Preeclampsia and Eclampsia

• Abnormal Placentation and Angiogenic Imbalance: In early-onset preeclampsia (typically <34 weeks), inadequate remodeling of spiral arteries by extravillous trophoblasts results in poor placental perfusion. This hypoxic placenta releases excess soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which antagonize placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), respectively. The elevated sFlt-1/PlGF ratio (>85 or rising trajectory) defines the angiogenic imbalance and directly mediates endothelial dysfunction, the pathogenic hallmark of preeclampsia. This mechanism drives the "placental" phenotype, usually presenting with severe features and fetal growth restriction.

• Endothelial Dysfunction as the Central Mechanism: Both early and late-onset preeclampsia are characterized by widespread endothelial injury and activation. The sFlt-1-mediated inhibition of VEGF and PlGF signaling disrupts the normally quiescent endothelium, leading to increased vascular permeability, microvascular thrombosis, and loss of vasodilatory capacity. Endothelial dysfunction explains the cardinal manifestations: systemic vasoconstriction increases blood pressure; increased vascular permeability causes proteinuria and pulmonary edema; platelet consumption results in thrombocytopenia; and hepatic sinusoidal endothelial injury produces hemolysis, elevated liver enzymes, and right upper quadrant pain (the HELLP syndrome). The endothelium becomes pro-thrombotic via upregulation of tissue factor and increased circulating microparticles.

• Immune and Inflammatory Activation: Preeclampsia involves a state of systemic inflammation with increased circulating cytokines (TNF-α, IL-6, IL-8), activated endothelial cells expressing adhesion molecules (ICAM-1, VCAM-1), and increased recruitment of leukocytes. Oxidative stress and dysregulation of complement activation (particularly the alternative pathway) contribute further. In the "maternal" phenotype (late-onset preeclampsia, typically ≥34 weeks), maternal constitutional factors—including maternal obesity, insulin resistance, chronic hypertension, and systemic inflammation—may dominate over placental insufficiency.

• Renal Endotheliosis and Proteinuria: A pathognomonic renal lesion occurs: glomerular endotheliosis with swelling of endothelial cells, subendothelial deposits, and foot process effacement on electron microscopy. This lesion impairs glomerular filtration and increases protein leakage without immune complex deposition, explaining the "non-selective" proteinuria of preeclampsia. The proteinuria is typically <3 g/day but may exceed 5 g/day in severe cases.

• Cerebral Endothelial Dysfunction and Hypertensive Encephalopathy: Severe hypertension overwhelms cerebral autoregulation, particularly in chronically normotensive women, leading to arteriolar vasospasm, endothelial injury, increased blood-brain barrier permeability, and vasogenic edema. This mechanism precipitates eclamptic seizures, which are not primarily due to cerebral edema per se but represent hypertensive encephalopathy with associated seizure activity. Posterior reversible encephalopathy syndrome (PRES) frequently accompanies severe preeclampsia.

• Nulliparity and Primigravidity: Nulliparous women have a 2–3-fold increased risk compared to multiparous women, suggesting an immunological mechanism whereby prior exposure to paternal antigens (via pregnancy) provides immune tolerance. This underlies why preeclampsia is rare after one successful pregnancy in a multiparous woman, though risk resets with a new partner.

• Preexisting Hypertension: Women with chronic hypertension have substantially increased risk (10–25% develop superimposed preeclampsia) and typically develop early-onset disease with severe features. The distinction between chronic hypertension with superimposed preeclampsia versus gestational hypertension is clinically important for management intensity.

• Diabetes Mellitus (Type 1, Type 2, and Gestational Diabetes): Maternal diabetes increases preeclampsia risk 2–3 fold, particularly in those with poor glycemic control or microvascular complications. The mechanism involves endothelial dysfunction from hyperglycemia, oxidative stress, and AGE formation.

• Maternal Age >35 Years: Advanced maternal age increases risk, though this association is partially confounded by higher baseline hypertension and metabolic syndrome prevalence.

