Pre-eclampsia and Eclampsia

Preeclampsia

Preeclampsia is a multisystem disorder of pregnancy characterized by hypertension developing after 20 weeks of gestation in a previously normotensive woman, accompanied by one or more of the following:

• Proteinuria: Defined as ≥300 mg/24 hours or a protein/creatinine ratio of ≥0.3. Severe proteinuria is no longer mandatory for diagnosis.
• Maternal organ dysfunction: May include:
  • Renal impairment: Serum creatinine >1.1 mg/dL or doubling of baseline levels without an alternate cause.
  • Hepatic dysfunction: Elevated liver enzymes (twice the upper limit of normal) or severe right upper quadrant/epigastric pain.
  • Hematological complications: Thrombocytopenia (<100,000/μL).
  • Neurological complications: Visual disturbances, severe headache, or altered mental status.
• Uteroplacental dysfunction: Evidenced by fetal growth restriction or abnormal Doppler studies.

Eclampsia

Eclampsia is the occurrence of generalized tonic-clonic (grand mal) seizures in a woman with preeclampsia, after excluding other neurological or metabolic causes (e.g., epilepsy, meningitis, hypoglycemia).

• Preeclampsia and eclampsia contribute to 14% of global maternal deaths, accounting for 60,000–75,000 deaths annually.
• The incidence varies geographically, reported to be 4–18% in developing countries.
• Associated with high maternal and perinatal morbidity and mortality, including complications such as:
  • HELLP syndrome: Hemolysis, elevated liver enzymes, low platelets.
  • Placental abruption.
  • Fetal prematurity.

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• Hypertension is defined as:
  • Systolic blood pressure (SBP): ≥140 mmHg, or
  • Diastolic blood pressure (DBP): ≥90 mmHg, measured on two separate occasions at least 4 hours apart.
• Severe hypertension is defined as:
  • SBP ≥160 mmHg or
  • DBP ≥110 mmHg, requiring immediate management.

Preeclampsia is a disease with multiple theories of pathogenesis, and its precise cause and progression remain unknown.

The disease likely results from poor trophoblastic invasion into the myometrium, leading to inadequate remodeling and poor vasodilation of maternal spiral arteries. This defect causes reduced placental perfusion and ischemia, particularly in the second half of pregnancy.

A significant role is played by an imbalance of angiogenic and anti-angiogenic factors, such as elevated levels of soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), along with reduced levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). This imbalance contributes to systemic endothelial dysfunction, a hallmark of preeclampsia.

Many researchers believe the placenta is the primary trigger for maternal endothelial cell injury, which manifests as the clinical features of the disease.

Theories of Pathogenesis:

1. Endothelial Cell Injury Theory
   • Generalized endothelial dysfunction caused by placental ischemia and the release of anti-angiogenic factors (e.g., sFlt-1, sEng).
   • Leads to hypertension, proteinuria, and multi-organ damage.
2. Immunologic Theory
   • Failure of maternal immune tolerance to the semi-allogenic fetus.
   • Associated with abnormal maternal-fetal immune interactions, including natural killer (NK) cell activity and altered HLA-C antigen expression.
3. Angiogenic Imbalance Theory
   • Dysregulation between pro-angiogenic factors (VEGF, PlGF) and anti-angiogenic factors (sFlt-1, sEng).
   • Results in endothelial dysfunction, abnormal vascular permeability, and placental insufficiency.
4. Prostaglandin Imbalance Theory
   • Altered balance between vasodilatory prostaglandins (prostacyclin) and vasoconstrictive thromboxanes.
   • Contributes to increased vascular reactivity and hypertension.
5. Compromised Placental Perfusion Theory
   • Reduced blood flow due to failed spiral artery remodeling and shallow trophoblastic invasion.
   • Causes placental hypoxia and ischemia, releasing toxic mediators into maternal circulation.
6. Altered Vascular Reactivity Theory
   • Increased sensitivity to vasoconstrictors (e.g., angiotensin II) and reduced production of vasodilators (e.g., nitric oxide).
7. Disseminated Intravascular Coagulation (DIC) Theory
   • Microvascular injury leads to widespread activation of the coagulation cascade.
   • Contributes to thrombocytopenia and multi-organ microthrombi.
8. Oxidative Stress and Inflammation Theory
   • Hypoxia and reperfusion injury in the placenta generate reactive oxygen species (ROS).
   • Exacerbates inflammation and endothelial dysfunction.

