Pregnancy, Preeclampsia

Background

Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm that occurs after 20 weeks' gestation and can present as late as 4-6 weeks postpartum. It is clinically defined by hypertension and proteinuria, with or without pathologic edema.

Preeclampsia is part of a spectrum of hypertensive disorders that complicate pregnancy. These include chronic hypertension, preeclampsia superimposed on chronic hypertension, gestational hypertension, preeclampsia, and eclampsia. Although each of these disorders can appear in isolation, they are thought of as progressive manifestations of a single process and are believed to share a common etiology.

The diagnostic criteria for preeclampsia focus on measurement of elevated blood pressure and proteinuria that develop after 20 weeks' gestation. This must be differentiated from gestational hypertension, which is more common and may present with symptoms similar to preeclampsia, including epigastric discomfort or thrombocytopenia, but is not characterized by proteinuria. Additionally, patients with preexisting chronic hypertension may present with superimposed preeclampsia presenting as new-onset proteinuria after 20 weeks' gestation.

Consensus is lacking among the various national and international organizations about the values that define the disorder, but a reasonable limit in a woman who was normotensive prior to 20 weeks' gestation is a systolic blood pressure (BP) greater than 140 mm Hg and a diastolic BP greater than 90 mm Hg on 2 successive measurements 4-6 hours apart. Preeclampsia in a patient with preexisting essential hypertension is diagnosed if systolic BP has increased by 30 mm Hg or if diastolic BP has increased by 15 mm Hg.

Proteinuria is defined as 300 mg or more of protein in a 24-hour urine sample. In the emergency department, a urine protein-to-creatinine ratio of 0.19 or greater is somewhat predictive of significant proteinuria (negative predictive value [NPV], 87%).^[1] Serial confirmations 6 hours apart increase the predictive value. Although more convenient, a urine dipstick value of 1+ or more (30 mg/dL) is not reliable.

For the purposes of guiding management, a distinction can be made between mild preeclampsia and severe preeclampsia.

Diagnostic criteria for severe preeclampsia include at least one of the following:

• Systolic BP greater than 160 mm Hg or diastolic BP greater than 110 mm Hg on 2 occasions 6 hours apart with the patient at bed rest
• Proteinuria greater than 5000 mg in a 24-hour collection or more than 3+ on 2 random urine samples collected at least 4 hours apart
• Oliguria with less than 500 mL per 24 hours
• Persistent maternal headache or visual disturbance
• Pulmonary edema or cyanosis
• Concerning abdominal pain
• Impaired liver function test findings
• Thrombocytopenia
• Oligohydramnios, decreased fetal growth, or placental abruption

Eclampsia is defined as seizures in a patient with preeclampsia.

For more information, see Medscape's Pregnancy Resource Center

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Pathophysiology

The mechanism by which preeclampsia occurs is not certain, and a number of maternal, paternal, and fetal factors have been implicated in its development. The factors currently considered to be the most important include abnormal placental implantation; maternal immunological intolerance; cardiovascular and inflammatory changes; and genetic, nutritional, and environmental factors.^[2]

Placental implantation with abnormal trophoblastic invasion of uterine vessels is a major cause of hypertension associated with the preeclampsia syndrome.^[3] Normally, uterine invasion by endovascular trophoblasts cause extensive remodeling of uterine spiral arteries, resulting in enlarged vessel diameter. In preeclampsia, there is only shallow invasion, and the deeper uterine arterioles do not widen appropriately. Studies have shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly correlated with the severity of subsequent maternal hypertension. Subsequently, the resulting placental hypoperfusion leads by an unclear pathway to the release of systemic vasoactive compounds that cause an exaggerated inflammatory response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and platelet dysfunction, all of which contribute to organ dysfunction and the various clinical features of the disease.

Immunological factors have long been considered to be key players in preeclampsia. One important component is a poorly understood dysregulation of maternal tolerance to paternally derived placental and fetal antigens.^[4] This maternal-fetal immune maladaptation is characterized by defective cooperation between uterine natural killer (NK) cells and fetal HLA-C, and results in histological changes similar to those seen in acute graft rejection. The endothelial cell dysfunction that is characteristic of preeclampsia may be partially due to an extreme activation of leukocytes in the maternal circulation, as evidenced by an upregulation of type 1 helper T cells.

