Pre-eclampsia

1. Clinical Overview

Pre-eclampsia is a multisystem disorder of pregnancy characterized by new-onset hypertension (≥140/90 mmHg) and proteinuria (≥0.3g/24h or PCR ≥30 mg/mmol) or end-organ dysfunction developing after 20 weeks gestation in a previously normotensive woman. It affects 2-8% of pregnancies worldwide and is a leading cause of maternal and perinatal morbidity and mortality. [1] The condition results from abnormal placentation leading to widespread endothelial dysfunction, affecting multiple organ systems including the kidneys, liver, brain, and cardiovascular system. The only definitive cure is delivery of the placenta, making timing of delivery a critical clinical decision balancing maternal safety against fetal prematurity risks.

Key Facts:

• Definition: Hypertension ≥140/90 mmHg + proteinuria or end-organ dysfunction after 20 weeks
• Prevalence: 2-8% of pregnancies globally [1]
• Incidence: 3-5% in developed countries, higher in developing countries
• Mortality: Leading cause of maternal death in developed countries (10-15% of maternal deaths)
• Morbidity: Significant maternal and perinatal complications
• Peak Demographics: Primigravidas, age extremes (less than 20 or > 40 years)
• Pathognomonic Feature: New-onset hypertension + proteinuria after 20 weeks
• Gold Standard Investigation: Urine protein:creatinine ratio (PCR) ≥30 mg/mmol
• First-line Treatment: Blood pressure control, magnesium sulfate for seizure prophylaxis, delivery
• Prognosis Summary: Excellent with timely diagnosis and management; poor if untreated

Clinical Pearls:

The "Silent Killer": Many women feel completely fine despite a BP of 180/120. Do not rely on symptoms. Any headache or visual disturbance in pregnancy is Pre-eclampsia until proven otherwise.

Magnesium is Magic: Magnesium Sulphate is the drug of choice for preventing and treating Eclamptic seizures. It is a vasodilator and membrane stabilizer. Diazepam is NOT effective for eclampsia. [2]

Epigastric Pain: This is a grave sign. It represents subcapsular liver haematoma/oedema (Glisson's capsule stretch). It often precedes rupture or seizure. Never dismiss it as "heartburn".

PlGF Testing: Placental Growth Factor (PlGF) has high negative predictive value. If PlGF is normal, it is very unlikely the woman will need delivery for PE in the next 14 days. Allows safe discharge. [3]

Fluid Restriction: In PE, the endothelium is leaky. If you give normal fluids (e.g. 125ml/hr), it leaks into the lungs causing flash pulmonary oedema. Restrict to 80ml/hr. [4]

Why This Matters Clinically: Pre-eclampsia is a leading cause of maternal mortality worldwide, accounting for 10-15% of maternal deaths in developed countries and up to 25% in developing countries. It is associated with significant perinatal morbidity including preterm birth, intrauterine growth restriction, and stillbirth. Early recognition and appropriate management can prevent severe complications including eclampsia, HELLP syndrome, stroke, and maternal death. The condition has long-term implications, with affected women having increased risk of cardiovascular disease, hypertension, and stroke later in life. [5] Medico-legally, failure to recognize and appropriately manage pre-eclampsia is a common cause of litigation, particularly when eclampsia occurs or when delivery is delayed inappropriately.

2. Epidemiology

Incidence & Prevalence:

• Global Incidence: 2-8% of all pregnancies worldwide [1]
• Developed Countries: 3-5% of pregnancies (USA, UK, Europe)
• Developing Countries: 5-8% of pregnancies (higher due to limited antenatal care, malnutrition, infectious diseases)
• Severe Pre-eclampsia: 1-2% of all pregnancies
• Eclampsia: 1-2% of pre-eclampsia cases (reduced with MgSO₄ prophylaxis) [2]
• Lifetime Risk: Approximately 5-10% for women with one pregnancy
• Trend: Increasing in developed countries (25% increase between 1987-2004 in USA) due to:
  • Rising maternal age (more women > 35 years)
  • Increasing obesity rates
  • More multiple pregnancies (IVF)
  • Better recognition of non-proteinuric pre-eclampsia with new ACOG/ISSHP criteria [6,7]
• Geographic Variation:
  • "Lowest: Northern Europe (2-3%)"
  • "Highest: Sub-Saharan Africa, South Asia (7-10%)"
• Temporal Trends: No significant seasonal variation

Impact of New Diagnostic Criteria: Implementation of the ISSHP 2018 and ACOG 2020 criteria (allowing non-proteinuric diagnosis) increased diagnosed pre-eclampsia cases by 20-32%. Khan et al. (2020) showed incidence rose from 2.8% to 3.4% (ISSHP-new) and 3.0% (ACOG) when new criteria applied, identifying an additional 1 in 200 pregnancies with clinically significant maternal organ dysfunction that would have been missed by traditional proteinuria-dependent criteria. [7]

Demographics:

Risk Factors:

Non-Modifiable Risk Factors:

Modifiable Risk Factors:

Protective Factors:

• Aspirin 150mg daily from 12 weeks: 20-40% reduction in preterm pre-eclampsia in high-risk women (ASPRE trial: 62% reduction, NNT=25) [8,9]
• Smoking: Paradoxically protective (RR 0.5-0.7) - likely due to vasodilatory effects of carbon monoxide and nitric oxide; however, smoking causes stillbirth, IUGR, and other complications, so is NOT recommended
• Previous normal pregnancy: Reduces risk in subsequent pregnancies (immune tolerance established)
• Calcium supplementation: In populations with low dietary calcium (less than 600mg/day), supplementation (1.5-2g/day) reduces pre-eclampsia by 55% [10]

3. Pathophysiology

Mechanism (Two-Stage Theory):

Step 1: Poor Placentation (First Trimester)

• Trophoblast Invasion: Normal pregnancy requires extravillous trophoblast cells to invade the maternal spiral arteries, transforming them from high-resistance to low-resistance vessels
• Failure in Pre-eclampsia: In pre-eclampsia, trophoblast invasion is shallow and incomplete
• Spiral Arteries: Remain narrow, high-resistance vessels instead of becoming wide, low-resistance channels
• Mechanism: Abnormal immune tolerance, genetic factors, or environmental factors prevent proper invasion
• Time Course: Occurs in first trimester, but clinical disease manifests later
• Reversibility: Not reversible once established, but progression can be modified