• Obesity (BMI ≥30 kg/m²): Maternal obesity is associated with increased preeclampsia risk through mechanisms involving insulin resistance, adipokine dysregulation, systemic inflammation, and constitutive endothelial activation.

• Previous Preeclampsia or Adverse Pregnancy Outcome: Women with a prior preeclamptic pregnancy have recurrence risk of 20–25% with the same partner (lower than previously thought, implicating both maternal and paternal factors). Recurrence risk is highest if prior preeclampsia was early-onset or associated with severe features. A history of fetal death, severe growth restriction, or placental abruption also increases risk.

• Antiphospholipid Syndrome and Thrombophilia: Antiphospholipid antibodies (anticardiolipin, anti-β2 glycoprotein I, lupus anticoagulant) significantly increase preeclampsia risk through placental thrombosis and inflammation. Other thrombophilias (Factor V Leiden, prothrombin mutation) show modest associations.

• Systemic Autoimmune and Vascular Diseases: SLE, antiphospholipid syndrome, and chronic kidney disease substantially elevate preeclampsia risk. SLE increases risk by 10-fold or more.

• Polycystic Ovary Syndrome (PCOS): PCOS increases risk through associated insulin resistance and chronic inflammation.

• Maternal Metabolic Syndrome: Pregestational insulin resistance, dyslipidemia, and hypertension create a prothrombotic and pro-inflammatory milieu predisposing to preeclampsia.

• Multiple Gestation: Multifetal pregnancy (twins, triplets) carries 2–3-fold increased risk and more frequent severe disease.

• Assisted Reproductive Technology (ART): Independent increased risk, though partially attributable to confounders such as maternal age and increased twinning.

• Parental/Genetic Factors: Strong genetic contribution (heritability ~40%) and familial clustering. Paternal factors matter: preeclampsia risk is lower with multiparous women exposed to the same partner and higher with new partners, implicating paternal antigen-specific tolerance.

Cardinal Symptoms

• Hypertension: New-onset elevation in blood pressure (systolic ≥140 or diastolic ≥90 mmHg) documented on two occasions ≥4 hours apart (or same visit if severe range ≥160/110). Critical: systolic-diastolic discordance may occur (e.g., elevated systolic with normal diastolic), and the definition includes both thresholds separately. Severe hypertension (≥160/110) constitutes a severe feature mandating expedited evaluation and delivery planning.

• Proteinuria: Typically >0.3 g/24-hour urine collection (or ≥1+ on dipstick in absence of UTI) in the context of new hypertension. Nephrotic range proteinuria (>3.5 g/24 hours) may occur but is not necessary for diagnosis; importantly, dipstick-negative proteinuria does not exclude preeclampsia, and serum creatinine elevation or oliguria without proteinuria can define end-organ dysfunction.

• Headache: Often the most distressing symptom in severe preeclampsia, typically diffuse, throbbing, and resistant to analgesics. Headache reflects cerebral endothelial dysfunction and is an important red flag symptom that may precede eclampsia. Migraine sufferers report qualitatively different headaches.

• Right Upper Quadrant or Epigastric Pain: Often severe and pleuritic, reflecting hepatic capsular distension from inflammation and edema or, in HELLP syndrome, from hepatic infarction or hemorrhage. This symptom carries high specificity for severe disease and warrants immediate lab assessment for HELLP.

• Visual Disturbances: Cortical blindness, scotomata, blurred vision, or photopsia reflect posterior reversible encephalopathy syndrome (PRES) or hypertensive retinopathy. Findings include retinal arteriolar narrowing, flame hemorrhages, cotton-wool spots, and papilledema in severe cases.

• Dyspnea and Chest Pain: Dyspnea may reflect pulmonary edema from increased capillary permeability and reduced plasma oncotic pressure (especially if associated with severe proteinuria or HELLP). Chest pain suggests pulmonary involvement or, rarely, peripartum cardiomyopathy.

