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Apr.14.2022

Preeclampsia and Eclampsia

Synopsis

Key Points

  • Preeclampsia is a pregnancy-specific condition defined by new-onset hypertension (greater than 140 mm Hg systolic or 90 mm Hg diastolic) that occurs after 20 weeks of gestation or postpartum, accompanied by either proteinuria (greater than 300 mg/24 hours) or other maternal organ dysfunction r1
  • Preeclampsia can progress to the obstetric emergency of eclampsia, which refers to the onset of seizures in patients with preeclampsia
  • Diagnosis of preeclampsia requires evidence of hypertension (greater than 140 mm Hg systolic or 90 mm Hg diastolic) on at least 2 occasions 4 hours apart and either proteinuria (24-hour urine protein level greater than 300 mg) or the presence of maternal organ dysfunction that can be shown with results of blood, renal, and liver function tests r2
  • Management of preeclampsia depends on disease severity and gestational age and may include: r3
    • Frequent observation and fluid management for preeclampsia
    • Administration of antihypertensive drugs in cases of severe preeclampsia to control high blood pressure and administration of corticosteroids to improve fetal growth
  • Management of eclampsia involves immediate delivery after maternal stabilization regardless of gestational age or full benefit from steroids r2
  • Several severe obstetric complications can occur as a result of preeclampsia, including abruptio placentae, acute renal failure, liver dysfunction, pulmonary edema, disseminated intravascular coagulation syndrome, stroke, cardiomyopathy, and heart failure
  • Developing countries have high death rates associated with preeclampsia/eclampsia, whereas maternal mortality associated with preeclampsia/eclampsia is declining in developed countries

Urgent Action

  • Hypertensive emergency
    • Acute-onset, severe systolic (160 mm Hg or greater) and/or diastolic (110 mm Hg or greater) hypertension during pregnancy or during the postpartum period lasting more than 15 minutes is an obstetric emergency r4
      • Goal of emergent therapy is to achieve a blood pressure range of 140 to 150 mm Hg systolic/90 to 100 mm Hg diastolic (not lower, to avoid hypoperfusion of fetusr5)
      • To reduce risk of stroke, treat with first line agent as soon as identified
    • Treatment
      • Give 20 mg IV labetalol or 5 mg IV hydralazine (first line drugs) r4
      • If blood pressure remains elevated after 10 or 20 minutes, double the dosage r6
      • Give up to a total of 4 doses; if blood pressure remains above 160/110 mm Hg, consult specialists in maternal fetal medicine, anesthesia, or critical care r6
      • Magnesium sulfate is the drug of choice for seizure prophylaxis in severe preeclampsia and seizures in eclampsia r2
      • Consider intubation in patients whose condition does not respond to therapy
  • Eclamptic seizure
    • Treatment r7
      • Position the patient in a lateral decubitus position to minimize aspiration
      • Give IV magnesium sulfate loading dose (4-6 g) followed by continuous infusion (1-2 g/hour)

Pitfalls

  • Individual symptoms of preeclampsia have limited predictive value for adverse maternal outcomes, so conduct routine blood pressure monitoring regularly in patients with preeclampsia r1
  • In a pregnant patient with chronic hypertension, do not diagnose preeclampsia with a rise in blood pressure alone. When there is underlying essential hypertension, diagnose preeclampsia by the presence of proteinuria or by documenting the presence of end-organ dysfunction
  • Do not give immediate-release oral nifedipine sublingually (risk of hypotension)

Terminology

Clinical Clarification

  • Preeclampsia is a pregnancy-specific condition defined by new-onset hypertension (greater than 140 mm Hg systolic or 90 mm Hg diastolic) that occurs after 20 weeks of gestationr1 or postpartum, accompanied by either proteinuria (greater than 300 mg/24 hours) or other maternal organ dysfunction r2
  • Can occur superimposed on chronic or preexisting hypertension (ie, discovered preconception or before 20 weeks of gestation) r5r8
    • In these patients, superimposed preeclampsia is identified by new-onset proteinuria or end-organ dysfunction (usually in conjunction with worsening blood pressure) in the second half of pregnancy
  • Eclampsia is an obstetric emergency defined by onset of seizures, unexplained coma, or both in patients with preeclampsia before, during, or after labor

Classification

  • Gestational hypertension r9
    • Systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg (or both) documented on 2 separate readings that are at least 4 hours apart, with no proteinuria or features of severe preeclampsia r2
    • Up to one-half of patients with gestational hypertension will go on to develop proteinuria or organ dysfunction characteristic of preeclampsia; increased likelihood when hypertension is diagnosed before 32 weeks of gestation r2
  • Preeclampsia r2
    • Systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg documented on 2 separate readings that are at least 4 hours apart; classified as severe hypertension if blood pressure is 160/110 mm Hg or higher (in this case can diagnose based on 2 consecutive blood pressure measures within a short interval to initiate prompt treatment)
      • and
    • Proteinuria greater than 300 mg/24-hour urine collection, protein to creatinine ratio of at least 0.3, or dipstick result of 2+ (if quantitative methods unavailable)
      • or
    • In the absence of proteinuria, the presence of new-onset maternal organ dysfunction
      • Thrombocytopenia (platelet count below 100 × 10⁹ cells/L)
      • Renal insufficiency (serum creatinine level greater than 1.1 mg/dL or doubling of original value)
      • Hepatic dysfunction (elevated liver enzyme levels twice the upper reference range)
      • Pulmonary edema
      • New-onset headache or visual symptoms
  • Preeclampsia with severe features
    • Defined by presence of any of the following features: r2r9
      • Systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 110 mm Hg or higher (considered a medical emergencyr5) on 2 separate readings that are 4 hours apart or longer
      • Thrombocytopenia (platelet count below 100 × 10⁹ cells/L)
      • Renal insufficiency (serum creatinine level greater than 1.1 mg/dL, or doubling of original value)
      • Hepatic dysfunction (elevated liver enzymes twice the upper reference limit, or severe right upper quadrant or epigastric pain)
      • Pulmonary edema
      • New-onset headache or visual symptoms
  • HELLP syndrome r9d1
    • Rare, potentially life-threatening obstetric condition that is a combination of hemolysis, elevated liver enzyme levels, and thrombocytopenia
    • May represent a severe variant of preeclampsia, but the exact relationship between preeclampsia and HELLP is not fully understood
    • Up to 15% of patients do not have hypertension or proteinuria
  • Eclampsia r2
    • New-onset tonic-clonic, focal, or multifocal seizures (in absence of alternative cause) in association with hypertension in pregnancy
    • May be preceded by preeclampsia or occur abruptly without prior signs and symptoms