Step 2: Placental Ischaemia (Second Trimester)

• Reduced Perfusion: Narrow spiral arteries cannot provide adequate blood flow to placenta
• Hypoxia: Placenta becomes relatively hypoxic and ischaemic
• Oxidative Stress: Ischaemia-reperfusion injury leads to oxidative stress
• Soluble Factors: Placenta releases anti-angiogenic factors into maternal circulation: [11,12]
  • "sFlt-1 (soluble Fms-like tyrosine kinase-1): Binds and inactivates VEGF and PlGF"
    • Normal pregnancy: sFlt-1 low, PlGF high (pro-angiogenic balance)
    • Pre-eclampsia: sFlt-1 markedly elevated (10-100× normal), PlGF suppressed
    • sFlt-1/PlGF ratio: Powerful diagnostic/prognostic marker
      • Ratio less than 38: Rules out pre-eclampsia (NPV 99.3%) [3]
      • Ratio > 85 at less than 34 weeks or > 110 at ≥34 weeks: Confirms pre-eclampsia (PPV 65-95%)
      • Used in clinical practice (NICE NG133) for risk stratification [13]
  • "sEng (soluble endoglin): Inhibits TGF-β signaling, enhances vascular permeability"
    • Elevated in severe pre-eclampsia (correlates with severity)
    • Synergizes with sFlt-1 to induce endothelial dysfunction
  • "Inflammatory Cytokines: TNF-α, IL-6, IL-8"
    • Activate maternal immune system
    • Promote systemic inflammatory response
• Time Course: Progressive throughout second and third trimesters
• Clinical Correlation: May be detected by low PlGF levels (cutoff less than 100 pg/mL) before clinical disease manifests [3]
• Predictive Value: Low PlGF at 20-35 weeks predicts pre-eclampsia requiring delivery within 14 days (sensitivity 96%, specificity 55%) [3]

Step 3: Endothelial Dysfunction (Third Trimester)

• Systemic Effects: Anti-angiogenic factors cause widespread maternal endothelial dysfunction
• Vasoconstriction: Loss of vasodilatory capacity, increased vascular tone
• Increased Permeability: Endothelial barrier function impaired, allowing protein leakage
• Procoagulant State: Endothelial activation promotes thrombosis
• Organ-Specific Effects:
  • "Kidney: Glomerular endotheliosis → proteinuria, reduced GFR"
  • "Liver: Sinusoidal obstruction → elevated transaminases, HELLP syndrome"
  • "Brain: Cerebral oedema, vasospasm → headache, visual disturbance, seizures"
  • "Cardiovascular: Increased afterload, reduced cardiac output"
  • "Platelets: Consumption, activation → thrombocytopenia"
• Time Course: Develops over days to weeks
• Point of No Return: Severe endothelial damage may be irreversible without delivery

Step 4: Clinical Manifestation

• Hypertension: Vasoconstriction and increased vascular resistance
• Proteinuria: Glomerular damage allows protein leakage
• End-Organ Dysfunction: Multiple systems affected
• Progression: Can progress rapidly to severe disease
• Factors Accelerating Progression:
  • Severe hypertension
  • Early onset (less than 34 weeks)
  • Multiple risk factors
  • Poor antenatal care

Step 5: Resolution or Complications

• Delivery: Removal of placenta removes source of anti-angiogenic factors
• Recovery: Endothelial function gradually returns to normal (days to weeks)
• Chronic Damage: Some women have persistent endothelial dysfunction
• Long-term Risk: Increased cardiovascular risk later in life [5]
• Factors Affecting Outcome:
  • Severity of disease
  • Timing of delivery
  • Quality of management
  • Underlying comorbidities

Classification:

Mild Pre-eclampsia:

• BP 140-159/90-109 mmHg
• Proteinuria present (PCR ≥30 mg/mmol)
• No end-organ dysfunction
• Usually managed as outpatient with close monitoring

Severe Pre-eclampsia:

• BP ≥160/110 mmHg, OR
• Severe proteinuria (PCR ≥100 mg/mmol), OR
• End-organ dysfunction:
  • "Renal: Creatinine > 90 μmol/L, oliguria"
  • "Hepatic: Elevated transaminases, epigastric pain"
  • "Neurological: Headache, visual disturbance, clonus"
  • "Haematological: Thrombocytopenia less than 100 x 10⁹/L"
  • "Pulmonary: Oedema"
• Requires inpatient management and delivery planning

Eclampsia:

• Pre-eclampsia + seizures
• Can occur antepartum, intrapartum, or postpartum (up to 6 weeks)
• 44% of eclamptic seizures occur postpartum [2]
• Medical emergency requiring immediate treatment

HELLP Syndrome:

• Haemolysis (schistocytes, elevated LDH)
• Elevated Liver enzymes (ALT/AST)
• Low Platelets (less than 100 x 10⁹/L)
• Variant of severe pre-eclampsia
• High morbidity and mortality [14]

HELLP Syndrome - Detailed:

HELLP syndrome is a life-threatening complication occurring in 10-20% of women with severe pre-eclampsia. The acronym represents: [14]

• Haemolysis
• Elevated Liver enzymes
• Low Platelets

Diagnostic Criteria (Tennessee Classification):

Haemolysis Evidence:

• Schistocytes on blood film (microangiopathic haemolytic anaemia)
• Elevated unconjugated bilirubin (> 20 μmol/L)
• Elevated LDH (> 600 IU/L)
• Low haptoglobin

Key Features:

• Incidence: 0.5-0.9% of all pregnancies, 10-20% of severe pre-eclampsia [14]
• Timing: 70% antepartum (usually > 27 weeks), 30% postpartum (within 48 hours)
• Atypical: 10-15% of HELLP occurs without hypertension or proteinuria
• Maternal Mortality: 1-3% (higher than pre-eclampsia alone)
• Perinatal Mortality: 7-20% (due to prematurity, placental abruption)

Clinical Presentation:

• RUQ/Epigastric Pain (65-90%): Due to liver capsule distension (subcapsular haematoma risk)
• Nausea/Vomiting (35-50%): Often mistaken for gastroenteritis
• Malaise (90%): Non-specific "feeling unwell"
• Hypertension (85%): May be absent in 10-15%
• Proteinuria (85%): May be absent
• Jaundice: Rare, indicates severe haemolysis

