Preeclampsia (Toxemia of Pregnancy)

INTRODUCTION

Background: Preeclampsia is a disorder associated with pregnancy consisting of hypertension, proteinuria, and new-onset nondependent edema that presents, in most cases, after the 20th week of pregnancy. Eclampsia is defined as seizure activity in a patient with the presentation described above.

The hypertension component of the disease is present when the systolic blood pressure is above 140 (30 mm Hg above the prepartum levels), the diastolic blood pressure is above 90 (15 mm Hg above the prepartum level). The diagnosis requires 2 such abnormal blood pressure measurements at least 6 hours apart.

Proteinuria is present when the urinary protein concentration is greater than 300 mg during a 24-hour period or 2+ proteinuria or higher on a clean-catch urine specimen in a woman without a urinary tract infection.

Pathophysiology: The etiology of preeclampsia is unknown. However, placental delivery reverses the symptoms of preeclampsia, suggesting that the placenta has a controlling role in the condition. Additionally, women with increased placental tissue for gestational age, such as hydatiform moles and twin pregnancies, have an increased incidence of preeclampsia. In fact, the presence of proteinuric hypertension prior to 20 weeks gestation should initiate a search for molar pregnancy, because it raises the possibility of increased placental tissue for a given gestational age, which could cause the symptoms. Other causes include drug withdrawal or chromosomal abnormality in the fetus (eg, trisomy).

Several theories, which are not mutually exclusive, attempt to explain the pathophysiology of preeclampsia. One theory holds that an increase of a number of active circulating mediators during pregnancy causes the symptoms. For example, increased levels of angiotensin II during pregnancy may lead to increased vasospasm. A second theory holds that improper placental development results in placental vascular endothelial dysfunction and a relative uteroplacental insufficiency. The vascular endothelial dysfunction results in increased permeability, hypercoagulability, and diffuse vasospasm. Finally, another model suggests that the increased cardiac output seen during pregnancy causes preeclampsia. The increased blood flow and pressure is felt to lead to capillary dilatation, which damages end organ sites, leading to hypertension, proteinuria, and edema.

Additional theories have arisen from epidemiologic research, suggesting the important role of genetic and immunologic factors. The increased incidence seen in patients using barrier contraception, in multiparous women conceiving with a new partner, and in nulliparous women suggest an immunologic role. Also, inheritance pattern analysis supports the hypothesis of transmission of preeclampsia from mother to fetus by a recessive gene.

Newer research suggests primapaternity plays a larger role than primagravidity as a risk factor for the development of preeclampsia. Moreover, the duration of time the woman is exposed to the male antigens prior to conception is inversely related to the risk of developing preeclampsia.

The pathophysiology of eclamptic seizures is not understood. These events are believed to arise from the same preeclamptic effects seen in other areas of the body. In the brain, cerebral vasospasm, edema, ischemia, and ionic shifts between intracellular and extracellular compartments are believed to incite eclamptic seizures.

Nearly 10% of severely preeclamptic women and 30-50% of eclamptic women are affected by the hemolysis, elevated liver enzymes, and low platelet (count) (HELLP) syndrome. The exact relationship between the HELLP syndrome and preeclampsia is unknown. Preeclamptics with this syndrome develop hepatocellular necrosis and liver dysfunction. They also have an increased mortality and one third of women with preeclampsia develop disseminated intravascular coagulation (DIC).

Frequency:
　

• In the US: Preeclampsia occurs in 6-8% of all pregnancies. The incidence of eclampsia is 0.05%. Preeclampsia is associated with high perinatal morbidity and mortality, a result of iatrogenic prematurity.

Mortality/Morbidity: Preeclampsia is the second leading cause of maternal mortality, constituting 12-18% of pregnancy-related maternal deaths.

Race: African American women have up to twice the relative risk of whites of developing preeclampsia.

CLINICAL

History:

• Seizures, coma, headache, focal neurologic complaints, and visual disturbances in pregnant women all can be evidence of the development of preeclampsia or a suggestion of cerebral hemorrhage, edema, vasospasm, or thrombosis.

• Patients note decreased urine output and abdominal pain.

Physical:

• Asymptomatic hypertension is discovered on routine prenatal examination.

• Diffuse edema has a high specificity for preeclampsia.

• Neurologic findings such as papilledema and hyperreflexia must be addressed quickly, as they can herald the onset of eclampsia.

• Petechiae and bruising could suggest coagulopathy.

• Right upper quadrant or mid epigastric tenderness develops as a result of hepatocellular necrosis.

Causes: The exact cause of preeclampsia has not been elucidated. Current research utilizes the known risk factors to help shape theory about the exact etiology of preeclampsia.