Diagnosis

Clinical Presentation

History

  • Medical history
    • Patients may have a history of hypertension and/or preeclampsia during previous pregnancies c1c2c3c4c5
    • Patients may have coexisting medical conditions that increase risk (eg, diabetes mellitus, lupus, antiphospholipid antibody syndrome)
  • Severity of symptoms ranges from mild to severe c6c7c8
    • Some patients may be asymptomatic at the time they are found to have hypertension and proteinuria, whereas others may present with symptoms of severe preeclampsia r10c9c10
    • Up to 25% of patients who develop eclampsia are asymptomatic before onset of seizures r11
  • Timing of symptoms r10c11c12c13c14c15
    • Onset is gradual in some cases, whereas others proceed to life-threatening complications within hours
    • Preeclampsia and eclampsia may develop before, during, or after delivery
    • Approximately 40% of eclamptic seizures occur before delivery and approximately 16% occur more than 48 hours after delivery
  • Evolving symptoms that develop as preeclampsia progresses include: r12
    • Epigastric pain accompanied by nausea and vomiting (reflects significant liver damage) c16c17
    • Fatigue and malaise c18c19
    • Severe headache with pounding or throbbing quality c20c21
    • Visual disturbances (eg, blurred vision, photophobia, diplopia) c22c23c24
      • May be related to hypertension or cerebral or retinal edema
    • Sudden-onset edema, pronounced in the face c25
    • Chest pain, cough, and dyspnea (with pulmonary edema) c26c27c28
    • Prolonged oliguria (urine output less than 500 mL/24 hours) c29
      • Suggests renal injury outside of pregnancy
  • Symptoms that occur before an eclamptic episode include: r1
    • Persistent headache c30
    • Blurred vision c31
    • Right upper quadrant abdominal pain c32
    • Photophobia c33
    • Altered mental status c34

Physical examination

  • Prenatal blood pressure measurements r10
    • Elevations range from mild to severe (equal to or greater than 160 mm Hg/90 mm Hg) c35
  • Rapid weight gain and facial edema due to fluid retention r10c36c37
    • Signs are not unique to preeclampsia/eclampsia, but presence prompts assessment for proteinuria and hypertension
  • Measured fundal height may be low for gestational age owing to intrauterine growth retardation r10c38
    • Typically occurs before diagnostic criteria of preeclampsia are met
  • Tachypnea and crackles/rales if pulmonary edema develops r13c39c40
  • Eclamptic seizures are noted by tonic-clonic seizures lasting for approximately 1 minute, followed by postictal coma of short duration r14c41c42

Causes and Risk Factors

Causes

  • Exact cause of preeclampsia/eclampsia is unknown, but its pathophysiology is linked to immunologic and angiogenic abnormalities in the placenta r2
    • Abnormal trophoblast invasion of decidual spiral arteries and myometrium r15c43c44
    • Diminished uteroplacental circulation, leading to ischemia and oxidative stress in the placenta r15c45c46
    • Poor development of the fetoplacental vasculature r15c47
    • Secretion of angiogenic factors into the maternal circulation, resulting in hypertension and proteinuria r16c48c49

Risk factors and/or associations

Age
  • Maternal age older than 35 years is a clinical risk factor for development of preeclampsia/eclampsia r17c50
Sex
  • Male fetal sex is associated with an increased maternal risk of preeclampsia/eclampsia in all but Asian-ethnicity populations r18c51c52
Genetics
  • Preeclampsia/eclampsia has a familial association, but no genetic variants have been reproducibly associated with the condition r19c53
Other risk factors/associations
  • All of the following are associated with increased risk of developing preeclampsia: r17
    • High prepregnancy BMI c54
      • Rate of preeclampsia in pregnant patients with a baseline BMI of 30 or higher is approximately 5.1%
    • Nulliparity c55
    • Multiple gestation c56
    • Prior preeclampsia c57
    • Use of assisted reproductive technology r2c58c59c60c61
    • Coexisting medical problems r2r20
      • Chronic hypertension (pooled adjusted relative risk of 5.1) r17c62
      • Type 1 diabetes mellitus c63
      • Gestational diabetes c64
      • Antiphospholipid antibody syndrome (pooled adjusted relative risk of 2.3) r17c65
      • Systemic lupus erythematosus c66
      • Renal disease c67
      • Obstructive sleep apnea c68