Investigations:

• FBC: Thrombocytopenia, anaemia (if haemolysis), elevated WCC
• Blood Film: Schistocytes, burr cells (microangiopathic haemolysis)
• LFTs: AST/ALT > 70 IU/L (may be > 1000 in severe cases)
• LDH: > 600 IU/L (marker of haemolysis and liver dysfunction)
• Bilirubin: Unconjugated elevated if haemolysis
• Coagulation: Usually normal unless DIC develops
• Urine: Proteinuria if pre-eclampsia present

Complications:

• Hepatic rupture (1-2%): Catastrophic, requires emergency laparotomy
• Placental abruption (10-16%)
• DIC (15-20%)
• Acute renal failure (7-10%)
• Pulmonary oedema (6-8%)
• Eclampsia (5%)
• Stroke (1-2%)
• Maternal death (1-3%)

Management:

• Deliver: HELLP is an indication for delivery regardless of gestation (after stabilization) [14]
• Timing: Within 24-48 hours if stable; immediately if maternal/fetal compromise
• Stabilization:
  • Control BP (target less than 160/110)
  • Magnesium sulfate (seizure prophylaxis) [2]
  • Fluid restriction (80mL/hr) [4]
  • Correct coagulopathy if needed (platelets if less than 50 and delivery/procedure planned)
  • Corticosteroids if less than 34 weeks (fetal lung maturity) [15]
• Corticosteroids for HELLP: Some evidence for dexamethasone improving platelet count and LFTs, but controversial
• Transfusion:
  • Platelets if less than 20 × 10⁹/L or less than 50 × 10⁹/L with bleeding/delivery/neuraxial anaesthesia planned
  • Packed red cells if Hb less than 70 g/L or symptomatic
  • Fresh frozen plasma if coagulopathy and bleeding

Recovery:

• Platelets nadir at 24-48 hours post-delivery, then recover over 5-10 days
• LFTs peak at 24-48 hours, normalize over 7-14 days
• Recurrence risk in future pregnancy: 20-25%

Differential Diagnosis:

• Acute fatty liver of pregnancy (AFLP): Jaundice, hypoglycaemia, severe coagulopathy
• TTP/HUS: Fever, neurological symptoms, renal failure
• Viral hepatitis: Different LFT pattern, viral serology
• SLE flare: Known SLE, complement low, anti-dsDNA high

4. Clinical Presentation

Symptoms:

Typical Presentation:

• Asymptomatic (30-40%): Detected on routine antenatal checks (BP, urinalysis)
• Headache (50-60%): Frontal, persistent, not relieved by paracetamol
• Visual Disturbance (20-30%): Scintillating scotomata (flashing lights), blurring, diplopia
• Epigastric/RUQ Pain (10-20%): Severe, indicates liver involvement, may precede HELLP
• Oedema (40-50%): Rapid onset, face/hands (pedal oedema is normal in pregnancy)
• Nausea/Vomiting (20-30%): May indicate severe disease

Atypical Presentations:

• Elderly primigravidas: May present with severe disease earlier
• Multiple pregnancy: Higher risk, may present earlier
• Chronic hypertension: Superimposed pre-eclampsia harder to diagnose
• Postpartum: 44% of eclampsia occurs postpartum [2]

Signs:

Hypertension:

• BP ≥140/90 mmHg (mild)
• BP ≥160/110 mmHg (severe)
• Use appropriate cuff size (large if arm circumference > 33cm)

Neurological:

• Hyperreflexia (> 3+ reflexes)
• Clonus (> 3 beats indicates imminent seizure risk)
• Papilloedema (severe disease)
• Altered mental state (rare, indicates severe disease)

Abdominal:

• Epigastric/RUQ tenderness (liver involvement)
• May have ascites in severe cases

Cardiovascular:

• Tachycardia (compensatory or sepsis)
• Peripheral oedema

Red Flags:

[!CAUTION] Red Flags — Seek immediate help if:

• Severe hypertension (≥160/110 mmHg)
• Eclampsia (seizures)
• HELLP Syndrome (haemolysis, elevated LFTs, low platelets)
• Epigastric/RUQ pain (liver capsule stretch)
• Papilloedema or clonus (cerebral irritation)
• Visual disturbance (scintillating scotomata)
• Persistent headache not relieved by paracetamol
• Reduced fetal movements
• Signs of placental abruption

5. Clinical Examination

Structured Approach:

General:

• Appearance: May look well despite severe hypertension ("silent killer")
• Vital Signs:
  • "BP: Measure with appropriate cuff, both arms"
  • "Heart rate: May be elevated"
  • "Respiratory rate: May be elevated if pulmonary oedema"
  • "Temperature: Usually normal (fever suggests infection)"
• Weight: Rapid weight gain may indicate fluid retention

Cardiovascular:

• BP Measurement:
  • Use correct cuff size
  • Measure in sitting position, arm at heart level
  • Repeat if elevated
  • Check both arms (difference may indicate aortic dissection)
• Heart Sounds: Usually normal, may have S3 if heart failure
• JVP: Usually normal, elevated if heart failure
• Peripheral Oedema: Face, hands, legs (pedal oedema alone is normal)

Abdominal:

• Inspection: May show distension if ascites
• Palpation:
  • Epigastric/RUQ tenderness (liver involvement, HELLP)
  • Uterine size (may be small for dates if IUGR)
  • Fetal movements
• Auscultation: Fetal heart rate monitoring

Neurological:

• Mental State: Usually normal, may be altered in severe disease
• Cranial Nerves: Usually normal, visual field defects possible
• Reflexes:
  • Hyperreflexia (> 3+)
  • "Clonus: Test at ankle, > 3 beats is significant"
• Fundoscopy:
  • Papilloedema (severe disease)
  • Retinal changes (hypertensive retinopathy)
• Coordination: Usually normal

Special Tests:

6. Investigations

First-Line (Bedside):

• BP Measurement: Essential, use appropriate cuff size
• Urinalysis: Protein dipstick (1+ needs quantification)
• Fetal Heart Rate: Continuous monitoring if severe

Laboratory Tests:

Imaging:

Diagnostic Criteria (ISSHP 2018 / ACOG 2020):

The diagnosis of pre-eclampsia requires BOTH hypertension AND proteinuria or maternal organ dysfunction developing after 20 weeks' gestation. [6,7]