According to ACOG 2013

1. PE without severe features
2. PE with severe features

Subclassification

1. Early-onset PE (with delivery at <34 + 0 weeks of gestation)
2. Preterm PE (with delivery at <37 + 0 weeks of gestation)
3. Late-onset PE (with delivery at ≥34 + 0 weeks of gestation)
4. Term PE (with delivery at ≥37 + 0 weeks of gestation)

Pre-eclampsia can also be classified as mild or severe; however, this is an old classification.

Severe when it is associated with complications such as—

• Systolic BP of 160 mmHg or diastolic BP of 110 mmHg
• Proteinuria >2g in 24h
• Oliguria < 500ml in 24h
• Cerebral or visual disturbances
• Epigastric pain
• Elevated liver enzymes
• Thrombocytopenia
• Retinal hemorrhages, exudates or papilledema
• Pulmonary edema

The classification of hypertensive diseases in pregnancy according to the NHBPEP Working Group is as follows:

Gestational hypertension

• BP of 140/90 mmHg or greater for the first time during pregnancy
• No proteinuria
• BP returns to normal less than 12 weeks post-partum
• Final diagnosis made only post-partum

Chronic hypertension

• BP of 140/90 mmHg or greater before pregnancy or diagnosed before 20 weeks gestation, not attributable to gestational trophoblastic disease
OR
• Hypertension first diagnosed after 20 weeks gestation and persistent after 12 weeks post-partum

Superimposed pre-eclampsia (on chronic hypertension)

• New onset proteinuria (≥300 mg/24h) in a woman with hypertension but no proteinuria before 20 weeks gestation.
• A sudden increase in proteinuria or blood pressure, or platelet count less than 100,000 in women with hypertension and proteinuria before 20 weeks gestation.

Maternal Factors

• First pregnancy (nulliparity)
• Previous history of preeclampsia
• Family history of preeclampsia (first-degree relative)
• Black race
• Maternal age >40 years
• 10 years or more since last baby
• Low socioeconomic status
• Hydatidiform mole
• Polyhydramnios
• Multiple pregnancy
• Obesity (BMI >30)
• Diabetes mellitus (DM)
• Chronic hypertension
• Pre-existing renal disease
• Thrombophilia
• Autoimmune disease (e.g., systemic lupus erythematosus, antiphospholipid syndrome)
• Low vitamin D levels
• Low dietary and serum calcium
• High level of glycosylated fibronectin in the first trimester

Couple-Related Factors

• Limited sperm exposure
• Primiparity (first pregnancy)
• Pregnancies after donor insemination, oocyte donation, or embryo donation
• Protective effect of partner change in the case of previous pre-eclamptic pregnancy
• Maternal susceptibility genes

Other Factors

• Smoking (reduced risk)
• Hydropic degeneration of the placenta

Clinical Features of Severe Preeclampsia and Eclampsia

Hypertension

• Present in all cases, often the earliest clinical finding.
• Typically develops in the third trimester, especially after 37 weeks of gestation.
• Blood pressure rises to ≥140/90 mmHg, with some cases developing before 34 weeks or postpartum.
• Differential Diagnosis: Pheochromocytoma can present similarly.

Epigastric Pain

• Associated with severe preeclampsia; constant and severe pain, often at night.
• May radiate to the right hypochondrium or back; nausea and vomiting may also occur.
• Signs of Severity: Liver tenderness due to swelling or bleeding from Glisson capsule.
• Complications: Liver rupture, hemorrhage, or acute pancreatitis.

Headache

• Common in severe preeclampsia, often throbbing, may be temporal, frontal, or diffuse.
• Persistent despite over-the-counter analgesics; can be incapacitating.
• Mechanism: Cerebral edema, vasospasm, loss of cerebrovascular autoregulation, or posterior reversible leukoencephalopathy syndrome (PRES).
• Management: Acetaminophen may be used, but not in severe hepatic insufficiency.