Diagnostic Procedures

Primary diagnostic tools c69

  • Diagnosis is typically pursued and further investigated when elevated blood pressures are found at prenatal obstetric appointments in pregnant patients after 20 weeks of gestation r5
  • Diagnosis requires measurements of blood pressure and proteinuria along with clinical and laboratory assessments to determine presence of end-organ involvement
    • Note: all pregnant patients with new-onset high blood pressure or worsening of preexisting high blood pressure after 20 weeks of gestation should undergo laboratory evaluation r5
    • Blood pressure r21
      • Systolic blood pressure above 140 mm Hg, diastolic blood pressure above 90 mm Hg, or both, meet blood pressure criteria for preeclampsia r2
      • Blood pressure readings above 160/110 mm Hg meet blood pressure criteria for severe preeclampsia r2
      • Manage a pregnant patient who presents with hypertension after 20 weeks of gestation whose prepregnancy or earlier blood pressures are unknown as if they have gestational hypertension or preeclampsia
      • Blood pressure technique c70
        • Must document at least 2 measurements of high blood pressure taken at least 4 hours apart r21
        • Patient must be sitting and should rest for 5 minutes before measurement; cuff must fit properly and be placed on bare upper arm r21
        • Blood pressure can be measured using auscultatory devices or automated methods r21
    • Proteinuria r5c71
      • Assess quantitatively by measuring urine protein after either a 12- or 24-hour urine collection, or by using a spot measurement of protein to creatinine ratio c72c73
        • Urine protein dipstick test may be administered if other methods of measurement are not available (reading of 2+ meets diagnostic parameter of proteinuria) r2c74
    • Other maternal end-organ dysfunction r5
      • CBC with peripheral smear c75c76
      • Comprehensive metabolic panel, including renal and liver function tests (include serum creatinine clearance and uric acid level) c77
  • Formal diagnosis of preeclampsia is made when the following criteria are met: r2
    • Hypertension (greater than 140 mm Hg systolic or 90 mm Hg diastolic) and 1 of the following: c78
      • Proteinuria (greater than 300 mg of protein in a 24-hour urine collection, or spot protein to creatinine ratio of 0.3) c79c80c81
      • 1 or more of the following markers of maternal end-organ dysfunction:
        • Thrombocytopenia (platelet count under 100 × 10⁹ cells/L) c82
        • Impaired liver function (transaminases twice the upper reference limit) c83c84
        • New renal insufficiency (over 1.1 mg/dL or doubling of serum creatinine clearance) c85
        • Pulmonary edema c86
        • New-onset cerebral or visual disturbances c87c88c89c90
  • In a pregnant patient with chronic hypertension, do not diagnose preeclampsia with a rise in blood pressure alone. When there is underlying essential hypertension, diagnose preeclampsia by the presence of proteinuria or by documenting the presence of end-organ dysfunction
  • Formal diagnosis of eclampsia
    • Eclampsia is diagnosed if new-onset seizures occur in setting of hypertensive disorders of pregnancy c91
  • Assess fetal well-being with nonstress test and ultrasonographic evaluation to estimate fetal weight and amniotic fluid index; biophysical profile is indicated if nonstress test findings are nonreactive r22c92
    • In potentially unstable situations, fetal monitoring is always performed first using bedside ultrasonography
  • Determine if patient is in labor and evaluate cervix with Bishop score r7

Laboratory

  • Urine protein measurement c93
    • Preeclampsia proteinuria criterion met with 1 of the following: r2
      • Quantitative urine protein greater than 300 mg over a 24-hour period
        • Accuracy of a 12-hour urine collection is similar to that of 24-hour collection and can be substituted as it is less burdensome r23
        • 12-hour results are doubled
      • Protein urine dipstick reading of 2+ (only if quantitative measurement is not available) c94
      • Spot urine protein to creatinine ratio of at least 0.3
  • Serum chemistry
    • Renal function panel c95
      • Serum creatinine measurement (greater than 1.1 mg/dL or doubling of serum creatinine levelr2) is a diagnostic parameter for maternal organ dysfunction r12c96
      • Uric acid level c97c98
        • Not required, but an increase is associated with renal failure and adverse maternal and perinatal outcomes r12
    • Liver function tests c99
      • ALT or AST level that is twice the upper reference limit is a diagnostic parameter for maternal organ dysfunction r2c100c101
      • Lactate dehydrogenase level c102c103
        • Not required, but elevated levels can be a marker of hemolysis r12
      • Bilirubin level c104c105c106
        • Not required, but increased levels may reflect hemolysis or liver dysfunction r12
      • Albumin level c107c108
        • Not required, but may be decreased in association with liver failure r12
  • CBC panel c109
    • Thrombocytopenia indicated by a platelet count of less than 100 × 10⁹ cells/L is a diagnostic parameter for maternal organ dysfunction r2
    • Hemoglobin level may be increased owing to intravascular volume depletion or decreased owing to microangiopathic process r12
      • Microangiopathic hemolytic anemia on review of peripheral blood smear showing RBC fragmentation is a finding in HELLP syndrome

Imaging

  • Fetal ultrasonography r24c110
    • All patients diagnosed with preeclampsia should have fetal ultrasonography to assess for suboptimal fetal growth r25
    • Measurements of biparietal diameter, head circumference, abdominal circumference, and femur length are commonly used to identify intrauterine growth restriction that may be associated with preeclampsia r24
      • An abnormal (increased) ratio of head circumference to abdominal circumference is common
    • Other findings include decreased volume of amniotic fluid (index obtained by summing the largest cord-free vertical pocket in each of the 4 quadrants of an equally divided uterus) r24

Functional testing

  • Pulse oximetry r12c111
    • Not required to make a diagnosis, but a measurement of oxygen saturation at the time of diagnostic investigation can indicate likelihood of complications developing owing to preeclampsia
    • Oxygen saturation less than 97% is associated with a risk of severe maternal complications (eg, pulmonary hypertension, peripartum cardiomyopathy, pulmonary embolism)

Other diagnostic tools

  • Additional laboratory studies and imaging may be needed to determine disease severity and to identify associated components of multisystemic disease r5
    • If oxygen saturation (measured via pulse oximetry) is reduced, or if there are abnormal pulmonary or cardiac findings, order a chest radiograph and ECG and/or echocardiogram c112c113c114
    • MRI or CT scan of the brain is indicated if intracranial hemorrhage, cerebral thrombosis, or posterior reversible encephalopathy syndrome is suspected c115c116
      • Presence of focal neurologic deficits r7c117c118
      • Repeated seizures despite adequate magnesium levels r7c119c120
      • Presence of blindness r7c121c122
      • Onset of eclamptic seizures before 20 weeks of gestation or after 48 hours postpartum r7c123c124
    • If abdominal pain is present and liver function test results are abnormal, order abdominal imaging (ultrasonogram or CT) to evaluate for liver hematoma c125c126