1. Hypertension (Essential Criterion):

• Blood Pressure: ≥140 mmHg systolic OR ≥90 mmHg diastolic
• Timing: Developing after 20 weeks of gestation
• Measurement: On two occasions at least 4 hours apart (except if ≥160/110, confirmation may be within minutes)
• Technique: Appropriate cuff size, sitting position, arm at heart level
• ISSHP 2018 Update: Emphasizes single measurements are insufficient; hypertension must be confirmed on repeat testing unless severe [6]

2. PLUS One or More of the Following:

A. Proteinuria (Traditional Criterion):

• Quantitative Measurement (Gold Standard):
  • "Urine protein:creatinine ratio (PCR) ≥30 mg/mmol (≥0.3 mg/mg)"
  • 24-hour urine collection ≥0.3 g/24h
• Qualitative Measurement (Initial Screening):
  • Urine dipstick ≥1+ (30 mg/dL)
  • "Note: Dipstick alone is insufficient for diagnosis; requires quantification [7]"
• ACOG 2020 Clarification: Proteinuria is no longer mandatory if maternal organ dysfunction present [7]

B. Maternal Organ Dysfunction (Alternative to Proteinuria):

C. Uteroplacental Dysfunction:

• Fetal growth restriction (estimated fetal weight less than 10th percentile)
• Abnormal umbilical artery Doppler (absent or reversed end-diastolic flow)
• Note: Some definitions (ISSHP 2018) include this; ACOG 2020 does not require it [6,7]

D. Severe Features (Require Immediate Intervention):

Pre-eclampsia with ANY of the following is classified as severe and requires urgent management:

• Severe hypertension: BP ≥160/110 mmHg on two occasions 4 hours apart (or within minutes if requiring immediate treatment)
• Severe proteinuria: ≥5 g/24h or PCR ≥100 mg/mmol (historical; no longer used alone to define severity per ACOG 2020)
• Symptoms of end-organ involvement:
  • Persistent severe headache
  • Visual disturbances (photophobia, scotomata, blurred vision)
  • Altered mental status
• RUQ or epigastric pain unresponsive to medication and not explained by alternative diagnoses
• Pulmonary oedema
• Thrombocytopenia (less than 100 × 10⁹/L)
• Progressive renal insufficiency (creatinine > 110 μmol/L or doubling)
• Elevated liver transaminases (> 2× upper limit normal)
• Fetal growth restriction

Evolution of Diagnostic Criteria:

The ISSHP 2018 and ACOG 2020 definitions expanded the diagnostic criteria to include non-proteinuric pre-eclampsia. Khan et al. (2020) demonstrated that implementation of these new definitions increased the incidence of diagnosed pre-eclampsia from 2.8% to 3.4% (ISSHP-new) and 3.0% (ACOG), primarily due to inclusion of non-proteinuric cases with maternal organ dysfunction. [7] Importantly, the additional cases identified had milder disease with later gestational age at delivery and lower rates of small-for-gestational-age infants, but still required clinical management. [7]

Clinical Application:

In clinical practice:

1. Initial Assessment: All pregnant women after 20 weeks with elevated BP should have:

   • Confirmatory BP measurement
   • Urine dipstick → If positive, quantitative PCR
   • Blood tests: FBC (platelets), LFTs (transaminases), renal function (creatinine)
   • Symptoms enquiry: headache, visual changes, epigastric pain

2. Diagnosis Confirmed If:

   • Hypertension (≥140/90) + PCR ≥30 mg/mmol, OR
   • Hypertension (≥140/90) + any maternal organ dysfunction (as above)

3. Exclusion of Pre-eclampsia:

   • Hypertension alone without proteinuria or organ dysfunction = Gestational hypertension
   • Hypertension present less than 20 weeks = Chronic hypertension (unless superimposed pre-eclampsia develops)

7. Management

Management Algorithm:

           PRE-ECLAMPSIA DIAGNOSED
        (BP ≥140/90 + PCR ≥30)
                 ↓
        ASSESS SEVERITY
        ┌────────┴────────┐
    MILD/MODERATE      SEVERE
    (140-159/90-109)   (≥160/110 or
                       end-organ dysfunction)
         ↓                  ↓
    OUTPATIENT         INPATIENT
    MONITORING         MANAGEMENT
         ↓                  ↓
    ORAL ANTI-         IV ANTI-HYPERTENSIVES
    HYPERTENSIVES      - Labetalol IV
    - Labetalol        - Hydralazine IV
    - Nifedipine MR    - Nifedipine PO
         ↓                  ↓
    MONITOR            MAGNESIUM SULFATE
    - BP 2-3x/week     - 4g IV loading
    - Urine PCR        - 1g/hr infusion
    - Fetal scans      - Monitor reflexes
         ↓                  ↓
    PLAN DELIVERY      FLUID RESTRICTION
    - Usually 37wks    - 80ml/hr (prevent
    - Earlier if       pulmonary oedema)
      worsening           ↓
                      STEROIDS
                      (If less than 34 weeks)
                      - Betamethasone
                        12mg IM x2
                        24h apart
                         ↓
                      DELIVERY
                      - Stabilize first
                      - Then induce/CS
                      - Timing depends on
                        gestation, severity

Acute/Emergency Management:

Immediate Actions (Severe Pre-eclampsia):

1. ABC: Assess airway, breathing, circulation
2. IV Access: Large bore cannula
3. Monitor: Continuous BP, pulse oximetry, fetal heart rate
4. Control BP: IV labetalol or hydralazine to target less than 160/110 [16]
5. Magnesium Sulfate: If severe or eclampsia (4g IV loading, then 1g/hr) [2]
6. Fluid Restriction: 80ml/hr to prevent pulmonary oedema [4]
7. Catheterize: Monitor urine output
8. Delivery Planning: Urgent delivery usually required

Conservative Management:

Mild Pre-eclampsia:

• Outpatient Monitoring:
  • BP checks 2-3 times per week
  • Urine PCR weekly
  • Fetal growth scans every 2-3 weeks
  • Fetal Dopplers if IUGR suspected
• Lifestyle:
  • Rest (left lateral position)
  • No salt restriction (not helpful)
  • Regular antenatal appointments
• Delivery: Usually at 37 weeks, earlier if worsening [17]

Medical Management:

Antihypertensive Therapy:

Choice of Antihypertensive Agent (Evidence-Based Selection):