• Altered Mental Status, Confusion, or Agitation: Heralds eclampsia or cerebral involvement and requires urgent neuroimaging and immediate delivery planning.

Physical Examination Findings

• Hypertension with Pathologically Elevated Blood Pressure: Severe range (≥160/110) or significantly elevated from baseline. Mean arterial pressure (MAP) ≥125 mmHg also denotes severity.

• Edema: Facial or hand edema (pathologically, rapid-onset after 20 weeks), which differs from dependent edema. Pulmonary edema presents as crackles on auscultation and may progress to frank respiratory distress. Note: edema is neither sensitive nor specific and can occur in normal pregnancy; sudden, rapid onset is more concerning.

• Hyperreflexia and Clonus: Exaggerated deep tendon reflexes (≥3+) and, critically, positive clonus (sustained rhythmic contraction of calf muscles when ankle dorsiflexed passively and held)—clonus is a sign of severe disease and increased seizure risk. Clonus should be sought systematically as it predicts eclampsia better than other physical findings.

• Right Upper Quadrant Tenderness: Hepatic tenderness from capsular distension, particularly important when combined with elevated liver enzymes (HELLP).

• Fundoscopic Changes: Papilledema, retinal arteriolar narrowing, hemorrhages, exudates, or cotton-wool spots indicate severe hypertensive retinopathy.

• Fetal Findings: Fetal growth restriction on ultrasound (>20% estimated weight below 10th percentile), oligohydramnios (amniotic fluid index <5 cm or largest pocket <2 cm), and abnormal fetal heart rate patterns (elevated baseline, reduced variability, variable decelerations) suggest placental insufficiency and fetal compromise.

Important Clinical Variants

• Preeclampsia Without Severe Features ("Non-Severe" Preeclampsia): New hypertension ≥140/90 and proteinuria in absence of severe range BP or end-organ dysfunction findings. May be managed expectantly at ≥37 weeks or in select cases with close outpatient surveillance if <37 weeks (though delivery remains gold standard).

• Preeclampsia With Severe Features: Includes any of the following: systolic BP ≥160 or diastolic BP ≥110 mmHg (confirmed on two occasions ≥15 minutes apart), platelet count <100,000/μL, creatinine >1.1 mg/dL, pulmonary edema, cerebral or visual symptoms, or impaired liver function (AST/ALT >2× upper limit normal). Severe features mandate expedited delivery at any gestational age.

• HELLP Syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets): A subset of severe preeclampsia occurring in 0.5–1.4% of preeclamptic pregnancies, classically presenting in the third trimester with right upper quadrant pain, hemolytic anemia (schistocytes on smear, elevated LDH, low haptoglobin), transaminitis (AST >70 IU/L), and thrombocytopenia (<100,000/μL). HELLP carries higher morbidity/mortality (15–25% maternal complications) and requires expedited delivery regardless of gestational age.

• Atypical or Superimposed Preeclampsia: Women with chronic hypertension who develop superimposed preeclampsia show sudden worsening of blood pressure control, new or worsening proteinuria (or a 0.3 g/24-hour increase in previously normotensive women), or new end-organ dysfunction. The baseline BP may be chronically elevated, making the diagnosis subtle.

• Postpartum Preeclampsia and Eclampsia: Occurs in 1–2% of pregnancies, typically within 48 hours of delivery but may occur up to 4 weeks postpartum. Often insidious, with delayed recognition because hypertension or seizures in the puerperium may be attributed to other causes. Carries similar morbidity to antepartum disease.

• Eclampsia: The convulsive manifestation of preeclampsia, occurring in <1% of preeclamptic pregnancies in developed countries but up to 5–10% in low-resource settings. Seizures are typically generalized tonic-clonic, last 30 seconds to several minutes, and may be multiple. Seizures can occur antepartum, intrapartum, or postpartum. Some cases are "atypical eclampsia" with seizures in the absence of prodromal hypertension or proteinuria, though virtually all have biochemical evidence of preeclampsia.