Visual Symptoms

• Include blurred vision, photopsia (flashing lights), scotomata (dark spots), and diplopia.
• Retinal arteriolar spasm is a common cause.
• Complications: Retinal artery occlusion, retinal detachment, optic nerve damage, and possible cortical blindness.

Generalized Hyperreflexia

• Hyperreflexia is common, and sustained ankle clonus may be present.

Peripheral Edema

• Sudden, rapid weight gain and facial edema are common, requiring diagnostic evaluation for preeclampsia.
• Edema may be caused by capillary leakage or overfill edema.

Pulmonary Edema

• Occurs in severe preeclampsia, marked by dyspnea, chest pain, and decreased oxygen saturation.
• Etiology: Due to elevated pulmonary vascular pressure, capillary leak, left heart failure, severe hypertension, or iatrogenic volume overload.

Oliguria

• Urine output may fall to <500 mL/24 hours in severe cases, indicating acute kidney injury.
• Rare Case: Polyuria from transient diabetes insipidus due to hepatic dysfunction.

Stroke

• Severe stroke, often hemorrhagic, leading to death or disability in severe preeclampsia/eclampsia.
• Risk Factors: Persistent severe hypertension, headache, seizures.
• Prevention: Lowering blood pressure may reduce the risk.

Abruptio Placentae

• Occurs in 3% of pregnancies with severe preeclampsia, with less than 1% in mild cases.

Seizure

• A hallmark of eclampsia, occurring in 1 in 50 cases of severe preeclampsia.
• Histopathology: Brain hemorrhage, edema, ischemic damage, microinfarcts, fibrinoid necrosis.
• Neuroimaging: May show findings consistent with posterior reversible encephalopathy syndrome (PRES).

1. Urinalysis

• Proteinuria: Proteinuria is a hallmark of preeclampsia, and daily urine tests should be performed. A 24-hour urine collection is recommended to quantify protein loss and assess disease progression. The degree of proteinuria correlates with the severity of renal involvement and can be used as a prognostic marker.

2. Hematocrit/Hemoglobin

• Hematocrit: Elevated hematocrit can indicate hemoconcentration, which is due to reduced plasma volume in preeclampsia. This is often seen in the early stages of the disease.
• Hemoglobin: Anemia is also important to assess, as severe anemia can increase the risk of developing preeclampsia. Monitoring hemoglobin helps detect changes in blood volume or oxygen-carrying capacity.

3. Platelet Count

• Platelet Count: Thrombocytopenia is common in severe preeclampsia, occurring due to platelet consumption and microvascular damage. A platelet count below 100,000/µL is a critical finding, suggesting worsening disease or the development of HELLP syndrome (Hemolysis, Elevated Liver Enzymes, and Low Platelets).

4. Electrolytes, Creatinine, and Uric Acid

• Serum Uric Acid: Uric acid levels are elevated in preeclampsia due to impaired renal excretion. Elevated uric acid correlates with poor maternal and fetal outcomes, particularly in severe cases.
• Creatinine: Serum creatinine may rise in preeclampsia, indicating impaired kidney function or renal failure. Monitoring creatinine helps assess renal compromise.
• Electrolytes: Electrolyte imbalances, particularly sodium and potassium, should be monitored regularly, as disturbances can occur due to renal dysfunction.

5. Liver Function Tests

• Liver Enzymes: Elevated liver enzymes, including alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH), may indicate hepatic involvement, especially in severe preeclampsia or HELLP syndrome. These tests are essential for monitoring liver function and detecting liver damage.

6. Fetal Ultrasound

• Fetal Well-being: Ultrasound is crucial for assessing fetal development and placental health. In cases of preeclampsia, intrauterine growth restriction (IUGR) is common due to poor placental perfusion, which can lead to reduced fetal oxygen and nutrient supply.
• Doppler Flow Studies: Doppler ultrasound can assess placental circulation and fetal blood flow. Abnormal Doppler results, such as increased resistance in the umbilical artery, may indicate compromised placental function and predict poor fetal outcomes.