Genetics have long been understood to play an important role, and preeclampsia has been shown to involve multiple genes. Importantly, the risk of preeclampsia is positively correlated between close relatives; a recent study showed that 20-40% of daughters and 11-37% of sisters of preeclamptic women also develop preeclampsia.^[4] Twin studies have also shown a high correlation, approaching 40%. Over a hundred maternal and paternal genes have been studied for their association with the syndrome, including those known to play a role in vascular diseases, blood pressure regulation, diabetes, and immunological functions. Because preeclampsia is genetically and phenotypically a complex disease, it is unlikely that any one gene will be shown to play a dominant role in its development.

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Epidemiology

Frequency

United States

Preeclampsia occurs in approximately 5-7% of all pregnancies. The incidence of preeclampsia is 23.6 cases per 1,000 deliveries in the United States. The incidence of eclampsia is estimated to be 1 in 2000 deliveries.

International

The global incidence of preeclampsia has been estimated at 5-14% of all pregnancies. In developing countries, hypertensive disorders were the second most common obstetrical cause of stillbirths and early neonatal deaths, accounting for 23.6%.^[5]

Mortality/Morbidity

Preeclampsia is the third leading pregnancy-related cause of death, after hemorrhage and embolism. Preeclampsia is the cause in an estimated 790 maternal deaths per 100,000 live births.

Morbidity and mortality is related to systemic endothelial dysfunction; vasospasm and small-vessel thrombosis leading to tissue and organ ischemia; CNS events such as seizures, strokes, and hemorrhage; acute tubular necrosis; coagulopathies; and placental abruption in the mother.

Hemolysis, elevated liver enzyme levels, and low platelets (HELLP) syndrome may be an outcome of severe preeclampsia, although some authors believe it to have an unrelated etiology.

In the fetus, ischemic encephalopathy, growth retardation, and the various sequelae of premature birth can occur.

Race

The frequency of mortality differs among race and ethnicity, with African Americans having a worse mortality rate than white women.

Age

Preeclampsia occurs more frequently in women at the extremes of reproductive age.

• Younger women (< 20 y) have a slightly increased risk. Primigravid patients in particular seem to be predisposed.
• Older women (>35 y) have a markedly increased risk.

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History

Mild-to-moderate preeclampsia may be asymptomatic. Many cases are detected through routine prenatal screening. Patients with severe preeclampsia display end-organ effects and may complain of the following:

• CNS

  • Headache
  • Visual disturbances - Blurred, scintillating scotomata
  • Altered mental status
  • Blindness - May be cortical^[6] or retinal

   

  

   
• Dyspnea
• Edema: This exists in many pregnant women but sudden increase in edema or facial edema is more concerning for preeclampsia. The edema of preeclampsia occurs by a distinct mechanism that is similar to that of angioneurotic edema.
• Epigastric or right upper quadrant (RUQ) abdominal pain: Hepatic involvement occurs in 10% of women with severe preeclampsia. This pain is frequently accompanied by elevated serum hepatic transaminase levels.
• Weakness or malaise: This may be evidence of hemolytic anemia.

Preeclampsia in a prior pregnancy is strongly associated with recurrence in subsequent pregnancies. A history of gestational hypertension or preeclampsia should strongly raise clinical suspicion. Uncommonly, patients can have antepartum preeclampsia treated with delivery that then recurs in the postpartum period.^[7] Although this is highly unusual, recurrent preeclampsia does occur and should be considered in postpartum patients who present with hypertension and proteinuria.

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Physical

Findings on physical examination may include the following:

• Increased BP compared with the patient's baseline or greater than 140/90 mm Hg
• Altered mental status
• Decreased vision or scotomas
• Papilledema
• Epigastric or RUQ abdominal tenderness
• Peripheral edema: Edema can be normal in pregnancy, and a gradual increase in dependent edema is not necessarily ominous. However, a sudden increase in edema or swelling of the face is more suggestive of preeclampsia and should be promptly investigated.
• Hyperreflexia or clonus: Although deep tendon reflexes are more useful in assessing magnesium toxicity, the presence of clonus may indicate an increased risk of convulsions.
• Seizures
• Focal neurologic deficit

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Causes

• Pregnancy-associated risk factors

  • Chromosomal abnormalities
  • Hydatidiform mole
  • Multifetal pregnancy: Incidence is increased in twin gestations but is unaffected by their zygosity.
  • Oocyte donation or donor insemination
  • Urinary tract infection

   

  

