trophoblastic invasion. Preeclampsia also may be associated with significant alterations in the immune response.

  1. Vascular Changes: hemoconcentration, in addition to hypertension, is a significant vascular change, because women with preeclampsia-eclampsia syndrome may not develop the normal hypervolemia of pregnancy. The vasospasm and subsequent hemoconcentration are associated with contraction of the intravascular space. Because of capillary leak and decreased colloid oncotic pressure often associated with vigorous fluid therapy, this may result in elevation of the pulmonary capillary wedge pressure and even pulmonary edema.
  2. Hematologic Changes: thrombocytopenia and hemolysis may occur as part of the HELLP syndrome, although etiology is unknown. The hematocrit level may be very low because of hemolysis or very high secondary to the hemoconcentration in the absence of hemolysis. Lactate dehydrogenase is present in erythrocytes in high concentration. A disproportionate elevation of levels of lactate dehydrogenase in serum may be a sign of hemolysis.
  3. Hepatic Changes: it may be significantly altered in women with severe preeclampsia. Alanine aminotransferase and aspartate aminotransferase may be elevated. Hyperbilirubinemia may occur, especially in the presence of hemolysis. Hepatic hemorrhage, which usually manifests as a subcapsular hematoma, also may occur, especially in women with preeclampsia and upper abdominal pain. Rarely, hepatic rupture, which is associated with a high mortality rate, occurs.
  4. HELLP Syndrome: women with preeclampsia and hepatic involvement may develop HELLP syndrome. Some studies show it may occur in approximately 20% of women with severe preeclampsia. It is associated with an increased risk of adverse outcomes, including placental abruption, renal failure, subcapsular hepatic hematoma, recurrent preeclampsia, preterm delivery, and even fetal or maternal death.
  5. Neurologic and Cerebral Manifestations: eclampsia remains a cause of maternal mortality, usually in association with intracranial hemorrhage. Although uncommon, temporary blindness also may accompany severe preeclampsia and eclampsia. Other nervous system manifestations include headache, blurred vision, scotomata, and hyperreflexia.
  6. Renal Changes: as a result of vasospasm, the normal expected increase on glomerular filtration rate and renal blood flow and the expected decrease in serum creatinine may not occur in women with preeclampsia, especially if the disease is severe. Oliguria is defined as less than 500 ml in 24 hours, also may occur secondary to the hemoconcentration and decreased renal blood flow. Rarely, persistent oliguria may reflect acute tubular necrosis, which may lead to acute renal failure.
  7. Fetal Changes: as a result of impaired uteroplacental blood flow or placental infarction, manifestations of preeclampsia also may be seen in the fetal placental unit. These include intrauterine growth restriction, oligohydramnios, placental abruption, and non-reassuring fetal status demonstrated on antepartum surveillance.

Differential Diagnosis of Severe Preeclampsia:

There are several obstetric, medical, and surgical disorders that share many of the clinical and laboratory findings of patients with severe preeclampsia-hemolysis, elevated liver enzymes, and low platelet syndrome. These conditions are associated with high maternal mortality, and survivors may face long-term sequelae. Differential diagnosis may be difficult due to the overlap of several clinical and laboratory findings of these syndromes.

  1. Acute Fatty Liver of Pregnancy (AFLP) - it is a rare but potentially fatal complication of the third trimester. The incidence of this disorder ranges from 1 in 10,000 to 1 in 15,000 deliveries. The clinical onset of symptoms ranges from 27 to 40 weeks, with an average of 36 weeks of gestation. In some cases, the first signs and symptoms may be in the postpartum period. The patient typically presents with a 1- to 2- week history of malaise, anorexia, nausea, vomiting, mid epigastric or right upper quadrant pain, headache, or jaundice. Symptoms of preterm labor or lack of fetal movement may be the presenting complaint in some of these patients. Physical examination reveals an ill-appearing patient with jaundice. Some patients have low grade fever. Coagulation findings are consistent with disseminated intravascular coagulopathy (DIC). The increase in bilirubin is mainly of the conjugated form, with levels usually exceeding 5 mg/dL. Ammonia levels are also increased, particularly in the late stage of the disease. Amylase and lipase values may be elevated in the presence of concomitant pancreatitis (4). Hepatitis profile for A, B, and C will be negative. Ultrasonography of the liver may reveal the presence of increased echogenicity in severe cases; however it is less sensitive than computed tomography and magnetic resonance imaging. Liver biopsy is the standard for confirming the diagnosis of acute fatty liver of pregnancy, but it is rarely used in clinical practice. In general, most patients with acute fatty liver of pregnancy will start to improve 2-3 days after delivery. In some cases, however, deterioration in liver function tests and coagulopathy may continue for about 1 week. In rare cases, a patient will progress into fulminant hepatic failure requiring liver transplantation.