Diagnostic Criteria

• Hypertension in Pregnancy: Defined as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg (either threshold alone suffices), documented on two separate occasions ≥4 hours apart between 20 weeks and end of first postpartum week (or same visit if severe range ≥160/110). Measurement should be done with the patient seated with feet on floor and arm at heart level. Severe range hypertension (≥160/110) alone constitutes a severe feature and warrants immediate evaluation and delivery planning at ≥34 weeks.

• Proteinuria Assessment: Quantified by 24-hour urine protein (≥0.3 g) or protein/creatinine ratio (≥0.3 g/g or 30 mg/mmol).

Immediate stabilisation (eclamptic seizure = obstetric emergency)

• Airway, left lateral decubitus, oxygen, padded rails: most eclamptic seizures are self-limited; the first priority is preventing maternal aspiration and hypoxia, not stopping the convulsion. Fetal bradycardia during and just after a seizure is expected and usually resolves with maternal resuscitation — do not rush to cesarean for a post-ictal fetal heart tracing until the mother is stable and the tracing has been given time to recover (ACOG Practice Bulletin 222).
• Magnesium sulfate: the drug of choice for both treatment and prevention of eclamptic seizures per ACOG. Typical regimen is a 4–6 g IV load over 20–30 minutes followed by 1–2 g/hour infusion, continued 24 hours after delivery or after the last seizure. A recurrent seizure is treated with an additional 2 g bolus; truly refractory seizures get a benzodiazepine (lorazepam) or levetiracetam and prompt neuroimaging to exclude hemorrhage. Magnesium is renally cleared — reduce or hold the infusion with oliguria or rising creatinine.

Acute severe-range hypertension (≥160/110 mmHg persisting ≥15 minutes)

• First-line antihypertensives: IV labetalol, IV hydralazine, or immediate-release oral nifedipine — ACOG considers all three acceptable, with treatment initiated within 30–60 minutes. Goal is a controlled reduction to roughly 130–150/80–100 mmHg; overshooting compromises uteroplacental perfusion.
• Escalation: switch agents if two doses of the first fail; refractory hypertension warrants ICU-level care and consultation with maternal-fetal medicine and critical care.

Definitive management

• Delivery of the placenta is the only cure. ACOG recommends delivery at ≥37 weeks for preeclampsia without severe features and at ≥34 weeks for preeclampsia with severe features or HELLP. Before 34 weeks, expectant management at a tertiary center with antenatal betamethasone for fetal lung maturity is reasonable only if mother and fetus remain stable; eclampsia, abruption, pulmonary edema, DIC, non-reassuring fetal status, or uncontrollable hypertension mandate delivery regardless of gestational age.
• Route: vaginal delivery is preferred; cesarean is reserved for standard obstetric indications.

Prevention and contraindications

• Low-dose aspirin (81 mg daily): recommended by USPSTF and ACOG for high-risk women, started between 12 and 28 weeks (ideally before 16 weeks).
• ACE inhibitors, ARBs, and direct renin inhibitors are contraindicated (fetal renal dysgenesis, oligohydramnios, skull hypoplasia) — captopril included, despite its utility outside pregnancy. Avoid prolonged nitroprusside (cyanide/thiocyanate accumulation) and do not use diuretics for volume expansion.