Differential Diagnosis

Most common

  • Gestational hypertension r20c127
    • De novo development of high blood pressure after 20 weeks of gestation without proteinuria or other features of preeclampsia, which also resolves by 12 weeks postpartum
    • Similar to preeclampsia in that elevated blood pressure develops in the second half of pregnancy
    • Differentiated from preeclampsia by absence of proteinuria and absence of end-organ dysfunction (ie, no renal or liver dysfunction, thrombocytopenia, pulmonary edema, or cerebral or visual abnormalities)
  • Prepregnancy-onset (chronic) hypertension r20c128d2
    • Elevations in blood pressure (greater than 140 mm Hg systolic and/or 90 mm Hg diastolic) that develop before pregnancy, or before the 20th week of gestation, or that persist beyond 12 weeks postpartum
    • Similar to preeclampsia by virtue of elevated blood pressures
    • Formally differentiated from preeclampsia by time course
      • Identify date of onset or document persistence of hypertension postpartum
    • Note: preeclampsia can occur superimposed on chronic or preexisting hypertension
  • HELLP syndrome c129c130d1
    • A combination of hemolysis, elevated liver enzymes, and thrombocytopenia that occurs in the third trimester of pregnancy or postpartum
    • The relationship between preeclampsia and HELLP syndrome is debated; HELLP syndrome may represent a severe form of preeclampsia and there is significant overlap in clinical and biochemical features
    • Similarly to preeclampsia, HELLP syndrome symptoms can include headache, epigastric abdominal pain, and visual disturbances; however, neither hypertension nor proteinuria are required for a diagnosis of HELLP syndrome
    • HELLP syndrome is distinguished from preeclampsia by evidence of a microangiopathic hemolytic anemia (schistocytes) on peripheral blood smear
      • Additional criteria for HELLP syndrome include thrombocytopenia (platelet count of 100 × 10⁹ cells/L or higher), total bilirubin level of 1.2 mg/dL or higher, and serum AST and/or ALT level twice the upper reference limit
  • Systemic lupus erythematosus (exacerbation) r26c131d3
    • Type 3 hypersensitivity reaction in which the body produces autoantibodies, most commonly antinuclear autoantibodies; a high percentage of patients will experience lupus nephritis
    • Similarly to preeclampsia, systemic lupus erythematosus with lupus nephritis presents with proteinuria
    • Unlike preeclampsia, systemic lupus erythematosus with lupus nephritis presents with a characteristic rash, joint pain, and fever, whereas blood pressure is often within reference range
    • Systemic lupus erythematosus is distinguished from preeclampsia by blood pressure measurements and laboratory testing for autoantibodies
  • Antiphospholipid antibody disease r27c132
    • Autoimmune condition complicated by multiple episodes of arterial and venous thromboses, which may lead to morbidity in pregnancy (ie, recurrent miscarriages, fetal deaths)
    • Antiphospholipid antibody disease can mimic preeclampsia by virtue of fetal intrauterine growth restriction, which may occur in both
    • Antiphospholipid antibody disease also serves as a risk factor for preeclampsia, or
    • Antiphospholipid antibody disease alone (without meeting criteria for preeclampsia) can cause premature delivery of a fetus owing to placental insufficiency
    • The following laboratory criteria for antiphospholipid antibody disease must be met to make a diagnosis:
      • Presence of antiphospholipid antibodies on 2 or more occasions at least 12 weeks apart and no more than 5 years before clinical manifestations with 1 or more of the following present: r28
        • Lupus anticoagulant
        • Medium- to high-titer (40 or more IgG phospholipid units or IgM antiphospholipid units, or over 99th percentile) anticardiolipin IgG or IgM
        • Anti-β2 glycoprotein-I IgG or IgM over 99th percentile
    • Negative test results for antiphospholipid antibodies exclude this disorder
  • Mirror syndrome r29c133
    • Rare condition characterized by maternal edema in conjunction with fetal hydrops
    • Similarly to preeclampsia, mirror syndrome presents with hypertension and proteinuria
    • Mirror syndrome usually occurs during the first 2 trimesters of pregnancy and is identified by fetal ultrasonography r5
    • Distinguishing between preeclampsia and mirror syndrome in the presence of hypertension and proteinuria requires ruling out fetal hydrops or twin-to-twin transfusion syndrome

Treatment

Goals

  • Control maternal blood pressure to reduce risk of maternal hemorrhagic stroke r30
  • For eclampsia:
    • Prevent maternal injury and aspiration during seizures
    • Prevent further seizures
  • For preeclampsia
    • Prevent seizures
  • Deliver a mature newborn that does not require prolonged or intensive neonatal care

Disposition

Admission criteria

All patients should be assessed in hospital initially; some may be managed as outpatients providing their condition is stable and the patient can reliably monitor their blood pressure and report problems r9

Admit patients with severe manifestations (eg, severely elevated blood pressure, unstable neurologic findings) or those who are unable to be monitored adequately as an outpatient r2

Criteria for ICU admission
  • Delivery in patients with preeclampsia should take place in a hospital setting with access to a neonatal ICU

Recommendations for specialist referral

  • Patients diagnosed with preeclampsia should have an integrative care plan managed by obstetricians and perinatologists
  • Refer to specialists in maternal fetal medicine, hypertension, anesthesiology, or critical care if blood pressure is resistant to first line pharmacotherapy r26r31
  • Refer to anesthesiologist to plan neuraxial analgesia or anesthesia during labor for patients undergoing cesarean delivery r1