Preeclampsia and Eclampsia: Clinical Management and Treatment

Delivery is the definitive treatment for preeclampsia. Once the diagnosis of preeclampsia is established, delivery is the only cure for the disease, as it prevents the development of maternal or fetal complications due to disease progression. The resolution of the condition is achieved after delivery, regardless of the gestational age. The progression of the disease is life-threatening and can develop suddenly, necessitating careful monitoring and management.

The optimal management of a woman with preeclampsia depends on several key factors:

• Gestational age
• Severity of the disease
• Maternal and fetal condition

Management Strategy Based on Disease Severity

1. Asymptomatic Patients

In asymptomatic patients with mild preeclampsia, ambulatory care with close monitoring can be considered, as long as there are no signs of progression to severe preeclampsia.

2. Mild Disease

For mild preeclampsia, the recommended management includes bed rest and delivery once the gestational age is appropriate. However, in preterm cases, the risks associated with preterm birth (e.g., neonatal complications) should be carefully balanced against the risks of disease progression. If the mother and fetus are stable and there is no evidence of serious end-organ dysfunction, a conservative approach may be adopted, with close monitoring for any signs of progression.

3. Severe Disease

Severe preeclampsia requires more aggressive management, with an immediate focus on:

• Preventing convulsions (eclampsia)
• Controlling maternal blood pressure
• Prompt delivery, particularly at or beyond 37 weeks gestation
• In cases between 32-34 weeks, delivery should occur after confirming fetal lung maturity, often with the use of corticosteroids to promote fetal lung development.
• Prophylactic magnesium sulfate (MgSO4) is recommended for seizure prevention in severe cases.

Timing of Delivery

• A pregnancy complicated by mild preeclampsia at or beyond 37 weeks should be delivered, as the risks associated with continuing the pregnancy generally outweigh the benefits.
• For pregnancies with mild disease before 37 weeks, close monitoring is essential. A biophysical profile (BPP) is often performed twice per week to assess fetal well-being and guide management decisions. If there are signs of fetal compromise or worsening maternal condition, delivery may be indicated.
• In severe preeclampsia, delivery should be initiated as soon as lung maturity is confirmed or when maternal or fetal well-being is at risk. This often involves corticosteroids for fetal lung development and magnesium sulfate for seizure prophylaxis.

Monitoring and Investigations

• Daily urinalysis and blood pressure monitoring are essential in tracking the progression of preeclampsia.
• Baseline investigations should include complete blood count (CBC), liver and renal function tests, and coagulation profile to assess for complications such as hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome).
• Be vigilant for dangers suggesting complications, including:
  • Severe headache or visual disturbances
  • Epigastric pain or right upper quadrant pain (which could indicate liver involvement)
  • Oliguria or significant changes in urine output

Pharmacologic Management

• Antihypertensives: If diastolic blood pressure (DBP) is consistently above 100 mmHg, antihypertensive medications are indicated. Common choices include:
  • Labetalol (preferred due to its dual alpha- and beta-blocking properties)
  • Nifedipine (extended-release)
  • Methyldopa
• Sedatives: The use of sedatives in the management of preeclampsia is generally not recommended unless necessary for seizure prevention. If seizures occur, magnesium sulfate is the drug of choice.

Vaginal vs. Cesarean Delivery

• Vaginal delivery is preferred whenever possible, as it is associated with fewer complications than cesarean delivery.
• However, cesarean delivery should be considered if there are obstetric indications, such as fetal malpresentation, non-reassuring fetal heart tracing, or maternal complications that make vaginal delivery unsafe.

Emergency Management of Severe Preeclampsia and Eclampsia

Severe preeclampsia and eclampsia are medical emergencies that require prompt action to prevent maternal and fetal complications, including seizures, stroke, organ failure, and fetal demise. Immediate resuscitation and stabilization of the mother are essential before considering delivery.

1. Resuscitation and Stabilization

• Ensure Airway Patency: Ensure the patient has an open airway, especially if seizures have occurred. Prepare for suctioning to clear the airway and ensure adequate oxygenation.
• Oxygen Therapy: Administer oxygen to maintain adequate oxygen saturation.
• Monitor Vital Signs: Continuous monitoring of blood pressure, heart rate, and oxygen saturation is essential.