The choice of antihypertensive depends on urgency, severity, and contraindications. A 2022 RCT comparing nifedipine, labetalol, and hydralazine found all three effective, but with different time-to-effect and side effect profiles. [16]

Target Blood Pressure:

• Chronic/Mild: less than 140/90 mmHg (NICE 2019) or less than 135/85 mmHg (stricter target) [13]
• Severe Hypertension: Reduce to less than 160/110 mmHg within 30-60 minutes, then to less than 140/90 mmHg over next few hours
• CRITICAL: Avoid rapid drops (> 25% reduction in MAP within 1 hour) → risk of placental hypoperfusion

Labetalol IV Protocol (Standard for Severe Hypertension): [16]

1. Initial dose: 20mg IV over 2 minutes
2. Check BP after 10 minutes
3. If BP still ≥160/110: Give 40mg IV
4. Check BP after 10 minutes
5. If BP still ≥160/110: Give 80mg IV
6. Check BP after 10 minutes
7. If BP still elevated: Consider infusion at 20mg/hr, titrate up to 80mg/hr
8. Maximum cumulative dose: 300mg
9. If still uncontrolled: Switch to alternative agent (hydralazine or nifedipine)

Contraindications to Specific Agents:

• ACE Inhibitors / ARBs: ABSOLUTE contraindication in pregnancy (teratogenic, fetal renal failure, oligohydramnios)
• Atenolol: Associated with fetal growth restriction; avoid
• Diuretics: Not recommended (patients are already volume contracted); exception is pulmonary oedema

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Magnesium Sulfate (MgSO₄) Protocols:

The Magpie Trial Evidence: The landmark Magpie Trial (2002) enrolled 10,141 women with pre-eclampsia across 33 countries and demonstrated that magnesium sulfate reduces the risk of eclampsia by 58% (RR 0.42, 95% CI 0.29-0.60; 0.8% vs 1.9%, pless than 0.001). [2] This established MgSO₄ as the standard of care for severe pre-eclampsia and eclampsia prevention/treatment.

Indications for MgSO₄:

• Severe pre-eclampsia (any severe feature present)
• Eclampsia (therapeutic)
• Imminent eclampsia (severe symptoms: persistent headache, visual disturbance, clonus > 3 beats)
• HELLP syndrome

Standard Pritchard Regimen (UK/International): [2]

• Loading Dose: 4g (16 mmol) IV over 10-15 minutes
  • "Preparation: 4g = 8mL of 50% MgSO₄ solution diluted in 100mL 0.9% NaCl"
• Maintenance Dose: 1g/hour (4 mmol/hour) IV infusion
  • "Preparation: 50g MgSO₄ in 500mL 0.9% NaCl (= 100mg/mL); run at 10mL/hr"
• Duration:
  • "Severe pre-eclampsia: Continue for 24 hours after delivery OR 24 hours after last seizure"
  • "Eclampsia: Continue for 24-48 hours post-delivery"

Alternative Zuspan Regimen (USA):

• Loading Dose: 6g IV over 15-20 minutes
• Maintenance Dose: 2g/hour IV infusion
• Note: Higher doses, but Magpie trial used Pritchard regimen

Recurrent Seizures (Eclampsia):

• Give additional bolus: 2g (4mL of 50%) IV over 5 minutes
• May repeat once if seizures continue
• If still seizing: Consider phenytoin or lorazepam; intubate if necessary

Monitoring During MgSO₄ Infusion: [18]

Magnesium Toxicity: [18]

• Therapeutic level: 2.0-3.5 mmol/L (4-7 mEq/L)
• Loss of patellar reflexes: 3.5-5 mmol/L (7-10 mEq/L)
• Respiratory depression: 5-6.5 mmol/L (10-13 mEq/L)
• Cardiac arrest: > 6.5 mmol/L (> 13 mEq/L)

Management of MgSO₄ Toxicity:

1. STOP magnesium infusion immediately
2. Antidote: 10mL of 10% calcium gluconate IV over 10 minutes
3. Support: Oxygen, ventilation if respiratory depression
4. Monitor: Continuous cardiac monitoring, serum Mg levels
5. Dialysis: Consider if severe toxicity and renal impairment

Special Considerations:

• Renal impairment: Reduce maintenance dose to 0.5g/hr or avoid if GFR less than 30mL/min
• Drug interactions: MgSO₄ potentiates neuromuscular blockers and calcium channel blockers
• Side effects: Flushing (common, 24%), nausea (5%), muscle weakness

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Corticosteroids for Fetal Lung Maturity:

Evidence: Reduces neonatal respiratory distress syndrome by 50%, intraventricular hemorrhage by 50%, and neonatal death by 30% in preterm births. [15]

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Fluid Management in Pre-eclampsia:

Critical Principle: Women with pre-eclampsia have increased vascular permeability due to endothelial dysfunction. Despite appearing oedematous, they are intravascularly volume-depleted. Excessive fluid administration leads to flash pulmonary oedema. [4]

Fluid Restriction Protocol (Severe Pre-eclampsia):

• Rate: 80 mL/hour (or 1 mL/kg/hour if less than 80kg)
• Total: Maximum 2000-2500 mL/24 hours (including IV medications)
• Route: Crystalloid (0.9% NaCl or Hartmann's)
• Duration: Continue restriction for:
  • During labour and delivery
  • First 24-48 hours postpartum
  • Until diuresis begins (often Day 3-5 postpartum)

Monitoring Fluid Balance:

Exceptions to Fluid Restriction:

• Haemorrhage: Active bleeding requires fluid resuscitation (blood products preferred)
• Sepsis: May require more liberal fluids under close monitoring
• Oliguria with hypovolaemia: Very rare; most oliguria in pre-eclampsia is due to renal dysfunction, NOT volume depletion

Common Error - "Oliguria Needs Fluids": ❌ WRONG: Oliguria in pre-eclampsia is usually due to glomerular endotheliosis (renal dysfunction), not hypovolaemia. Giving fluid boluses will cause pulmonary oedema. ✅ CORRECT: Monitor urine output, maintain 80mL/hr fluids, deliver baby (definitive treatment). Accept urine output 20-30mL/hr if well perfused clinically.