  2. Thrombotic thrombocytopenic purpura (TTP) - the underlying pathologic disturbance involves systemic or intra-renal aggregation of platelets within the arterioles and capillaries in association with endothelial cell injury. Patients with TTP during pregnancy may have the congenital (familial) type or the acquired idiopathic type. Anemia and thrombocytopenia are frequently severe. The presenting symptoms may include abdominal pain, nausea, vomiting, gastrointestinal bleeding, epistaxis, petechiae, or purpura. Neurologic abnormalities are often difficult to diagnose and include headache, visual changes, confusion, aphasia, transient paresis, weakness, and seizures (5). Laboratory findings will reveal thrombocytopenia (platelet count less than 100,000/mm3, usually less than 20,000), marked elevation of serum levels of lactate dehydrogenase (LDH), and the presence of fragmented erythrocytes (schistocytes and helmet cells).


  3. Hemolytic uremic syndrome (HUS) - it is extremely rare during pregnancy, and almost all cases have been described in the postpartum period (within 48 hours to 10 weeks). The microvascular injury mainly affects the kidneys and results from glomerular and arteriolar fibrin thrombi. Patients presents with edema, hypertension, bleeding manifestations, or severe renal failure (6). Renal involvement is more severe than other microangiopathies. Acute renal failure is an important feature in the clinical course of the disease, and most patients with HUS in pregnancy-postpartum will be left with some form of residual renal deficit.


  4. Systemic lupus erythematosus (SLE) exacerbation - it is an autoimmune disorder that is characterized by deposits of antigen-antibody complexes in capillaries and various visceral structures. Most patients are female and of reproductive age (26-40 years old). The clinical findings may be mild or severe, affecting multiple organ systems, including the kidneys (nephritis), lungs (pleuritis or pneumonitis), liver, and brain. During the active phase of SLE exacerbation, laboratory findings will show pancytopenia, thrombocytopenia, hemolytic anemia, and an increase in anti-DNA antibodies (7). The exact diagnosis may be difficult, particularly in those with associated antiphospholipid antibodies (APA). These patients are at increased risk for thrombotic events.

Laboratory Findings Among Imitators of Preeclampsia - Eclampsia (8):

Laboratory Findings

HEELP Syndrome

     AFLP

      TTP

     HUS

Exacerbation of SLE

Thrombocytopenia (less than 100,000/mm3)

More than 20,000

More than 50,000

20,000 or less

More than 20,000

More than 20,000

Hemolysis (%)

50-100

15-20

100

100

14-23 with APA

Anemia (%)

Less than 50

Absent

100

100

14-23 with APA

DIC (%)

Less than 20

50-100

Rare

Rare

Rare

Hypoglycemia (%)

Absent

50-100

Absent

Absent

Absent

Von Willebrand factor multimers (%)

Absent

Absent

80-90

80

Less than 10

ADAMTS13 less than 5% (%)

Absent

Absent

33-100

Rare

Rare

Impaired renal function (%)

50

90-100

30

100

40-80

LDH (IU/L)

600 or more

Variable

More than
1,000

More than 1,000

With APA

Elevated ammonia (%)

Rare

50

Absent

Absent

Absent

Elevated bilirubin (%

50-60

100

100

Not available

Less than 10

Elevated transaminases (%)

100

100

Usually less than 100 IU/L

Usually less than 100IU/L

With APA

Making the right diagnosis is extremely important regarding decisions about need for delivery as well as treatment and complications. Finally, a rapid diagnosis and close consultation with an interdisciplinary team of physicians such as a maternal-fetal medicine specialist, nephrologist, hematologist, and critical care specialist, may result in optimal outcome for the mother and fetus.

Antenatal Surveillance for Preeclampsia:

No single screening test for preeclampsia has been found to be reliable and cost-effective. Uric acid is one of the most commonly used tests but it has a positive predictive value of only 33% and has not proved useful in predicting preeclampsia. Fetal and maternal evaluation is essential. The Working Group recommends weekly non-stress tests, biophysical profiles, or both, which should be repeated as indicated according to maternal condition. Testing is recommended twice weekly for suspected fetal growth restriction or oligohydramnios. Daily fetal movement assessment also may prove useful. Doppler velocimetry of the uterine arteries was reported not to be a useful test for screening pregnant women at low risk for eclampsia. It is useful in the cases where there is fetal growth restriction or oligohydramnios. (1)

Maternal Evaluation: consists of primarily of frequent evaluation for worsening preeclampsia. Initial laboratory tests consist of evaluation of platelet count, liver enzymes, and renal function and a 12 hour to 24 hour urine collection for protein. With mild disease and no progression, these tests can be repeated weekly. The tests should be repeated sooner if disease progression is questionable. The decision to deliver a patient with preeclampsia must balance both the maternal and fetal risk.