Maternal emergencies

• Eclampsia: cerebral autoregulatory failure with vasogenic edema produces generalized tonic-clonic seizures; heralded by intractable headache, visual scotomata, and clonus. Immediately life-threatening.
• Intracranial hemorrhage: the leading cause of death in eclampsia. Sustained severe systolic hypertension ruptures cerebral arterioles; signalled by a focal neurologic deficit, a seizure that fails to resolve, or persistent coma. Emergency non-contrast head CT.
• HELLP syndrome and hepatic subcapsular hematoma: sinusoidal endothelial injury and periportal necrosis distend Glisson capsule. Escalating right upper quadrant or shoulder pain with hemodynamic collapse suggests hepatic rupture — a surgical emergency requiring transfusion, imaging, and hepatic packing or embolization.
• Placental abruption and DIC: decidual vessel disruption causes painful vaginal bleeding with a tetanic, tender uterus and a non-reassuring tracing; consumptive coagulopathy follows (falling fibrinogen, rising D-dimer).
• Pulmonary edema: capillary leak plus low oncotic pressure plus iatrogenic fluid loading; dyspnea, crackles, and hypoxemia, most often postpartum when interstitial fluid mobilizes. Emergency.
• Acute kidney injury and cortical necrosis: renal endotheliosis plus hypoperfusion; oliguria with rising creatinine.
• PRES and cortical blindness: posterior parieto-occipital vasogenic edema on T2/FLAIR MRI; usually reversible with BP control and delivery.

Fetal and neonatal

• Fetal growth restriction, oligohydramnios, and stillbirth from chronic placental underperfusion; iatrogenic prematurity is the most common neonatal consequence, since delivery is the cure.

Treatment-related

• Magnesium toxicity: magnesium blocks neuromuscular transmission in a dose-dependent sequence — loss of deep tendon reflexes first, then respiratory depression, then cardiac conduction arrest. Risk rises sharply with oliguria or renal insufficiency. Monitor reflexes, respiratory rate, and urine output; the antidote is IV calcium gluconate (1 g), plus stopping the infusion and supporting ventilation.
• Abrupt maternal hypotension from over-aggressive antihypertensive dosing reduces uteroplacental perfusion and causes fetal decelerations; hydralazine additionally causes reflex tachycardia and headache that can mimic worsening disease.

Long term

• Cardiovascular risk: ACC/AHA prevention guidance names a history of preeclampsia a risk-enhancing factor, warranting lifelong BP, lipid, and glucose surveillance.

• Magnesium sulfate prevents and treats seizures — it is not an antihypertensive: the classic distractor is choosing magnesium to lower a BP of 170/115. Give IV labetalol, IV hydralazine, or oral immediate-release nifedipine for the pressure and magnesium for the brain (ACOG).
• Delivery of the placenta is the only cure: the stem asking "definitive management?" always answers delivery. Magnesium and antihypertensives buy time for steroids and transfer; they do not treat the disease.
• Loss of patellar reflexes is the earliest sign of magnesium toxicity, preceding respiratory depression and cardiac arrest. Best next step: stop the infusion and give IV calcium gluconate. Suspect it first in the oliguric or renally impaired patient.
• Proteinuria is not required for the diagnosis: new hypertension after 20 weeks plus thrombocytopenia, creatinine >1.1 mg/dL, transaminases >2× normal, pulmonary edema, or cerebral/visual symptoms is preeclampsia with severe features. A negative dipstick does not exclude it.
• HELLP can present with near-normal blood pressure: third-trimester right upper quadrant pain with schistocytes, high LDH, low haptoglobin, and platelets <100,000/μL is HELLP until proven otherwise — not gastritis, not cholecystitis. Sudden shoulder pain with shock = hepatic subcapsular hematoma rupture.
• After an eclamptic seizure, stabilise the mother before delivering the fetus: transient fetal bradycardia is expected and usually recovers. Emergent cesarean during maternal seizure activity is the classic wrong answer.
• Aspirin 81 mg daily from 12–28 weeks (ideally before 16 weeks) is the USPSTF/ACOG prophylaxis for high-risk women — prior preeclampsia, chronic hypertension, pregestational diabetes, renal disease, autoimmune disease (SLE/APS), or multifetal gestation.
• Preeclampsia and eclampsia occur up to 6 weeks postpartum: a woman seizing 5 days after an uncomplicated delivery has eclampsia, not new epilepsy. Magnesium is superior to phenytoin and to diazepam for eclamptic seizures — a favourite distractor pair.
• All ACE inhibitors and ARBs are contraindicated in pregnancy, captopril included; methyldopa, labetalol, and nifedipine are the pregnancy-safe oral agents.