   
• Maternal-specific risk factors

  • Extremes of age
  • Black race: In the United States, the incidence of preeclampsia is 1.8% among white women and 3% in African Americans.
  • Family history of preeclampsia
  • Nulliparity
  • Preeclampsia in a previous pregnancy
  • Diabetes
  • Obesity: Body weight is strongly correlated with progressively increased risk, ranging from 4.3% for women with a BMI < 20 kg/m to 13.3% in those with a BMI >35 kg/m. A United Kingdom study on obesity showed that 9% of extremely obese women were preeclamptic compared with 2% of matched controls.^[8]
  • Chronic hypertension
  • Renal disease
  • Collagen vascular disease
  • Antiphospholipid syndrome
  • Periodontal disease^[9]
  • Vitamin D deficiency: One literature review suggests that maternal vitamin D deficiency may increase the risk of preeclampsia and fetal grown restriction.

   

  

   

Recent studies have suggested that smoking during pregnancy is associated with a reduced risk of gestational hypertension and preeclampsia; however, this is controversial.^[10] Placenta previa has also been correlated with a reduced risk of preeclampsia.

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Laboratory Studies

• CBC count and peripheral smear

  • Microangiopathic hemolytic anemia (HELLP)
  • Thrombocytopenia < 100,000
  • Hemoconcentration may occur in severe preeclampsia.
  • Schistocytes on peripheral smear

   

  

   
• Liver function tests: Transaminase levels are elevated from hepatocellular injury and in HELLP syndrome.
• Serum creatinine level: Levels are elevated due to decreased intravascular volume and decreased glomerular filtration rate (GFR).
• Urinalysis

  • Proteinuria is one of the diagnostic criteria for preeclampsia.
  • Significant proteinuria defining preeclampsia is 300 mg or more of protein in a 24-hour urine sample.
  • Proteinuria suggestive of preeclampsia is greater than or equal to 1+ protein on urine dipstick or 300 mg/L or more on urine dipstick.
  • Microalbuminuria and urine albumin: Creatinine ratios have been shown to have poor clinical predictive values and should not be used.

   

  

   
• Abnormal coagulation profile: PT and aPTT are elevated.
• Disseminated intravascular coagulopathy testing will show fibrin split products and decreased fibrinogen levels.
• Uric acid

  • Hyperuricemia is one of the earliest laboratory manifestations of preeclampsia. It has a low sensitivity, ranging from 0-55%, but a relatively high specificity, ranging from 77-95%.^[11]
  • Serial levels may be useful to indicate disease progression.

   

  

   

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Imaging Studies

• Head CT: This study is used to detect intracranial hemorrhage in selected patients with sudden severe headaches, focal neurologic deficits, or seizures with a prolonged post-ictal state.
• Ultrasonography: This is used to assess the status of the fetus as well as to evaluate for growth restriction (typically asymmetrical — use abdominal circumference). Aside from transabdominal ultrasonography, umbilical artery Doppler ultrasonography should be performed to assess blood flow. The value of Doppler ultrasonography in other fetal vessels has not been demonstrated.
• Cardiotocography: This is the standard fetal nonstress test and the mainstay of fetal monitoring. Although it gives continuing information about fetal well being, it has little predictive value.

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Other Tests

A study at Yale University has shown preliminary results that Congo Red, a dye currently used to locate atypical amyloid aggregates in Alzheimer's disease, may also be effective in the early diagnosis of preeclampsia.^[12] This finding may lead to a spot urine test that can be used in emergency departments and internationally, especially in resource-poor countries where preeclampsia continues to be underdiagnosed and accounts for a large percentage of maternal and fetal mortality.

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Prehospital Care

Prehospital care for pregnant patients with suspected preeclampsia includes the following:

• Oxygen via facemask
• Intravenous access
• Cardiac monitoring
• Transportation of patient in left lateral decubitus position
• Seizure precautions

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Emergency Department Care

In the emergency setting, control of BP and seizures should be priorities. Definitive therapy is delivery of the fetus,^[13] although preeclampsia may paradoxically emerge in postpartum patients. In general, the further the pregnancy is from term, the greater the impetus to manage the patient medically.