Severe Preeclampsia: the management of a woman with severe preeclampsia remote from term is best managed in tertiary care setting or in consultation with maternal-fetal medicine sub-specialist. Laboratory evaluation and fetal surveillance may be indicated on a daily basis depending on the severity and progression of the disorder. Considering the serious nature of HELLP syndrome, women with this complication should be delivered regardless of their gestational age.

Management:

The two main goals of management of women with preeclampsia during labor and delivery are prevention of seizures or eclampsia and control of hypertension. Although there is no unanimity of opinion regarding the prophylactic use of magnesium sulfate for the prevention of seizures in women with mild preeclampsia or gestational hypertension, a significant body of evidence attests to the efficacy of magnesium sulfate in women with severe preeclampsia and eclampsia. Hospitalization is often initially recommended for women with new-onset preeclampsia. After maternal and fetal conditions are serially assessed, subsequent management may be continued in the hospital, at a day-care unit, or at home on the basis of the initial assessment. If day care or home management is selected, it should include frequent maternal and fetal evaluation and access to health care providers. If worsening of preeclampsia is diagnosed, as determined by laboratory findings, symptoms, and clinical signs, hospitalization is indicated.
Antihypertensive Treatment of Preeclampsia: it is generally recommended for diastolic blood pressure levels of 105-110 mm Hg or higher. The commonly used medicines are:

  1. Hydralazine: 5-10 mg doses intravenously every 15-20 minutes until desired response is achieved.
  2. Labetalol: 20 mg intravenous bolus dose followed by 40 mg of not effective within 10 minutes; then, 80 mg every 10 minutes to maximum total dose of 220 mg. (1)

Optimal mode of delivery for women with preeclampsia:

  • For mild preeclampsia, vaginal delivery at term is preferred. The decision to perform cesarean delivery should be individualized.
  • Induction of labor for severe preeclampsia remote from term is reasonable and studies have shown it was not "harmful" to low-birth-weight infants. Fetal monitoring during labor is essential. Cesarean delivery is also considered a method of choice in many cases.

Management of Eclampsia: women with eclampsia require prompt intervention. When an eclamptic seizure occurs, the woman should be medically stabilized. First, it is important to control convulsions and prevent their recurrence with intravenous or intramuscular magnesium sulfate. One protocol is a 4 g to 6 g loading dose diluted in 100 ml fluid administered intravenously for 15-20 minutes, followed by 2 g per hour as a continuous intravenous infusion. Antihypertensive medications should be used for women with diastolic blood pressure levels of 105-110 mm Hg or higher. In most situations, clinical assessment of respiration, deep tendon reflexes, and urine output is adequate to monitor for maternal magnesium toxicity without the need to determine the actual maternal serum magnesium levels. If toxic serum levels or side effects are encountered, magnesium sulfate infusion must be discontinued, and calcium gluconate may be administered to reverse the side effects. (2)
The patient with eclampsia should be delivered in a timely fashion. Fetal bradycardia frequently occurs during an eclamptic seizure. Once the patient is stabilized, the method of delivery should depend, in part, on factors such as gestational age, fetal presentation, and the findings of the cervical examination.

Anesthesia during labor and delivery in women with preeclampsia: with improved techniques over the past two decades, regional anesthesia has become the preferred technique for women with severe preeclampsia and eclampsia-both for labor and delivery. Many studies have shown that epidural anesthesia is not associated with an increased rate of cesarean delivery, pulmonary edema, or renal failure. The regional anesthesia is generally contraindicated in the presence of a coagulopathy because of the potential for hemorrhagic complications. Moreover general anesthesia carries more risk to pregnant women than does regional anesthesia. (3)

Can preeclampsia be prevented?

Much of the obstetric research in the past several decades has been directed at finding ways to prevent preeclampsia and eclampsia. Recent studies have focused on low-dose aspirin, calcium supplementation, and antioxidant therapy. Most evidence suggests that low-dose aspirin therapy is of little, if any, benefit in preventing preeclampsia in low-risk women. There is controversy regarding the use of calcium supplementation to prevent preeclampsia. Many studies have shown no benefit.
Antioxidant therapy with 1,000 mg per day of vitamin C and 400 mg per day of vitamin E has shown promise in preventing preeclampsia. Many more studies are needed to confirm the results.