Treatment Options

Management of preeclampsia depends on disease severity and gestational age r3

  • Preeclampsia without severe features r2
    • At less than 37 weeks of gestation (and no other indication for delivery), expectant management with fetal and maternal monitoring is recommended r2
    • At or beyond 37 weeks of gestation, delivery rather than observation is suggested r2
    • Threshold for initiating antihypertensive medication varies; the American College of Obstetricians and Gynecologists does not recommend treating blood pressure less than 160/110 mm Hg unless associated with comorbidities or end-organ damage r2r8
      • Canadian and British guidelines recommend treatment of blood pressure greater than 140/90 mm Hg r32r33
      • Treatment may reduce risk of developing severe hypertension but must be balanced against potential risk of adverse effects to fetus r34r35
    • Magnesium sulfate for universal prevention of eclampsia is not generally recommended in patients with blood pressure that is persistently lower than 160/110 mm Hg in the absence of maternal symptoms of severe disease r2
    • All commonly prescribed antihypertensives reduce the risk of severe hypertension pregnancy; however, labetalol may also reduce risk of proteinuria/preeclampsia r36
  • Preeclampsia with severe features r2
    • Initiate immediate antihypertensive therapy promptly in patients with persistent, severe hypertension (blood pressure of at least 160 mm Hg systolic or 110 mm Hg diastolic) r2
      • First line therapy for immediate urgent control of hypertension includes labetalol (IV), hydralazine (IV), and nifedipine (oral) r33
        • Second line therapy includes esmolol or nicardipine by infusion pump r5
        • Use sodium nitroprusside only in the short term and as a last resort because it can worsen maternal cerebral edema r5
        • Do not give immediate-release oral nifedipine sublingually (risk of hypotension)
      • For longer-term blood pressure control during expectant management, options include methyldopa (oral), labetalol (oral), and nifedipine (oral) r5
        • Second line therapy for long-term control of hypertension includes use of diuretics (thiazide diuretics) r5
    • Administer magnesium sulfate for seizure prophylaxis r2
    • Timing of delivery depends on gestational age and maternal and fetal condition
      • Deliver after maternal stabilization in patients with severe preeclampsia at or beyond 34 weeks of gestation and in those with unstable maternal or fetal conditions irrespective of gestational age r2
      • If less than 34 weeks of gestation but stable maternal and fetal conditions: r2
        • Continue pregnancy at facility with maternal and neonatal intensive care resources
        • Administer corticosteroids for benefit of fetal lung maturity r2
    • Route of delivery is selected based on gestational age, fetal presentation, cervical status, obstetric history, and maternal and fetal condition
      • Vaginal delivery is preferred in preeclampsia without severe features r2
      • Cesarean delivery is recommended for standard obstetric indications (eg, unfavorable cervix, oligohydramnios) and should be individualized r2
      • Spinal or epidural anesthesia is recommended if analgesia or anesthesia is required for delivery; risk of epidural hematoma is low in patients with platelet counts higher than 70 × 10⁹ cells/L r2
      • General anesthesia for delivery may increase risk of eclampsia in postpartum period r2
    • Therapy decisions related to preeclampsia are not based on amount of proteinuria r2
  • HELLP syndrome r2
    • At 34 weeks or more of gestation, delivery is recommended shortly after maternal stabilization
    • From gestational age of fetal viability to 33 weeks of gestation, delay delivery (24-48 hours) only if fetal and maternal conditions remain stable for completion of course of corticosteroids to assist fetal lung maturation r2
      • Role of high-dose corticosteroids in reducing maternal mortality and morbidity is uncertain r2
        • May improve maternal platelet counts, but no overall evidence of benefit exists r37
    • Before gestational age of fetal viability, delivery is recommended shortly after maternal stabilization r2

Therapy for eclampsia

  • For immediate management of seizures: r7
    • Position patient in lateral decubitus position to minimize aspiration of oral secretions and vomitus
    • Provide supplemental oxygen via face mask with or without reservoir at 8 to 10 L/minute to treat hypoxemia
  • Administer parenteral magnesium sulfate to treat eclampsia-related seizures and for seizure prophylaxis r30r38r39
  • Use antihypertensives to control blood pressure (same manner as for preeclampsia) r2
  • Proceed to prompt delivery after maternal stabilization irrespective of gestational age r2
    • A trial of vaginal labor is acceptable under selected circumstances r40
    • Decision on whether to proceed with cesarean delivery after maternal stabilization depends on gestational age of fetus, fetal condition, presence of labor, and cervical Bishop score r7

Postpartum management

  • Administer parenteral magnesium sulfate for postpartum patients who present with new-onset hypertension and headaches or blurred vision, or preeclampsia with severe hypertension
  • In patients with eclampsia, continue magnesium sulfate for at least 24 hours after delivery, or after the last seizure, or both

