pre-eclampsia/eclampsia

Introduction

Hypertension, proteinuria & generalized edema after 20 weeks of gestation.

Eclampsia includes the addition of tonic-clonic seizures.

Etiology

• not clearly understood
• placental insufficiency is fundamental
• possible abnormality of fetal side of placental circulation
• placental neurokinin B may play a role
• mutant mineralocorticoid receptor may play a role
• risk factors
  • highest risk factors
    • history of preeclampsia
    • chronic hypertension
    • connective tissue disease/rheumatologic disease
      • antiphospholipid antibody syndrome
    • multigestation (twins)
    • diabetes mellitus
    • obesity
    • chronic renal failure
  • moderate risk factors
    • primigravida
    • family history of pre-eclampsia
    • renal insufficiency (serum creatinine > 1.4 mg/dL)
  • other risk factors
    • extremes of child-bearing age
    • polyhydramnios
    • erythroblastosis fetalis
    • hydatidiform mole (1st trimester)
    • vascular disease
    • pheochromocytoma
  • no strong evidence supports a causal effect of vitamin D status on gestational hypertension or pre-eclampsia

Pathology

• maternal vascular hyper-reactivity
  • may be caused by subclinical endothelial dysfunction unmasked by the cardiovascular stress of pregnancy
  • unlike normal pregnant women, those with pre-eclampsia are sensitive to pressor effects of angiotensin II
• diminished glomerular filtration rate (GFR)
• possible imbalance in ratio of TxA2 to PGI2
• vasospasm & thrombosis
• uteroplacental hypoperfusion
• disordered endothelin metabolism
• widespread effects on endothelial cells
• decreased plasma volume
• changes in capillary permeability favoring edema
• renal Na+ retention
• endotheliosis (renal lesion)
  • generalized swelling of glomerular endothelial cells
  • glomerular deposition of fibrinogen
  • infiltration of lipid-laden macrophages
• liver injury

Genetics

• associated with defects in STOX1 gene (preeclampsia/eclampsia 4)
• susceptibility associated with genetic variation in EPHX1
• predisposition associated with fetal inheritance of chromosomally integrated human herpesvirus 6

Clinical manifestations

• headache
• visual disturbances
• abdominal pain +/-
• chest pain*
• dyspnea*
• new onset hypertension
  • systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg
• proteinuria (> 300 mg/24 hr or > 300 mg/g creatinine)
• rapidly worsening edema
• development of convulsions defines eclampsia
• generally occurs after 20th week of gestation*
  • 44% of cases occur postpartum

Diagnostic criteria

• >= 20 weeks of gestation
• hypertension
  • blood pressure >= 140 mm Hg systolic or >= 90 mm Hg diastolic on 2 occasions >= 4 hours apart with previously normal blood pressure OR
  • blood pressure >= 160 mm Hg systolic or >= 100 mm Hg diastolic (confirmed immediately) AND
• proteinuria
  • 24 hour urine protein >= 300 mg/24 hours OR
  • urine protein/creatinine ratio >= 300 mg/gram OR
  • urine dipstick reading of 1+ (urine protein measurement not available)

OR, in the absence of proteinuria

• new onset hypertension AND
• new onset of
  • thrombocytopenia (platelet count < 100,000/uL) OR
  • renal insufficiency in the absence of other kidney disease (serum creatinine > 1.1 mg/dL OR a doubling of serum creatinine) OR
  • liver dysfuction (elevation of serum transaminases to twice the upper limit of normal) OR
  • pulmonary edema OR
  • cerebral dysfunction or visual impairment

eclampsia includes the addition of seizures

Laboratory

• more useful in the management of pre-eclampsia than the diagnosis
• initial evaluation
  • complete blood count (decreased platelet count*)
  • urinalysis, urine protein: proteinuria (albuminuria)
  • 24 hour urine protein > 300 mg/24 hours
    • proteinuria is a sign of disease progression
    • generally warrants hospitalization
  • serum transaminases (mild increase in serum ALT, serum AST)
  • serum uric acid (generally increased)
    • levels may correlate with severity of disease
  • serum creatinine*
  • pulse oximetry*
• other testing as indicated
  • creatinine clearance
  • 24 hour urine protein
  • 24 hour urine vanillylmandelic acid (VMA) & metanephrines if suspecting pheochromocytoma
• investigational
  • serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1) are increased
  • serum placental growth factor (PlGF) levels are decreased

