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Preeclampsia and Eclampsia (Toxemia of Pregnancy)
Konstantinos E. Deligiannidis, MD, MPH, FAAFP
image BASICS
DESCRIPTION
  • Preeclampsia is a disorder of pregnancy developing at the 20th week (or beyond), with new-onset hypertension (HTN) and new-onset proteinuria and/or impaired organ function:
    • May progress from mild to life-threatening in hours to days
    • The disorder is reversible by delivery if at term or, if maternal/fetal health are in danger, by preterm delivery.
    • Eclampsia is defined as new-onset grand mal seizure activity in a patient with preeclampsia without underlying neurologic disease.
    • Most postpartum cases occur within 48 hours of delivery but can occur up to 4 weeks postpartum.
  • System(s) affected: cardiovascular, renal, reproductive, fetoplacental, CNS, hepatic
  • Synonym(s): toxemia of pregnancy
EPIDEMIOLOGY
Incidence
  • Predominant age
    • Most cases occur in younger women because of the higher incidence of preeclampsia in younger (primiparous) women.
    • However, older (>40 years) patients with preeclampsia have 4 times the incidence of seizures compared with patients in their 20s.
  • Preeclampsia: 5-8%
  • Eclampsia develops in 1.6 to 10/10,000 deliveries in developed countries. In developing countries, estimates range from 6 to 157/10,000.
  • 40% of eclamptic seizures occur before delivery; 16% occur >48 hours after delivery.
ETIOLOGY AND PATHOPHYSIOLOGY
Systemic derangements in eclampsia include the following:
  • Cardiovascular: generalized vasospasm
  • Hematologic: decreased plasma volume, increased blood viscosity, hemoconcentration, coagulopathy
  • Renal: decreased glomerular filtration rate
  • Hepatic: periportal necrosis, hepatocellular damage, subcapsular hematoma
  • CNS: cerebral vasospasm and ischemia, cerebral edema, cerebral hemorrhage
Genetics
2 to 4 times increased risk in pregnant women with family history of preeclampsia
RISK FACTORS
Nulliparity; age >40 years; family history of preeclampsia; high body mass index; diabetes; chronic HTN, chronic renal disease, or both; multifetal pregnancy; previous preeclampsia; systemic lupus erythematosus; in vitro fertilization (1)
GENERAL PREVENTION
  • Adequate prenatal care: Women who do not receive prenatal care are seven times more likely to die from complications.
  • Good control of preexisting HTN
  • Recent systematic reviews, meta-analyses, and task force recommendations show that low-dose aspirin (60 to 80 mg) started early in pregnancy may lower the risk of developing preeclampsia and the rate of preterm delivery and neonatal death in moderateto high-risk patients and has no significant effect on the rate of placental abruption/neonatal bleeding complications. The number needed to treat (NNT) to prevent one case of preeclampsia ranges from 18 to 118 depending on risk population, but more info is required to see which women would benefit and when to start therapy (1)[C],(2,3,4)[A]. It may be recommended in those with preeclampsia in >1 prior pregnancy or with a history of preeclampsia and preterm delivery (1)[C].
  • Low-dose calcium supplementation has been shown to reduce the risk and severity of preeclampsia (relative risk [RR] = 0.38) in calcium-deficient populations (1)[C],(5)[A].
  • Although some evidence suggests vitamin C (1,000 mg/day) and vitamin E (400 U/day) may reduce the risk for preeclampsia, recent guidelines recommend against their use (1)[C],(6).
COMMONLY ASSOCIATED CONDITIONS
Abruptio placentae, placental insufficiency, fetal growth restriction, preterm delivery, fetal demise, maternal seizures (eclampsia), maternal pulmonary edema, maternal liver/kidney failure, maternal death
image DIAGNOSIS
Diagnosis depends on new-onset elevated BP (SBP ≥140 mm Hg or DBP ≥90 mm Hg on two occasions at least 4 hours apart, or ≥160/110 mm Hg) after 20 weeks of gestation AND EITHER proteinuria (>300 mg/24 hr or spot protein:creatinine ≥0.3), OR new-onset thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral/visual symptoms (1)[C]. This 2013 ACOG guideline suggests defining preeclampsia as either without or with severe features. Older guidelines use the term “mild” and “severe.” The term “mild” is discouraged because preeclampsia is an evolving process that must be frequently evaluated for severity (1)[C].
PHYSICAL EXAM
  • BP criteria:
    • Preeclampsia without severe features: Elevated BP ≥140/90 mm Hg on two occasions at least 4 hours apart, or more rapid diagnosis may be made with BP ≥160/110 mm Hg.