Drug therapy

  • First line antihypertensive agents for severe hypertension r5c134
    • Most labor units have standard protocols in place for labetalol, hydralazine, or nitroprusside drip, if needed
    • Labetalol (immediate or emergent therapy for acute-onset hypertension) c135
      • Labetalol Hydrochloride Solution for injection; Adults: 10 to 20 mg IV, then 20 to 80 mg IV every 10 to 30 minutes until goal blood pressure is attained. Max cumulative dose: 300 mg.
      • Labetalol Hydrochloride Solution for injection; Adults: 10 to 20 mg IV, then 0.5 to 2 mg/minute continuous IV infusion initially. Titrate every 15 minutes until goal blood pressure is attained. May repeat or double bolus dose after 10 minutes before starting infusion. Max: 10 mg/minute. Max cumulative dose: 300 mg.
    • Hydralazine (immediate or emergent therapy for acute-onset hypertension) c136
      • Hydralazine Hydrochloride Solution for injection; Adult females: 5 to 10 mg IV over 2 minutes for SBP of 160 or more or DBP of 110 or more mmHg. Check BP in 20 minutes and if either BP threshold is exceeded, give 10 mg IV over 2 minutes. Check BP in 20 minutes and if either threshold is exceeded, switch to labetalol 20 mg IV over 2 minutes and check BP in 10 minutes. If either BP threshold is exceeded, give labetalol 40 mg IV over 2 minutes, obtain emergency consultation, and give additional antihypertensive medication per specific order. Once SBP is less than 160 and DBP is less than 110, check BP every 10 minutes for 1 hour, then every 15 minutes for 1 hour, then every 30 minutes for 1 hour, and then every hour for 4 hours.
    • Nifedipine c137
      • Immediate-release oral nifedipine may be considered as a first line therapy when IV access is not available. r2r41
        • Initiate fetal heart rate monitoring before first dose.
        • Nifedipine Oral capsule; Pregnant females: 10 to 20 mg PO every 20 minutes as needed for 2 doses; then 10 to 20 mg PO every 2 to 6 hours as needed. Maximum: 180 mg/day. r2r41
      • Used with caution (if at all) if patient is concurrently receiving magnesium sulfate owing to risk of hypotension and neuromuscular blockade when combined. r5
    • Sodium nitroprusside c138
      • Reserve for extreme emergencies (last resort), and use for the shortest time possible owing to risk of maternal/fetal cyanide toxicity and other possible adverse effects. r6
      • Sodium Nitroprusside Solution for injection; Adults: 0.3 to 0.5 mcg/kg/minute continuous IV infusion, initially. Titrate by 0.5 mcg/kg/minute every 5 minutes until desired effect or blood pressure cannot be further reduced without compromising organ perfusion. Max: 10 mcg/kg/minute for 10 minutes.
  • Second line agents for severe hypertension
    • Esmolol c139
      • Esmolol Hydrochloride Solution for injection; Adults: 500 to 1,000 mcg/kg IV over 1 minute, then 50 mcg/kg/minute continuous IV infusion, initially. Repeat bolus and titrate by 50 mcg/kg/minute until goal blood pressure is attained. Max: 200 mcg/kg/minute.
    • Nicardipine c140
      • Nicardipine Hydrochloride Solution for injection; Adults: 5 mg/hour continuous IV infusion, initially. Titrate by 2.5 mg/hour every 5 to 15 minutes until goal blood pressure is attained. Max: 15 mg/hour.
  • First line agents for long-term control of blood pressure
    • Labetalol c141
      • Avoid in asthma, heart disease, congestive heart failure, or if maternal heart rate is less than 60 beats per minute. r5
      • Labetalol Hydrochloride Oral tablet; Adults: 100 mg PO twice daily, initially. Titrate dosage by 100 to 200 mg twice daily every 2 to 3 days until goal blood pressure is attained. Usual dose: 200 to 400 mg twice daily. Max: 2,400 mg/day.
    • Nifedipine c142c143
      • Nifedipine Oral tablet, extended-release; Adults: Initially, 30 to 60 mg PO once daily. Max: 90 mg/day for most extended-release products; 120 mg/day for Procardia XL.
    • Methyldopa r5c144
      • May be less effective in controlling higher blood pressures than other commonly used medications.
      • Methyldopa Oral tablet; Adults and Adolescents: Initially, 250 mg PO given 2—3x/day. The usual dosage is 500—2000 mg/day PO, given in 2—4 divided doses. Max 3 g/day PO.
  • Second line agent for long-term control of blood pressure
    • Thiazide diuretics r5c145
      • Use with caution owing to potential for intravascular volume depletion and hypokalemia.
      • Hydrochlorothiazide Oral tablet; Adults: Initially, 12.5 to 25 mg PO once daily. Increase up to 50 mg/day PO given in 1 to 2 divided doses.
  • Corticosteroids c146c147
    • Betamethasone c148
      • Antenatally, to induce fetal lung maturation in preparation for premature delivery.
      • Betamethasone is the most well-studied and preferred corticosteroid for fetal lung maturation.
        • Betamethasone Acetate, Betamethasone Sodium Phosphate Suspension for injection; Pregnant females: 12 mg IM every 24 hours for 2 doses in all pregnant women between 24 and 34 weeks gestation who are at risk for preterm delivery within 7 days; administer first dose even if ability to administer second dose is unlikely. Consider therapy starting at 23 weeks gestation for pregnant women who are at risk of preterm delivery within 7 days. Consider a repeat or rescue course in women who are less than 34 weeks gestation, at risk of preterm delivery within the next 7 days, and prior course of antenatal corticosteroids was administered more than 14 days previously. Rescue course could be provided as early as 7 days from the prior dose if indicated by clinical situation.
    • Dexamethasone c149c150
      • For HELLP syndrome:
        • Dexamethasone Sodium Phosphate Solution for injection; Adults: 10 mg IV every 12 hours for 48 hours has been reported. r37
      • For preeclampsia:
        • Antenatally, to promote fetal pulmonary maturity when delivery is anticipated within the next 7 days and gestational age is less than 34 weeks. r37
        • Acceptable alternative to betamethasone for fetal lung maturation.
  • Anticonvulsant (for both treatment and prophylaxis) c151
    • Magnesium sulfate r42c152
      • Dosage schedule for severe preeclampsia is the same as for eclampsia. r40
      • Continue magnesium sulfate for at least 24 hours after delivery, after the last seizure, or both. r7
      • Has been associated with an increased risk of postpartum hemorrhage and uterine atony in observational studies; however, this has not been confirmed in randomized trials. r43
      • Magnesium Sulfate Solution for injection; Adults: 4 to 6 g IV loading dose followed by a maintenance dose of 1 to 2 g/hour IV for at least 24 hours. Max: 30 to 40 g/day.
  • Low-dose aspirin prophylaxis for prevention of preeclampsia r44
    • Indicated in patients at high risk and should be initiated between 12 and 28 weeks gestation (optimally before 16 weeks).
      • High-risk status includes any of the following: history of preeclampsia, multifetal gestation, chronic hypertension, type 1 or 2 diabetes, renal disease, or autoimmune disease (systemic lupus erythematosus, the antiphospholipid syndrome).
    • Can be considered in patients at moderate risk if more than 1 of the following risk factors is present:
      • Nulliparity, BMI greater than 30, family history of preeclampsia (mother or sister), sociodemographic characteristics (African American race, low socioeconomic status), age 35 years or older, or personal history factors (eg, low birth weight or small for gestational age, previous adverse pregnancy outcome, more than 10-year pregnancy interval)
    • Aspirin Oral tablet; Adult Females: 81 mg PO once daily starting at 12 weeks of gestation.