BP control

• The goal is to lower BP to prevent cerebrovascular and cardiac complications while maintaining uteroplacental blood flow.
• Control of mildly increased BP does not appear to improve perinatal morbidity or mortality, and, in fact, it may reduce birth weight.
• Antihypertensive treatment is indicated for diastolic blood pressure above 105 mm Hg and systolic pressure above 160 mm Hg, though patients with chronic hypertension may tolerate higher values.
• Patients with severe preeclampsia who have BP below 160/105 mm Hg may benefit from antihypertensives because of the possibility of unpredictable acceleration of the disease and sudden increases in hypertension.
• The goal is to maintain diastolic blood pressure between 90 and 100 mm Hg and systolic pressure between 140 and 155 mm Hg.
• First-line medications are labetalol, given orally or IV; nifedipine, given orally or IV; or hydralazine IV. Doses are as noted below.
• Atenolol, ACE inhibitors, ARBs, and diuretics should be avoided.

Control of seizures

• The basic principles of airway, breathing, circulation (the ABCs) should always be followed as a general principle of seizure management.
• Active seizures should be treated with intravenous magnesium sulfate as a first-line agent.^{[14, 15]} A loading dose of 4 g should be given by an infusion pump over 5-10 minutes, followed by an infusion of 1 g/h maintained for 24 hours after the last seizure. Recurrent seizures should be treated with an additional bolus of 2 g or an increase in the infusion rate to 1.5 g or 2 g per hour.
• Prophylactic treatment with magnesium sulfate is indicated for all patients with severe preeclampsia.^[14] No consensus exists about whether patients with mild preeclampsia (elevated blood pressure without evidence of end-organ damage) need to be on magnesium seizure prophylaxis.
• Magnesium levels, respiratory rate, reflexes, and urine output must be monitored to detect magnesium toxicity. Magnesium sulfate is mostly excreted in the urine, and therefore urine output needs to be closely monitored. If urine output falls below 20 mL/h, the magnesium infusion should be stopped. Magnesium toxicity can be easily assessed by clinical examination; the first sign of toxicity is often a loss of deep tendon reflexes, followed by respiratory depression. If signs of toxicity are present, the magnesium sulfate infusion should be stopped. Calcium gluconate 1 g (10 mL) can be given over 10 minutes to reverse the effects.^{[11, 16]}
• Be aware of the risk of seizures following delivery — up to 44% of eclampsia cases have been reported to occur postnatally. This risk is especially elevated 48 hours postpartum, but it can occur at any time up to 4 weeks after delivery.^[11]
• For seizure refractory to magnesium sulfate therapy, benzodiazepines and/or phenytoin may be considered.

Fluid management^[17]

• Little clinical evidence exists in the published literature on which to base decisions regarding the management of fluids during preeclampsia. Currently, no prospective studies are available, and guidelines are largely based on consensus and retrospective review.
• Despite the peripheral edema, patients with preeclampsia are intravascularly volume depleted with high peripheral vascular resistance. Diuretics should be avoided.
• Aggressive volume resuscitation may lead to pulmonary edema, which is a common cause of maternal morbidity and mortality. Pulmonary edema occurs most frequently 48-72 hours postpartum, probably due to mobilization of extravascular fluid. Because volume expansion has no demonstrated benefit, patients should be fluid restricted when possible, at least until the period of postpartum diuresis.
• Volume expansion has not been shown to reduce the incidence of fetal distress and should be used judiciously, as discussed.
• Central venous or pulmonary artery pressure monitoring may be indicated in critical cases. A central venous pressure (CVP) of 5 mm Hg in women with no heart disease indicates sufficient intravascular volume, and maintenance fluids alone are sufficient. Total fluids should generally be limited to 80 mL/h or 1 mL/kg/h.
• Careful measurement of fluid input and output is advisable, particularly in the immediate postpartum period. Many patients will have a brief (up to 6 h) period of oliguria following delivery; this should be anticipated and not overcorrected.

Delivery

• Delivery is the definitive treatment for antepartum preeclampsia. Obstetrical consultation should be sought early to coordinate transfer to an obstetrical floor, as appropriate.
• Patients with mild preeclampsia are often induced after 37 weeks' gestation. Prior to this, the immature fetus is treated with expectant management with corticosteroids to accelerate lung maturity in preparation for early delivery.
• In patients with severe preeclampsia, induction of delivery should be considered after 34 weeks' gestation. In these cases, the severity of disease must be weighed against the risks of prematurity.
• Eclampsia is common after delivery and has occurred up to 6 weeks after delivery. Patients at risk for eclampsia should be carefully monitored postpartum.^[18] Additionally, patients with preeclampsia successfully treated with delivery may present with recurrent preeclampsia up to 4 weeks postpartum.