    • Preeclampsia with severe features: Elevated BP ≥160 systolic mm Hg or 110 mm Hg diastolic on two BP readings 4 hours apart while the patient is on bedrest, AND new onset of one or more of below:
      • Platelets <100,000/&mgr;L
      • >2 times normal liver transaminase levels, severe persistent right upper quadrant (RUQ)/epigastric pain, or both
      • Creatinine >1.1 mg/dL, or doubling of serum creatinine levels
      • Pulmonary edema
      • Cerebral or visual symptoms
  • Eclampsia: tonic-clonic seizure activity (focal/generalized)
    • Note: headache, visual disturbance, and epigastric or RUQ pain often precede seizure
    • Seizures may occur once/repeatedly.
    • Postictal coma, cyanosis (variable)
    • Temperatures >39°C may be consistent with CNS hemorrhage.
    • Normal BP, even in response to treatment; does not rule out potential for seizures
DIFFERENTIAL DIAGNOSIS
  • Chronic HTN: HTN before pregnancy; high BP before the 20th week
  • Chronic HTN with superimposed preeclampsia
  • Gestational HTN: Increased BP first discovered after 20 weeks, often close to term, with no proteinuria and without evidence of organ dysfunction. BP becomes normal by 12 weeks postpartum, or it is reclassified as chronic hypertension.
  • Seizures in pregnancy: epilepsy, cerebral tumors, meningitis/encephalitis, ruptured cerebral aneurysm. Until other causes are proven, however, all pregnant women with convulsions should be considered to have eclampsia.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Routine spot urine testing for protein should be done at each prenatal visit in all hypertensive patients
  • CBC, including platelets, creatinine, serum transaminase levels, and uric acid as baseline in hypertensive patients and if preeclampsia suspected or possible
  • Coagulation profiles: abnormalities suggest severe disease.
  • 24-hour urine or protein/creatinine ratio if urine protein dips 1+ on more than one occasion, or if preeclampsia is being considered
  • Daily fetal movement monitoring by mother (“kick counts”)
  • US imaging is used to monitor growth and cord blood flow; perform, as indicated, based on clinical stability and laboratory findings.
  • Nonstress test (NST) at diagnosis and then twice-weekly until delivery
  • Biophysical profile if NST is nonreactive (1)[C]
  • US imaging for growth progress every 3 weeks, and amniotic fluid volume at least once weekly (1)[C]
  • With seizures, CT scan and MRI should be considered if focal findings persist or uncharacteristic signs/symptoms are present.
Follow-Up Tests & Special Considerations
Disseminated intravascular coagulation, thrombocytopenia, liver dysfunction, and renal failure can complicate preeclampsia associated with HELLP syndrome.
Test Interpretation
CNS: cerebral edema, hyperemia, focal anemia, thrombosis, and hemorrhage. Cerebral lesions account for 40% of eclamptic deaths.
image TREATMENT
  • Preeclampsia without severe features:
    • Outpatient care
    • Maternal: daily home BP monitoring; daily weights; weekly labs (complete blood count [CBC], creatinine, liver function test [LFT])
    • Fetal:
      • Patient-measured: daily “kick counts”
      • Medical provider-measured: (see imaging section above)
      • Delivery at 37 weeks
  • P.839

  • Preeclampsia with severe features:
    • Inpatient care if patient condition deteriorates (BP ≥160/110 mm Hg; severe headache; visual changes [scotoma or “flashing lights”]; impaired mentation; pulmonary edema; epigastric/RUQ pain; increasing LFTs; oliguria; thrombocytopenia) or if fetal status is deemed “nonreassuring”
    • Maternal: daily labs, adding coagulation tests; IV magnesium sulfate as seizure prophylaxis; IV labetalol or hydralazine and oral sustained-release nifedipine antihypertensive therapy titrated to keep systolic BP <160 mm Hg and diastolic BP <110 mm Hg (some recommend <150/100 mm Hg postpartum). Keep diastolic BP >90 mm Hg to avoid hypoperfusing the uterus.
    • Fetal: continuous heart monitoring; daily US with BP, amniotic fluid levels, fetal growth assessment as deemed necessary
GENERAL MEASURES
Management by gestational age of severe preeclampsia:
  • <23 weeks: Offer to terminate pregnancy.
  • At 23 to 34 weeks: Antihypertensives; evaluate maternal-fetal condition; steroids to enhance fetal lung maturity; plan delivery at 34 weeks with magnesium sulfate prophylaxis.
  • If severe HTN, eclampsia, DIC, pulmonary edema, abnormal fetal test results/evaluation, or abruption placentae, then plan delivery once maternal condition is stable.
  • If HELLP syndrome (full or partial), severe oligohydramnios, significant renal dysfunction, persistent symptoms, fetal growth restriction, ≥33 5/7 weeks' gestation, labor, or PROM, then steroids and then delivery after 48 hours.
  • If the above do not apply, then expectant management until 34 weeks.
  • At ≥34 weeks: magnesium sulfate and delivery (1)[C]
MEDICATION
First Line
  • For seizure prophylaxis for women with severe preeclampsia: magnesium sulfate (MgSO4): loading dose 4 g IV in 200 mL normal saline over 20 to 30 minutes; maintenance dose 1 to 2 g/hr IV continuous infusion (although recent guidelines suggest it not be universally administered for seizure prophylaxis to prevent eclampsia, the quality of the evidence is low, and the strength of the recommendation is qualified) (1)[C]
  • For BP control
    • Antihypertensives are inadvisable for mildly elevated BP (without severe features).