2. Seizure Control

• Magnesium Sulfate (MgSO₄): The first-line treatment for seizure prevention and control in eclampsia. Magnesium sulfate is administered as a loading dose followed by maintenance doses.
  • Loading Dose: 4-6 g IV over 15-20 minutes.
  • Maintenance Dose: 1-2 g/hour IV.



• If seizures persist despite magnesium sulfate, additional benzodiazepines (e.g., diazepam) can be given:
  • Diazepam: 10-20 mg IV, repeated if necessary.
• Monitor for Magnesium Toxicity: Regular monitoring is crucial to prevent magnesium toxicity, which can lead to severe complications, including respiratory arrest and cardiac failure.

3. Control Hypertension (HTN)

• Antihypertensive Therapy is used to reduce the risk of maternal stroke and organ damage. The goal is to lower diastolic blood pressure (DBP) to 90-100 mmHg.
  • Hydralazine: The most commonly used antihypertensive in the acute setting. 5-10 mg IV slowly, repeated every 30 minutes as needed.
  • Labetalol: A beta-blocker and alpha-blocker combination, given IV. Initial dose is 10-20 mg IV; may be repeated or escalated as needed.
  • Nifedipine: A calcium channel blocker used orally in some settings. 20-30 mg every 12 hours.
• Note: Close monitoring of blood pressure and maternal condition is required to prevent overshooting and hypotension.

4. Delivery Considerations

• Cervical Assessment: Assess the state of the cervix to determine the possibility of vaginal delivery. If induction of labor is feasible, proceed accordingly. However, cesarean delivery may be needed depending on maternal condition or fetal distress.
• Maternal Stability: Only proceed with delivery once the mother’s condition is stabilized, and severe hypertension, organ dysfunction, or seizures are under control.
• Timing: Delivery should be planned once the mother is stable, taking into account the gestational age and fetal condition.

5. Fluid Management

• Adequate Fluid Resuscitation: Ensure appropriate fluid balance. However, avoid excessive fluid administration, as this may exacerbate edema and worsen pulmonary edema. Use isotonic saline or Ringer's lactate for resuscitation.
• Urine Output: Monitor urine output carefully to assess kidney function. A minimum of 25 mL/hr is expected.

6. Magnesium Sulfate Toxicity Monitoring

Magnesium sulfate toxicity can occur, and its effects can be life-threatening. Key parameters to monitor for signs of toxicity include:

• Knee Jerk: The knee jerk reflex should be present. Loss of the knee jerk is the first sign of magnesium toxicity, which occurs at serum levels of 3.5-5 mmol/L.
• Respiratory Rate: The respiratory rate should be greater than 16 breaths/min. Respiratory depression can occur at serum magnesium levels of 5-6.5 mmol/L.
• Urine Output: Maintain urine output above 25 mL/hr. Reduced urine output may indicate impending toxicity.
• Serum Magnesium Levels: Regular monitoring of serum magnesium levels is necessary to avoid toxicity.
  • Respiratory Paralysis: Occurs at serum magnesium levels of 5-6.5 mmol/L.
  • Cardiac Conduction Changes: Occurs at >7.5 mmol/L.
  • Cardiac Arrest: May occur at serum magnesium levels >12.5 mmol/L.

7. Magnesium Sulfate Toxicity Management

If signs of magnesium toxicity are detected, immediate action is required:

• Administer Calcium Gluconate: The antidote for magnesium toxicity is 1 g of 10% calcium gluconate, given IV slowly over 10 minutes.
• Close Monitoring: Continue to monitor vital signs, serum magnesium levels, and clinical parameters to assess the response to treatment.

Complications

Maternal Complications:

1. HELLP Syndrome (Hemolysis, Elevated Liver Enzymes, Low Platelets):

   A severe form of preeclampsia characterized by hemolysis, elevated liver enzymes, and low platelet count. It can lead to liver rupture, acute renal failure, and disseminated intravascular coagulation (DIC).