• Four times relative risk - Daughter or sister of a woman who has had preeclampsia

• Three times the relative risk - Young maternal age

• Nulliparity (85% of preeclampsia cases occur in primigravidas)

• Twin pregnancies

• Up to twice the relative risk

• Multiparous women conceiving with a new partner

• Unmarried women

• African American women

• Additional risk factors

• Diabetes - Gestational diabetics have a 15% increased risk, pregestational diabetics have a 30% risk of preeclampsia

• Hypertension

• Renal disease

• Smokers have a decreased incidence of preeclampsia

WORKUP

Lab Studies:
　

• Urine analysis of a clean-catch specimen

• Proteinuria 2+ or higher is significant and warrants further evaluation to rule out preeclampsia.

• A 24-hour urine collection with more than 300 mg of protein requires further workup.

• Uric acid level: Glomerular filtration rate and creatinine clearance decrease 25% in preeclamptic patients, resulting in elevated uric acid levels.

• Transaminases and prothrombin time: Elevated transaminases result from hepatocellular necrosis, but prothrombin time remains normal, underscoring that hepatic function remains intact.

Imaging Studies:
　

• Ultrasound

• Confirmation of normal fetal development is important and standard prenatal care in all pregnancies.

• In women developing signs and symptoms of preeclampsia prior to 20 weeks gestation, ultrasound should be utilized to rule out a molar pregnancy.

TREATMENT

Medical Care: The only definitive treatment for preeclampsia is delivery of the fetus and placenta. This is a reasonable choice for viable fetuses or in cases in which the mother's health is put at significant risk. Examples of significant health risk include; eclampsia, pulmonary edema, compromised renal function, abruptio placentae, platelet count below 100,000, a ratio of serum alanine aminotransferase to serum aspartate aminotransferase (ALT/AST) twice normal, with concomitant epigastric and right upper quadrant tenderness, persistent severe headache or visual changes, and uncontrolled severe hypertension. In these cases, glucocorticoids can be administered to women with preterm pregnancies, with delivery postponed for 48 hours to allow the steroids to improve fetal lung maturity.

However, symptoms often can be managed in women with preterm pregnancies if symptoms are mild to moderate. Examples of this type of preeclampsia include proteinuria of any amount, oliguria (<0.5 mL/kg/hour) that resolves with fluid intake, ALT/AST higher than twice normal, no abdominal tenderness, and controlled hypertension. In patients with controlled hypertension, the treatment is to lower blood pressure.

Medical management focuses on antihypertensive treatment and anticonvulsant prophylaxis.

Surgical Care: Failure of medical management necessitates iatrogenic vaginal delivery. Maternal or fetal deterioration calls for emergent caesarian section.

MEDICATION

Drug therapy focuses on treatment of hypertension and prophylaxis against seizures.

Hydralazine is the antihypertensive of choice. Notably, ACE inhibitors are contraindicated in pregnancy, because of their harmful fetal effects.

Seizures remain a great concern for any patient with preeclampsia. Magnesium sulfate is the first-line therapy for seizures because it prevents vascular spasm. The prevention of vasospasm in the brain is believed to protect against seizures.
　

Drug Category: Antihypertensives -- Hydralazine is the drug of choice for blood pressure control in preeclampsia. However, parenteral hydralazine is only provided to pharmacists via a special emergency request. Therefore, one must be comfortable in utilizing other antihypertensive agents when hydralazine is not immediately available. Labetalol has alpha- and beta-adrenergic blocking effects and can be utilized to rapidly control severe hypertension.

Drug Category: Anticonvulsants

FOLLOW-UP

Further Outpatient Care:
　

• Preeclamptic patients who have delivered must continue to follow-up regularly with their Obstetrician, because eclamptic seizures have been reported as late as 26 days postpartum. Blood, urine, and blood pressures should be analyzed as described above. This can help identify worsening preeclampsia. Postpartum patients without a history of preeclampsia rarely develop the disease.

Complications:
　

• An unusual complication of preeclampsia and eclampsia is maternal cardiopulmonary arrest. Causes include elevated magnesium levels, hypoxia, massive hemorrhage, and stroke. Cardiopulmonary resuscitation is necessary, but the presence of the fetus impedes its efficacy. The outcome of the mother and the fetus is improved by emergent caesarian section. Infant morbidity and mortality are inversely related to the time from maternal cardiopulmonary arrest to delivery of the fetus.

MISCELLANEOUS

Medical/Legal Pitfalls:
　

• Failure to diagnose preeclampsia

• Failure to treat preeclampsia

• Failure to treat the sequelae of preeclampsia

• Failure to prevent eclampsia

• Physicians may be sued for inducing a premature fetus when it can be argued that the preeclampsia could have been medically managed. Alternately, inaction during worsening preeclampsia resulting in fetal or maternal morbidity can also result in litigation.