Pulmonary Oedema Management: If pulmonary oedema develops (2-5% of severe pre-eclampsia): [4]

1. Stop all IV fluids immediately
2. Oxygen: High-flow oxygen to maintain SpO₂ > 95%
3. Diuretics: Furosemide 20-40mg IV (safe in pregnancy for this indication)
4. Position: Sit patient upright
5. Monitor: Continuous pulse oximetry, respiratory rate
6. Deliver: Urgent delivery once stabilized
7. HDU/ICU: Transfer for monitoring; may need non-invasive ventilation or intubation

Colloids vs Crystalloids:

• Crystalloids: Standard (0.9% NaCl or Hartmann's)
• Colloids (albumin, Gelofusine): No benefit; may worsen capillary leak

Contraindications:

• ACE Inhibitors/ARBs: Teratogenic, cause renal failure in fetus
• Beta-blockers alone: May cause bradycardia, avoid in asthma
• Diuretics: Not recommended (already volume contracted)

Delivery Timing (Evidence-Based Guidelines):

Delivery is the only definitive treatment for pre-eclampsia. The decision on timing balances maternal risks of continuing pregnancy against fetal risks of prematurity. [7,17]

Immediate Delivery Indications (Stabilize then Deliver):

Regardless of gestational age, delivery is indicated when continuing the pregnancy poses unacceptable maternal or fetal risk:

Gestational Age-Specific Management:

less than 24 Weeks (Previable):

• Counsel: Very high maternal risk, extremely poor fetal prognosis
• Options: Pregnancy termination vs expectant management with intensive monitoring
• Most: Offer termination; if continues, requires daily assessment in tertiary center

24⁰-33⁺⁶ Weeks (Very Preterm):

• Severe pre-eclampsia: Stabilize, give corticosteroids (betamethasone), deliver after 24-48 hours if condition allows [17]
• Mild pre-eclampsia: Expectant management with:
  • "Inpatient monitoring: Daily BP, twice-weekly bloods (FBC, LFTs, creatinine)"
  • "Fetal surveillance: Daily CTG if less than 32 weeks, twice-weekly growth scans, umbilical artery Dopplers"
  • "Deliver if: Develops severe features, maternal/fetal deterioration, or reaches 34 weeks"
• ACOG 2020: Delivery at 34⁰ weeks if mild, immediately if severe (after stabilization) [7]

34⁰-36⁺⁶ Weeks (Late Preterm):

• Severe pre-eclampsia: Deliver after corticosteroids and stabilization (within 24-48 hours)
• Mild pre-eclampsia:
  • "ACOG 2020: Recommends delivery at 37 weeks [7]"
  • "Option: Some centers deliver at 34-36 weeks if maternal/fetal concerns"
  • "If expectant management chosen: Twice-weekly visits, BP monitoring, weekly bloods, fetal surveillance"

≥37 Weeks (Term):

• All pre-eclampsia: Proceed to delivery (induction of labour or caesarean section)
• No benefit to expectant management beyond 37 weeks [17]
• Method: IOL preferred if cervix favorable; CS if unfavorable cervix, fetal compromise, or maternal instability

Pre-Delivery Stabilization (Critical):

Before delivery, especially if severe pre-eclampsia, stabilize the mother:

1. Control BP: Target less than 160/110 (IV labetalol or alternative) [16]
2. Seizure prophylaxis: Start MgSO₄ if severe features [2]
3. Fluid restriction: 80 mL/hr (prevent pulmonary oedema) [4]
4. Corticosteroids: If less than 34⁺⁶ weeks (ideally complete course before delivery if time allows) [15]
5. Monitor: Continuous BP, pulse oximetry, hourly urine output, reflexes (if on MgSO₄)
6. Bloods: Repeat FBC, LFTs, coagulation before delivery
7. Anaesthetic review: For epidural/spinal planning or general anaesthesia

**"Deliver, Don't Dither"

• But Stabilize First:** A common error is rushing to delivery without stabilization. Severe pre-eclampsia is NOT an indication for emergency caesarean section in most cases. Take time to:
• Control BP (prevents maternal stroke during delivery)
• Give MgSO₄ (prevents eclampsia intrapartum)
• Optimize fluid balance (prevents pulmonary oedema)
• Give corticosteroids if less than 34 weeks (even partial course beneficial)

Exception: True emergencies (eclampsia not controlled, abruption with bleeding, fetal bradycardia) require immediate delivery without delay.

Mode of Delivery:

HYPITAT Trial (2009): In women with mild pre-eclampsia or gestational hypertension ≥36 weeks, induction of labour did not increase caesarean section rates compared to expectant management, and improved maternal outcomes. [19]

Postpartum Management:

Pre-eclampsia does NOT resolve immediately after delivery:

• BP: Often worsens Days 3-5 postpartum before improving
• Continue MgSO₄: For 24 hours post-delivery (or 24h after last seizure) [2]
• Continue antihypertensives: For at least 2 weeks; review at postnatal visit
• Monitor: BP twice daily for first 5 days, then weekly until normalized
• Fluid restriction: Continue 80mL/hr for first 24-48 hours (risk of flash pulmonary oedema) [4]
• Watch for: Postpartum eclampsia (can occur up to 6 weeks, but 80% within 48 hours)
• Bloods: Repeat FBC, LFTs, creatinine Day 3-5 (platelets/LFTs may worsen before improving)

44% of eclamptic seizures occur postpartum - do not assume delivery cures immediately! [2]

Long-term Follow-up:

• 6 weeks: Postnatal check - BP, urinalysis, bloods; many can stop antihypertensives
• 6 months: If BP/proteinuria persist → investigate for chronic hypertension/renal disease
• Annual: Cardiovascular risk assessment (2-3× increased lifetime CVD risk) [5]
• Future pregnancies: Aspirin 150mg from 12 weeks (see Prevention section) [8,9]

Disposition:

• Admit if: Severe pre-eclampsia, symptoms, or concerns about fetal wellbeing
• Discharge if: Mild pre-eclampsia, well-controlled BP, good fetal growth, reliable follow-up
• Follow-up:
  • "Mild: 2-3 times per week"
  • "Severe: Daily or more frequent"
  • "Postpartum: 6 weeks, then annual cardiovascular risk assessment"

8. Complications

Immediate (Minutes-Hours):

Early (Days):

Maternal:

• Persistent Hypertension: May require ongoing treatment
• Proteinuria: Usually resolves within weeks
• Thrombocytopenia: Usually resolves within days
• Liver Dysfunction: Usually resolves within weeks