2. Pulmonary Edema:

   Fluid accumulation in the lungs due to increased vascular permeability and renal dysfunction, often exacerbated by excessive fluid administration or hypertension. It can lead to respiratory distress and requires immediate management.

3. Hepatic Rupture:

   A rare but life-threatening complication of severe preeclampsia or HELLP syndrome, where the liver capsule becomes distended and may rupture, leading to internal bleeding, shock, and potentially death.

4. Renal Failure:

   Acute kidney injury can occur due to renal vasoconstriction, glomerular damage, or tubular injury. Elevated serum creatinine and urine output monitoring are key in identifying renal dysfunction.

5. Seizure :

   Seizures in the presence of preeclampsia, not caused by another underlying condition, represent eclampsia and are a direct consequence of hypertension and end-organ damage.

6. Cerebral Hemorrhage:

   Severe hypertension can lead to cerebral vasculature rupture, resulting in intracranial hemorrhage, which can be fatal or cause long-term neurological damage.

Fetal Complications:

1. Prematurity:

   Preterm delivery is common, often due to the need for early delivery to prevent maternal complications. Preterm birth increases the risk of neonatal morbidity and mortality, including respiratory distress syndrome (RDS).

2. Fetal Distress:

   The fetus may experience non-reassuring fetal heart tracings, indicating fetal hypoxia or acidosis, which may necessitate emergency delivery.

3. Intrauterine Growth Restriction (IUGR):

   Poor placental perfusion can result in restricted fetal growth, increasing the risk of stillbirth and long-term developmental issues for the baby.

4. Oligohydramnios:

   Decreased amniotic fluid due to placental insufficiency can lead to cord compression, fetal distress, and preterm labor.

5. Placental Abruption:

   Premature separation of the placenta from the uterine wall, often associated with severe hypertension or trauma, leading to bleeding, fetal hypoxia, and potential stillbirth.

6. Stillbirth:

   The most severe fetal complication of preeclampsia, often caused by placental insufficiency or severe maternal complications such as cerebral hemorrhage or renal failure.

Prevention

Prevention of Preeclampsia

• Aspirin (Low-dose):

  Aspirin (60–150 mg daily) given between 11-16 weeks of gestation has been shown to reduce the risk of preeclampsia, particularly in high-risk pregnancies (e.g., history of preeclampsia, chronic hypertension, diabetes, or renal disease).

• Vitamins C and E:

  Some studies have suggested that vitamins C and E may reduce oxidative stress, which is thought to play a role in the pathogenesis of preeclampsia. However, the clinical efficacy of this prevention strategy remains uncertain.

• Calcium:

  Calcium supplementation (1–2 g/day) is recommended in women with low calcium intake or those at risk for preeclampsia, as it may help reduce the incidence, particularly in low-income countries where calcium intake is typically low.

• Fish Oil:

  Omega-3 fatty acids in fish oil have shown promise in some studies to reduce the risk of preeclampsia by improving placental blood flow and reducing inflammatory processes, although more research is needed.

• Magnesium:

  Adequate levels of magnesium are important in maintaining vascular function and preventing the progression of preeclampsia. However, magnesium supplementation alone has not been conclusively shown to prevent preeclampsia but is essential for seizure prophylaxis in eclamptic patients.

Universal screening

The best combined test includes—

Maternal risk factors

Mean arterial pressure (MAP)

Serum placental growth factor (PLGF) and uterine artery pulsatility index (UTPI)

Serum pregnancy-associated plasma protein (PAPP-A)

Prognosis

Hypertension and other signs or symptoms of organ dysfunction associated with pre-eclampsia will have remitted by 6 weeks post-partum examination.

If abnormalities persist, the patient should be examined 6 weeks later, when any persisting pathologic conditions will probably be chronic.

Recurrence rates are higher among multiparous women with pre-eclampsia than among nulliparous women with pre-eclampsia.

Risk is also increased among multiparous women who conceive with a new father, even when the first pregnancy was normotensive.

Pre-eclampsia-eclampsia by itself is not a cause of chronic hypertension.

Women with normotensive births have a reduced risk for remote hypertension.