    • Labetalol (IV): 20 mg over 2 minutes followed at 20 to 30 minutes intervals with doses of 20 to 80 mg titrated to keep BP <160/110 mm Hg; max of 300 mg/24 hr. (Contraindicated in asthma, heart disease, congestive heart failure.)
    • Hydralazine (IV): 5 to 10 mg over 2 minutes, followed at 20 minutes intervals with 5 to 10 mg IV boluses; titrated to keep BP<160/110 mm Hg; max of 25 mg/24 hr.
    • Nifedipine sustained-release (PO) (used in the postpartum): 30 to 120 mg/day (caution with combination of nifedipine and magnesium sulfate resulting in hypotension and neuromuscular blockade)
  • For eclampsia/seizures
    • In recent randomized trials, magnesium sulfate was found to be superior to phenytoin in the treatment and prevention of eclampsia and probably more effective and safer than diazepam.
    • Magnesium sulfate for seizures
      • 4 to 6 g IV over 15 to 20 minutes followed by 1 to 2 g/hr infusion
      • Further boluses of magnesium may be given for recurrent convulsions with the amount given based on the neurologic examination and patellar reflexes.
      • Contraindications: myasthenia gravis, renal failure, pulmonary edema
    • Levels of 6 to 8 mEq/mL are considered therapeutic, but clinical status is most important and must ensure that
      • Patellar reflexes are present.
      • Respirations are not depressed.
      • Urine output is ≥25 mL/hr.
    • May be given safely, even in the presence of renal insufficiency
  • Fluid therapy
    • Ringer lactated solution with 5% dextrose at 60 to 120 mL/hr, with careful attention to fluid-volume status
  • Precautions: Do not use diuretics. Carefully monitor neurologic status, urine output, respirations, and fetal status.
  • Calcium carbonate (1 g, administered slowly IV) may reverse magnesium-induced respiratory depression.
Second Line
  • Diazepam 2 mg/min until resolution or 20 mg given or
  • Lorazepam 1 to 2 mg/min up to total of 10 mg or
  • Phenytoin 15 to 20 mg/kg at a maximum rate of 50 mg/min or
  • Levetiracetam 500 mg IV or oral, may be repeated in 12 hours (dose needs to be adjusted in renal impairment) or
  • Phenobarbital 20 mg/kg infused at 50 mg/min; may repeat with additional 5 to 10 mg/kg after 15 minutes
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Without severe features: restricted activity; with severe features: restricted activity, in hospital
  • Women with a history of preeclampsia should report this to physicians caring for them in later life. It is a potent cardiovascular disease risk factor.
DIET
  • Salt restriction is inadvisable because the patient often is experiencing intravascular hypovolemia (1)[C].
  • Calcium supplementation may be recommended for women who have low calcium intake (<600 mg/day) (1,6)[A].
PATIENT EDUCATION
American College of Obstetricians and Gynecologists, 409 12th St. SW, Washington, DC 20024-2188; (800) 762-ACOG; http://www.acog.org/
PROGNOSIS
  • For nulliparous women with preeclampsia before 30 weeks of gestation, the recurrence rate for the disorder may be as high as 40% in future pregnancies.
  • 25% of eclamptic women will have HTN during subsequent pregnancies, but only 5% of these will be severe and only 2% will be eclamptic again.
  • Preeclamptic, multiparous women may be at higher risk for subsequent essential HTN; they also have higher mortality during subsequent pregnancies than do primiparous women.
REFERENCES
1. American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122-1131.
2. Gauer R, Atlas M, Hill J. Clinical inquiries. Does low-dose aspirin reduce preeclampsia and other maternal-fetal complications? J Fam Pract. 2008;57(1):54-56.
3. Villa PM, Kajantie E, Räikkönen K, et al. Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials. BJOG. 2013;120(1);64-74.
4. Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database of Syst Rev. 2007;(2):CD004659. doi:10.1002/14651858.CD004659.pub2.
5. Hofmeyr GJ, Belizán JM, von Dadelszen P. Low-dose calcium supplementation for preventing preeclampsia: a systematic review and commentary. BJOG. 2014;121(8):951-957.
6. Magee LA, Helewa M, Moutquin JM, et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. J Obstet Gynaecol Can. 2008;30(3 Suppl):S1-S48.
Codes
&NA;
ICD10
  • O14.90 Unspecified pre-eclampsia, unspecified trimester
  • O15.00 Eclampsia in pregnancy, unspecified trimester
  • O14.00 Mild to moderate pre-eclampsia, unspecified trimester
Clinical Pearls
&NA;
  • Management of preeclampsia depends on both the severity of the condition and the gestational age of the fetus.
  • Diagnosis no longer requires presence of proteinuria.