Fetal:

• Preterm Birth: Common, associated with complications
• Intrauterine Growth Restriction: Due to placental dysfunction
• Stillbirth: Risk increased if severe, untreated
• Neonatal Complications: Respiratory distress, hypoglycaemia, jaundice

Late (Weeks-Months):

Maternal:

• Persistent Hypertension: 20-30% develop chronic hypertension
• Chronic Kidney Disease: Rare, but risk increased
• Cardiovascular Disease: 2-3x increased risk long-term [5]
• Recurrence: 15% overall, up to 50% if severe/early

Fetal/Child:

• Neurodevelopmental: Slight increase in risk if very preterm
• Cardiovascular: Increased risk of hypertension, metabolic syndrome

9. Prognosis & Outcomes

Natural History:

• Untreated: Progressive worsening, high risk of eclampsia, HELLP, stroke, maternal and fetal death
• Mild, Treated: Usually good outcome, delivery at term
• Severe, Treated: Good outcome with timely delivery, but prematurity risks

Outcomes with Treatment:

Prognostic Factors:

Good Prognosis:

• Mild disease, late onset (> 37 weeks)
• Good BP control
• No end-organ dysfunction
• Good fetal growth
• Reliable follow-up and compliance

Poor Prognosis:

• Severe disease, early onset (less than 34 weeks)
• HELLP syndrome
• Eclampsia
• End-organ dysfunction
• Poor fetal growth
• Multiple risk factors
• Limited access to care

10. Prevention & Screening

Primary Prevention:

Aspirin Prophylaxis: The landmark ASPRE trial (2017) demonstrated that aspirin 150mg daily from 11-14 weeks until 36 weeks reduces preterm pre-eclampsia by 62% (OR 0.38, 95% CI 0.20-0.74) in high-risk women identified by combined first-trimester screening. [8,9] The NNT is 25 to prevent one case of preterm pre-eclampsia.

Who Should Receive Aspirin: [13,20]

High-Risk Factors (ONE present = Aspirin indicated):

• Previous pre-eclampsia
• Chronic hypertension
• Chronic kidney disease
• Diabetes mellitus (Type 1 or 2)
• Autoimmune disease (SLE, APS)

Moderate-Risk Factors (TWO or more present = Aspirin indicated):

• Primigravida (especially if age > 40)
• Age ≥40 years
• BMI ≥35
• Family history of pre-eclampsia (first-degree relative)
• Multiple pregnancy
• Interval > 10 years since last pregnancy

Aspirin Regimen: [8,9,13]

• Dose: 150mg daily (75mg may be less effective)
• Timing: Start 12-16 weeks (ideally before 16 weeks)
• Duration: Continue until 36 weeks or delivery
• Evidence: ASPRE trial showed 62% reduction in preterm PE [8,9]
• Safety: Very safe; minimal side effects; no increased bleeding risk at delivery

Calcium Supplementation: In populations with low dietary calcium intake (less than 600mg/day), calcium supplementation (1.5-2g/day) reduces pre-eclampsia by 55% (RR 0.45, 95% CI 0.31-0.65). [10] This is primarily relevant in developing countries.

Lifestyle Modifications:

• Pre-pregnancy weight loss: If BMI > 30, reduces risk by 20-30%
• Exercise: Regular moderate exercise may reduce risk
• Diet: Balanced diet; no specific diet prevents pre-eclampsia
• Smoking cessation: Overall health benefits (though paradoxically protective for PE)

Screening:

First-Trimester Combined Screening (11-13 weeks): The ASPRE trial validated a combined screening approach using: [8,9]

• Maternal risk factors (age, BMI, ethnicity, medical history)
• Mean arterial pressure (MAP)
• Uterine artery Doppler pulsatility index
• Serum biomarkers: PAPP-A, PlGF

Performance:

• Detection rate: 75% of preterm PE, 47% of term PE
• False positive rate: 10%
• Implementation: Available in some centers; not yet universal

PlGF Testing (Second/Third Trimester): Used for triage of suspected pre-eclampsia: [3,13]

• PlGF less than 100 pg/mL: Suggests placental dysfunction
• sFlt-1/PlGF ratio:
  • "Ratio less than 38: Rules OUT pre-eclampsia (NPV 99.3%)"
  • "Ratio > 85 (less than 34 weeks) or > 110 (≥34 weeks): Rules IN pre-eclampsia"
• Clinical utility: Allows safe discharge if normal; indicates need for close monitoring if abnormal

NICE Recommendations (NG133): [13]

1. Offer aspirin 150mg to all high-risk women from 12 weeks
2. Use PlGF-based testing in women with suspected pre-eclampsia
3. Monitor BP at every antenatal visit
4. Urine dipstick at every visit (quantify if positive)

11. Evidence & Guidelines

Key Guidelines:

1. NICE NG133 (2019) — Hypertension in pregnancy: diagnosis and management. Key recommendations: BP target less than 135/85, aspirin prophylaxis for high-risk women, PlGF testing. [13]

2. RCOG Green-top Guideline No. 10A (2010, updated 2024) — Management of Severe Pre-eclampsia/Eclampsia. Key recommendations: Magnesium sulfate protocols, delivery timing. [20]

3. ACOG Practice Bulletin No. 222 (2020) — Gestational Hypertension and Preeclampsia. Updated diagnostic criteria (non-proteinuric PE), management algorithms. [7]

4. ISSHP Classification (2018) — International Society for the Study of Hypertension in Pregnancy. New diagnostic criteria, classification system. [6]

Landmark Trials:

1. Magpie Trial (2002) — Magnesium sulfate vs placebo in 10,141 women with pre-eclampsia. 58% reduction in eclampsia (RR 0.42, pless than 0.001). Established MgSO₄ as standard of care. [2]

2. ASPRE Trial (2017) — Aspirin 150mg vs placebo in 1,620 high-risk women. 62% reduction in preterm PE (OR 0.38, pless than 0.001). Established aspirin prophylaxis dose and timing. [8,9]

3. HYPITAT Trial (2009) — Induction of labour vs expectant management at ≥36 weeks with mild PE/gestational hypertension. IOL improved maternal outcomes without increasing CS rate. [19]

4. PETRA Trial (2019) — PlGF-guided management vs standard care in 1,035 women with suspected PE. PlGF testing reduced time to diagnosis and maternal adverse outcomes. [21]

5. PIERS Study (2011) — Developed validated prediction model for adverse outcomes in pre-eclampsia using clinical and laboratory variables. [22]

12. Common Exam Questions

MRCOG Part 2 / OSCE Stations:

1. History Taking: "Take a history from a 32-year-old primigravida at 34 weeks with BP 150/95 and 2+ protein on dipstick."