Complications

• seizures (i.e. eclampsia)
• HELLP syndrome (4-12%)
• risk factor for stroke later in life
• may increase risk for dementia later in life
• retinal disease later in life
  • retinal detachment (RR=2.2)
  • non-diabetic retinopathy (RR=2.2-4.6)
  • diabetic retinopathy (RR=4.1-9.3)
  • risk greatest for severe pre-eclampsia or onset before 34 weeks gestation
• 2-fold increase in risk of congenital heart defects (16.7 vs 8.6 per 1000 infants)
• iscreased risk for ischemic heart disease &/or stroke (RR=1.3) in offspring of mothers with pre-eclampsia
• increased risk for later life chronic kidney disease, especially hypertensive nephropathy & ESRD

Management

• pharmaceutical agents (diastolic BP > 100 mm Hg)
  • methyldopa (drug of choice)
  • intravenous labetalol or hydralazine or short-acting nifedipine (drugs of choice for hypertensive crisis)
  • diazoxide for hypertension refractory to hydralazine
  • MgSO4 to prevent seizures (eclampsia)
    • intrapartum or post-partum
    • 4-6 g loading dose
    • continuous infusion of 2-3 g/hr to maintain serum Mg+2 level of 4-7 meq/L
    • continue for at least 24 hours after delivery
    • cautions:
      • maternal respiratory paralysis
      • synergistic hypotensive effect with Ca+2 channel blockers
    • maintain diastolic pressure 90-105 mm Hg, MAP 105-126
    • reduces risk of progression to eclampsia (50%)
    • NNT = 90 for prevention of seizure
      • may reduce risk of maternal mortality
    • no benefit for infant
    • 25% of women report adverse events
      • flushing is most common adverse effect
      • NNH = 200 for respiratory depression
      • NNH = 37 to necessitate C-section
  • beta blockers are controversial
    • labetolol is beta-blocker of choice
  • Ca+2 channel blockers are promising
  • nitroprusside is a last resort
  • prazosin used in pregnant patients with pheochromocytoma
  • diuretics are controversial
  • peripartum fluid restriction may increase risk of acute renal failure in pregnancy
• pharmaceutical agents (prophylaxis in high-risk patients)
  • low dose aspirin 75-150 mg/day initiated at the end of the 1st trimester to inhibit formation of TxA2
  • USPSTF recommends aspirin 81 mg/day in high-risk women
    • low-dose aspirin reduces risks for preeclampsia by 24%, intrauterine growth restriction by 20%, & preterm birth by 14%
  • low-dose aspirin 150 mg/day in high-risk women from 11-14 weeks gestation until 36 weeks gestation lowers risk
    • discontinuation of aspirin at 24-28 weeks of gestation is noninferior to continuation until term if serum soluble fms-like tyrosine kinase-1 to serum placental growth factor (sFlt-1/PlGF) ratio is normal
  • calcium supplements may be of benefit
• delivery of fetus
  • progressive pre-eclampsia after 30th week of gestation
  • worsening maternal conditions
  • laboratory evidence of end-organ dysfunction
    • platelet count < 100,000/uL
    • elevated serum ALT, serum AST
  • eclampsia
  • HELLP syndrome
  • deterioration of fetal conditions
  • definitive therapy & treatment of choice
  • delivery decision should not be based on the extent of proteinuria
  • if hypertensive crisis, stabilize blood pressure prior to delivery
    • intravenous labetalol or hydralazine or short-acting nifedipine (drugs of choice for hypertensive crisis)
  • delivery of fetus at 37 weeks gestation optimizes maternal & fetal outcomes
• bedrest
• diet:
  • 1-2 g of calcium/day suggested, but no data to substantiate
    • calcium supplementation to prevent pre-eclampsia in populations where calcium intake is low [NGC, WHO]
  • supplmental vitamin C or vitamin E to prevent eclampsia to prevent eclampsia is not recommended
• post delivery
  • ambulatory BP monitoring
    • identifies hypertension in more women than office-based measurement
    • identifies lack of night-time dip in systolic BP
• screening:
  • screening with blood-pressure at every prenatal visit

Notes

* components of fullPIERS model predicting adverse maternal outcomes (see Clinical manifestations & Laboratory)

More general terms

• pregnancy-induced hypertension; gestational hypertension (PIH)
• hypertension & proteinuria

More specific terms

• eclampsia

Additional terms

• HELLP syndrome

Database

• OMIM: https://mirror.omim.org/entry/189800