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Consultations

Immediate obstetric consultation is warranted for all patients who present with preeclampsia.

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Medication Summary

Magnesium sulfate is the first-line treatment of prevention of primary and recurrent eclamptic seizures. For eclamptic seizures refractory to magnesium sulfate, lorazepam and phenytoin may be used as second-line agents.

In the setting of severe hypertension (systolic BP, >160 mm Hg; diastolic BP, >110 mm Hg), antihypertensive treatment is recommended. Antihypertensive treatment decreases the incidence of cerebrovascular problems but does not alter the progression of preeclampsia.

Traditionally, hydralazine has been used for control of severe hypertension in women with preeclampsia. However, the evidence regarding the side effects and maternal/fetal outcomes when compared with labetalol and nifedipine is conflicting.

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Class Summary

Agents that inhibit smooth muscle contractions are used.

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Magnesium sulfate

• Dosing, Interactions, etc.

Clinical Context:  First-line therapy for seizure prophylaxis. Antagonizes calcium channels of smooth muscle. Indicated in severe preeclampsia, eclampsia, and preeclampsia in the near term. Administer IV/IM for seizure prophylaxis in preeclampsia. Use IV for quicker onset of action in true eclampsia.

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Lorazepam (Ativan)

• Dosing, Interactions, etc.

Clinical Context:  Sedative hypnotic with short onset of effects and relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Important to monitor patient's blood pressure after administering dose. Adjust as necessary.

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Phenytoin (Dilantin)

• Dosing, Interactions, etc.

Clinical Context:  Phenytoin has been used successfully in eclamptic seizures, but cardiac monitoring is required secondary to associated bradycardia and hypotension.

Central anticonvulsant effect of phenytoin is by stabilizing neuronal activity by decreasing the ion flux across depolarizing membranes.

Some benefits to using phenytoin are that it can be continued orally for several days until the risk of eclamptic seizures has subsided, it has established therapeutic levels that are easily tested, and no known neonatal adverse effects are associated with short-term usage.

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Class Summary

These agents are used to decrease systemic resistance and to help reverse uteroplacental insufficiency.

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Hydralazine (Apresoline)

• Dosing, Interactions, etc.

Clinical Context:  First-line therapy against preeclamptic hypertension. Decreases systemic resistance through direct vasodilation of arterioles, resulting in reflex tachycardia. Reflex tachycardia and resultant increased cardiac output helps reverse uteroplacental insufficiency, a key concern when treating hypertension in a patient with preeclampsia. Adverse effects to the fetus are uncommon.

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Labetalol (Normodyne)

• Dosing, Interactions, etc.

Clinical Context:  Second-line therapy that produces vasodilatation and decreases in systemic vascular resistance. Has alpha-1 and beta-antagonist effects and beta2-agonist effects. Has more rapid onset than hydralazine and less overshoot hypotension. Dosage and duration of labetalol is more variable. Adverse effects to fetus are uncommon.

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Nifedipine (Procardia)

• Dosing, Interactions, etc.

Clinical Context:  Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Sublingual administration is generally safe, despite theoretical concerns.

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Further Inpatient Care

Hospitalization is indicated for all women with severe preeclampsia. The goals of hospitalization include the following:

• Daily weigh-ins
• Blood pressure readings every 4 hours
• Prophylactic anticonvulsive therapy
• Corticosteroids to enhance fetal lung maturity

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Further Outpatient Care

Outpatient management of preeclampsia has a limited role. The decision to treat on an outpatient basis must be made in consultation with an obstetrician. Detailed instructions on signs and symptoms of progression of disease, including headache, visual changes, abdominal pain, vaginal bleeding, or decreased fetal movement, as well as strict bed rest is recommended.

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Transfer

Patients with severe preeclampsia must be stabilized in the ED as much as possible prior to transfer to a tertiary care facility.

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Complications

Complications of preeclampsia may include the following:

• Abruptio placentae with disseminated intravascular coagulopathy
• Renal insufficiency or failure
• Hemolysis, elevated liver enzyme levels, and low platelet count (or HELLP syndrome)
• Eclampsia
• Cerebral hemorrhage
• Maternal death and/or fetal demise

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Prognosis

• Early detection and frequent obstetric assessment markedly improves prognosis.
• A history of preeclampsia increases a woman's subsequent risk of vascular disease, including hypertension, thrombosis, ischemic heart disease, myocardial infarction, and stroke.^[19]

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