Critical directions for the future:

Classic complications of pregnancy include preeclampsia and eclampsia which affect 2.8% of pregnancies in developing countries and 0.4% in developed countries, leading to many life-threatening cases and over 63,000 maternal deaths worldwide every year. Antenatal care started out in the first half of the 20th century as a means to educate "ignorant" women with an emphasis on the welfare of the infant and child. Antenatal care has come a long way, but can go much further. Four directions are critical: to rationalize the rituals of care, to roll out antenatal care as a platform for a number of other key health programs, to establish communication with women more effectively, and to avoid the over-medication that can do more harm than good. Most importantly, the unfinished agenda of reaching all women who are pregnant should be tackled (9). The mainstays of the management of severe preeclampsia include, full assessment of the mother and the baby; and delivery on the best day in the best way. It has been observed that standardizing care is associated with reduced adverse health outcomes. Failure to standardize care has been associated with poorer outcomes.

The standardized surveillance guidelines are developed by the PIERS (Preeclampsia Integrated Estimate of RiSk) Study Group (10). It has been shown to reduce maternal and perinatal mortality and morbidity. In addition to routine measurement of maternal blood pressure, the investigations are included: 1) Hematology - full blood screen, international normalized ratio (INR), activated partial thromboplastin time (APTT), and fibrinogen; 2) Renal - urea, creatinine, electrolytes, uric acid, and dipstick. While other testing occur twice weekly, urine was also assessed by 24-hour urine for protein and creatinine clearance (on admission and once weekly thereafter); 3) Hepatic - aspartate transaminases (AST), alanine transaminases (ALT), lactate dehydrogenase (LDH), bilirubin, albumin (plasma), and random glucose; 4) Respiratory - pulse oximetry; 5) Fetal surveillance (antenatally only) - cardiotocography (CTG; daily), ultrasound for assessment of fetal weight (every 14 days), and amniotic fluid volume and umbilical artery Doppler (twice weekly).

Summary:

Women should be considered as having severe preeclampsia if they have blood pressure levels of 160 mm Hg systolic or higher or 110 mm Hg diastolic or higher on two occasions at least 6 hours apart while the patient is on bed rest, proteinuria of 5 g or higher in a 24 hour urine samples or 3+ or greater on two random urine samples collected at least 4 hours apart, oliguria of less than 500 ml in 24 hours, cerebral or visual disturbances, pulmonary edema or cyanosis, epigastric or right upper-quadrant pain, elevated liver enzymes, thrombocytopenia, or fetal growth restriction. Magnesium sulfate should be used for the prevention and treatment of seizures on women with severe preeclampsia or eclampsia. If analgesia/anesthesia is required, regional or neuraxial analgesia/anesthesia should be used because it is efficacious and safe for Intrapartum management of women with severe preeclampsia in the absence of coagulopathy. Practitioners should be aware that although various laboratory tests may be useful in the management of women with preeclampsia, to date there is no reliable predictive test for preeclampsia.

Suggested Reading:

  1. World Health Organization
    What is the efficacy/effectiveness of antenatal care and the financial and organizational implications? (pdf)
  2. National Institutes of Health
    High Blood Pressure in Pregnancy

References:

  1. Report of the National High Blood Pressure Education Program Working Group in High Blood Pressure in Pregnancy: Am J Obstet. Gynecol 2000; 183: S1-S22.
  2. Cunningham FG, Grant NF, Leveno KJ, Gilstrap LC III, Hauth JC, Wenstrom KD: Hypertensive disorders in pregnancy. In: Williams obstetrics. 21st ed. New York: McGraw-Hill, 2001: 567-618.
  3. Hogg B, Hauth JC, Caritis SN, Sibai BM, Lindheimer M, Van Dorsten JP, et al. Safety of labor epidural anesthesia for women with severe hypertensive disease. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet. Gynecol. 1999; 181: 1096-1101 (Level II-2).
  4. Vigil-De Garcia P, Lavergne JA. Acute fatty liver of pregnancy. Am J Gynaecol Obstet 2001;72:193-195.
  5. George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006;354:1927-1935.
  6. Allford SL, Hunt BJ, Rose P, Machin SJ. Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003;120:556-573.
  7. Tincani A, Bompane D, Danieli E, Doria A. Pregnancy, lupus and antiphospholipid syndrome (Hughes syndrome). Lupus 2006;15:156-160.
  8. Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 2007;109:956-966.
  9. World Health Organization. The World Health Report 2005: Make every mother and child count.
  10. Menzies J, Magee LA, Li J et al. Instituting surveillance guidelines and adverse outcomes in preeclampsia. Obstet Gynecol 2007;110:121-127.

Published: 6 August 2009

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