Nondrug and supportive care

Fluid management r1c153

  • Resuscitation r45
    • Restrict fluid to a maximum of 80 mL/hour when IV is inserted r1
    • Titrate to systolic blood pressure above 90 mm Hg r45
  • Maintenance r45
    • NPO status (60-80 mL/hour crystalloid) r45
  • Preloading r45
    • Fluid challenge before vasodilation or regional anesthesia: administer volume expanders (300 mL crystalloid) r45

Bed rest is not indicated as a form of management r2r8

Procedures
Induction of labor r10c154
General explanation
  • Procedure to stimulate uterine contractions before development of spontaneous labor; may be preceded by measures to facilitate cervical ripening r46
    • Oxytocin is the most common medication used to induce labor
    • Other methods to induce labor include prostaglandin E analogues, mechanical cervix dilation, membrane stripping, and amniotomy
  • Vaginal delivery is preferred to avoid added physiologic stressors r10
Indication
  • Fetal indications in cases of preeclampsia include severe intrauterine growth restriction, nonreassuring fetal surveillance, and oligohydramnios r10
  • Maternal indications in cases of preeclampsia include deterioration of hepatic and/or renal function, suspected placental abruption, neurologic signs, severe epigastric pain, nausea or vomiting, gestational age of 38 weeks or greater, and eclampsia r10
Contraindications
  • Maternal hemodynamic instability
  • General contraindications for induction of labor
    • Active genital HSV infection
    • Vasa previa or complete placenta previa
    • Transverse fetal lie
    • Umbilical cord prolapse
    • Previous classic cesarean delivery
    • Previous myomectomy
Complications
  • Same as those associated with induction of labor for any cause
    • Uterine hyperstimulation
    • Uterine rupture
    • Fetal distress and fetal acidosis
    • Failed labor induction requiring cesarean delivery
    • Complications associated with prematurity
Cesarean delivery c155
General explanation
  • Fetus is delivered through abdominal wall (laparotomy) and uterine wall (hysterotomy) incisions r47
Indication r48
  • Demonstrable fetal hypoxia or imminent fetal demise
  • Unequivocal cephalopelvic disproportion, soft-tissue obstruction, or fetal malpresentation not caused by gross fetal malformations incompatible with life
Contraindications
  • No absolute contraindications and very few relative contraindications
    • Severe congenital abnormalities of the fetus predicting probable proximate fetal death
    • Compromise of maternal cardiovascular status (severe pulmonary disease)
  • Severe thrombocytopenia; platelet transfusions are required before procedure
Complications
  • Same as those with cesarean delivery for any cause
    • Uterine lacerations
    • Bladder lacerations
    • Ureter injury
    • Bowel injury
    • Uterine atony
    • Hemorrhage
    • Postoperative infection

Special populations

  • Patients with preeclampsia superimposed on chronic or prepartum hypertension
    • Preeclampsia can occur superimposed on chronic or preexisting hypertension that is often identified owing to worsening control of blood pressure
    • In these patients, superimposed preeclampsia is identified by de novo proteinuria and/or end-organ dysfunction in the second half of pregnancy
  • Patients with HELLP syndrome r2
    • If gestational age is before fetal viability, proceed to delivery shortly after maternal stabilization
    • At 34 weeks of gestation and beyond, proceed to delivery soon after maternal stabilization
    • From gestational age of fetal viability up until 34 weeks of gestation, delay delivery for 24 to 48 hours to complete a course of corticosteroids for fetal benefit if possible
  • Postpartum preeclampsia r49
    • New-onset hypertension developing 48 hours to 6 weeks after delivery; usually within the first 7 to 10 days
    • Most patients present with headache or other neurologic symptoms; other symptoms include shortness of breath, chest pain, and peripheral edema
      • Consider neuroimaging to exclude other causes of postpartum headache such as stroke or posterior reversible cerebral encephalopathy, or subarachnoid hemorrhage
    • Less frequently detected based on routine home or in-office blood pressure monitoring
    • Treatment consists of antihypertensive agents and magnesium as for preeclampsia of antenatal onset; diuresis is indicated for volume overload if present
    • May be associated with a higher risk of maternal morbidity than preeclampsia with antepartum onset

Monitoring

  • Closely monitor patients with preeclampsia without severe features for progression of disease r2
    • Measure blood pressure twice weekly c156
    • Measure platelet counts and serum creatinine and liver enzyme levels weekly r2c157
    • Assess for proteinuria once weekly r2c158
    • Serially assess maternal symptoms and fetal movement daily c159c160c161c162c163
    • Use ultrasonography to assess fetal growth every 3 to 4 weeks r2c164c165
      • If fetal growth restriction is found, fetoplacental assessment by umbilical artery Doppler velocimetry is recommended c166
    • Use ultrasonography to assess amniotic fluid volume at least once weekly r2c167c168
    • Obtain weekly amniotic fluid r30c169
    • Invasive hemodynamic monitoring is not routinely necessary c170
  • Postpartum monitoring of patients with preeclampsia or superimposed preeclampsia r2
    • Monitor blood pressure in the hospital for at least 72 hours postpartum and again 7 to 10 days after delivery c171
    • Monitor for symptoms of headache or blurred vision and treat with IV magnesium sulfate; continue for at least 24 hours or until symptoms resolve and blood pressure normalizes r30c172c173c174
  • Monitoring in eclampsia r30
    • Monitor for magnesium toxicity r40c175
      • Assess deep tendon reflexes periodically c176
      • Measure serum magnesium level at 4 to 6 hours and adjust infusion to maintain levels between 4 and 7 mEq/L (4.8-8.4 mg/dL) c177
      • Measure serum magnesium levels if serum creatinine level is equal to or greater than 1 mg/mL c178
    • Excessive magnesium can lead to respiratory and cardiac depression c179
  • Later-life monitoring of patients with prior preeclampsia
    • For patients with history of preeclampsia who gave birth preterm (less than 37 weeks) or who had recurrent preeclampsia, assess cardiovascular status yearly owing to elevated risk of cardiovascular disease in later life r1c180
    • Screen for and control cardiovascular risk factors such as obesity, hypertension, and dyslipidemia r50

Complications and Prognosis

Complications

  • Maternal complications of preeclampsia
    • Neurologic complications r1
      • Stroke (ischemic cerebral edema) c181
      • Cortical blindness (often a result of ocular edema) c182
      • Retinal detachment c183
      • Posterior reversible encephalopathy c184
    • Hepatic complications include liver dysfunction, hematoma, or hepatic rupture r1c185c186c187
  • Obstetric and fetal complications of preeclampsia r1
    • Abruptio placentae c188
    • Preterm birth c189
    • Intrauterine growth restriction c190
    • Stillbirth and neonatal death c191c192
    • Possible late adverse effects on neurodevelopmental outcomes r51
  • Eclampsia and severe preeclampsia are associated with additional maternal complications r52
    • Disseminated intravascular coagulation syndrome c193
    • Need for mechanical ventilation c194
    • Acute renal failure c195
    • Acute respiratory distress syndrome c196
    • Puerperal cerebrovascular disorder c197
    • Pulmonary edema c198
    • Increased risk of mortality c199

Prognosis

  • Outcomes depend on disease severity, coexisting medical conditions, and gestational age at which condition develops
    • Maternal and perinatal outcomes are favorable in patients with mild preeclampsia who develop disease after 33rd week of gestation
    • Maternal and perinatal morbidity and mortality rates are higher among patients who develop preeclampsia before 33 weeks of gestation, patients with preexisting medical conditions, and patients in developing countries
  • Preeclampsia and eclampsia account for approximately 50,000 maternal deaths worldwide each year r53
    • Eclampsia is associated with an increased risk of maternal death in developed countries (0%-1.8%) and a mortality rate as high as 15% in developing countries
  • There is evidence that preeclampsia is associated with long-term increased risk of cerebrovascular and cardiovascular disease r54r55

Screening and Prevention

Screening

At-risk populations r56

  • Patients with previous pregnancies complicated by preeclampsia, and especially those who had adverse outcomes
  • Patients with:
    • Type 1 or type 2 diabetes
    • Chronic hypertension
    • Chronic kidney disease
    • Multifetal gestation
    • Autoimmune disease

Screening tests

  • Screen all pregnant patients with routine measurement of blood pressure and obtain medical history to identify relevant risk factors r2r57c200c201
  • Screening tests to predict development of preeclampsia—including use of biomarkers and Doppler ultrasonographic characteristics—are not currently recommended outside of investigational settings in the United States r2r22r58
  • In the first trimester, a combination of maternal risk factors, blood pressure, placental growth factor, and uterine artery Doppler findings may be used to identify patients who may benefit from low-dose aspirin to prevent preeclampsia developing before 37 weeks of gestation (but not preeclampsia at term); the International Society for the Study of Hypertension in Pregnancy supports this approach, although cost effectiveness is unclear r9c202c203c204

Prevention

  • Low-dose aspirin c205
    • US Preventive Services Task Force and American College of Obstetricians and Gynecologists recommend the use of low-dose aspirin (81 mg/day) for prevention of preeclampsia in patients at high risk after 12 weeks of gestation r2r44r56r59
      • The World Health Organization makes similar recommendations r59
      • Low-dose aspirin significantly reduces risk of mild preeclampsia but not risk of severe preeclampsia r60
      • A 2019 Cochrane review reported that administering low-dose aspirin to pregnant patients led to small to moderate benefits, including reductions in preeclampsia incidence r61
      • Begin between 12 weeks and 28 weeks of gestation (ideally before 16 weeks) and continue daily until delivery r44
      • The following pregnant patients are at high risk for preeclampsia: r2
        • Those with history of preeclampsia in prior pregnancies, and especially those who had adverse outcomes (eg, delivery at an early gestational age)
        • Those with:
          • Multifetal gestation
          • Chronic kidney disease
          • Diabetes mellitus
          • Autoimmune disease
          • Chronic hypertension
        • Those with a combination (more than one) of the following moderate risk factors r44
          • Obesity
          • Nulliparity
          • Age 35 years or older
          • History of earlier adverse pregnancy outcomes, low birth weight, or long interval between pregnancies (more than 10 years)
          • Adverse socioeconomic circumstances
          • Family history of preeclampsia (mother or sister)
          • In vitro fertilization
          • Black race (as a proxy for underlying racism)
          • Lower income
      • May also consider use of low-dose aspirin in patients with one or more of the following factors that are associated with increased risk due to environmental, social, structural, and historical inequities affecting access to health care r44
        • Black race (as a proxy for underlying racism)
        • Lower income
  • Lifestyle interventions
    • Physical activity r50
      • All patients without contraindications should be physically active during pregnancy
      • Exercise may reduce risk of preeclampsia by 40%
  • Treatment of nonsevere hypertension in pregnancy
    • Optimal blood pressure goals vary among the professional organizations
    • Antihypertensive therapy treatment is known to prevent development of severe hypertension; however, until recently, it had not been shown to reduce rates of preeclampsia r34r50
    • More recent studies suggest tight blood pressure control during pregnancy is associated with a reduced risk of preeclampsia; in addition, may permit prolongation of pregnancy and avoidance of premature delivery and its complications r50
  • Strategies that have been investigated but are not currently recommended (by the American College of Obstetricians and Gynecologists) include: r2
    • Vitamin C or vitamin E supplementation c206c207
    • Dietary salt restriction c208
    • Bed rest, restriction of physical activity, or both c209c210
    • Calcium supplementation (unless dietary calcium intake is inadequate) c211
      • International Society for the Study of Hypertension in Pregnancy recommends supplemental calcium (1.2-2.5 g/day) for pregnant patients at increased risk for preeclampsia if their intake is low r9
      • Patients should aim to achieve the recommended daily allowance of calcium (1000 mg daily) through diet or calcium supplementation r62
    • Metformin c212
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