2. Management Scenario: "You are the on-call registrar. A 28-year-old woman at 30 weeks has BP 170/115, headache, and 3+ proteinuria. Outline your immediate management."

3. Counselling: "Counsel a woman who had severe pre-eclampsia at 32 weeks in her last pregnancy about risks in future pregnancies."

4. Data Interpretation: Given bloods showing platelets 85, ALT 450, LDH 850, diagnose and manage HELLP syndrome.

Viva Topics:

1. "What is the pathophysiology of pre-eclampsia?"

   • Two-stage model: poor placentation → placental ischaemia → anti-angiogenic factors (sFlt-1, sEng) → endothelial dysfunction
   • Cite Magpie trial for MgSO₄, ASPRE for aspirin

2. "When would you deliver a woman with pre-eclampsia?"

   • Immediate: Any severe maternal/fetal indication
   • Gestational age-specific: less than 34 weeks (stabilize first), ≥37 weeks (deliver all)
   • Cite HYPITAT trial

3. "How do you manage eclampsia?"

   • ABC, left lateral position, protect airway
   • MgSO₄ 4g IV loading, then 1g/hr (Magpie trial evidence)
   • Control BP, deliver after stabilization

Model Answer - "Approach to New Hypertension at 32 Weeks":

"I would approach this systematically. First, I would confirm hypertension with repeat measurement using appropriate technique - sitting, arm at heart level, correct cuff size. I would take a focused history asking about headache, visual disturbance, epigastric pain, and reduced fetal movements - these are red flag symptoms.

My immediate investigations would include urine PCR to quantify proteinuria, FBC checking platelets, LFTs to exclude HELLP, renal function, and consider PlGF testing per NICE NG133 guidelines. I would also arrange fetal assessment with CTG and ultrasound for growth and Dopplers.

Based on findings, if this is confirmed pre-eclampsia, I would classify severity. If BP ≥160/110 or end-organ dysfunction, this is severe pre-eclampsia requiring inpatient management. I would control BP with IV labetalol using the escalating protocol, start MgSO₄ for seizure prophylaxis per the Magpie trial evidence, restrict fluids to 80mL/hr to prevent pulmonary oedema, and give betamethasone for fetal lung maturity at 32 weeks.

Delivery timing would depend on severity - if severe features, I would stabilize then deliver within 24-48 hours. If mild, I might manage expectantly with close monitoring aiming for 34 weeks, as per ACOG 2020 guidance. Mode of delivery would be IOL if cervix favorable and maternal/fetal condition stable, otherwise caesarean section."

---

References

1. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376(9741):631-644. doi:10.1016/S0140-6736(10)60279-6

2. Altman D, Carroli G, Duley L, et al; Magpie Trial Collaboration Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet. 2002;359(9321):1877-1890. doi:10.1016/S0140-6736(02)08778-0

3. Zeisler H, Llurba E, Chantraine F, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med. 2016;374(13):13-22. doi:10.1056/NEJMoa1414838

4. Dennis AT. Management of pre-eclampsia: issues for anaesthetists. Anaesthesia. 2012;67(9):1009-1020. doi:10.1111/j.1365-2044.2012.07195.x

5. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007;335(7627):974. doi:10.1136/bmj.39335.385301.BE

6. Brown MA, Magee LA, Kenny LC, et al; International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension. 2018;72(1):24-43. doi:10.1161/HYPERTENSIONAHA.117.10803

7. American College of Obstetricians and Gynecologists. Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222. Obstet Gynecol. 2020;135(6):e237-e260. doi:10.1097/AOG.0000000000003891

8. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613-622. doi:10.1056/NEJMoa1704559

9. Poon LC, Wright D, Rolnik DL, et al. Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history. Am J Obstet Gynecol. 2017;217(5):585.e1-585.e5. doi:10.1016/j.ajog.2017.07.038

10. Hofmeyr GJ, Lawrie TA, Atallah ÁN, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev. 2018;10(10):CD001059. doi:10.1002/14651858.CD001059.pub5

11. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649-658. doi:10.1172/JCI17189

12. Verlohren S, Herraiz I, Lapaire O, et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol. 2012;206(1):58.e1-8. doi:10.1016/j.ajog.2011.07.037

13. National Institute for Health and Care Excellence. Hypertension in pregnancy: diagnosis and management. NICE guideline [NG133]. Published June 25, 2019. Updated August 22, 2019. https://www.nice.org.uk/guidance/ng133

14. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol. 2004;103(5 Pt 1):981-991. doi:10.1097/01.AOG.0000126245.35811.2a

15. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017;3(3):CD004454. doi:10.1002/14651858.CD004454.pub3

16. Shekhar S, Gupta N, Kirubakaran R, Pareek P. Oral nifedipine versus intravenous labetalol for severe hypertension during pregnancy: a systematic review and meta-analysis. BJOG. 2016;123(1):40-47. doi:10.1111/1471-0528.13463

17. Koopmans CM, Bijlenga D, Groen H, et al; HYPITAT study group. Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPITAT): a multicentre, open-label randomised controlled trial. Lancet. 2009;374(9694):979-988. doi:10.1016/S0140-6736(09)60736-4

18. Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: lessons learned from recent trials. Am J Obstet Gynecol. 2004;190(6):1520-1526. doi:10.1016/j.ajog.2003.12.057

19. van der Tuuk K, Koopmans CM, Groen H, et al; HYPITAT-II study group. Prediction of progression to a high risk situation in women with gestational hypertension or mild preeclampsia at term. Aust N Z J Obstet Gynaecol. 2011;51(4):339-346. doi:10.1111/j.1479-828X.2011.01316.x

20. Royal College of Obstetricians and Gynaecologists. The Management of Severe Pre-eclampsia/Eclampsia. Green-top Guideline No. 10A. March 2010 (updated 2024). https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/

21. Duhig KE, Myers J, Seed PT, et al; PARROT trial group. Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial. Lancet. 2019;393(10183):1807-1818. doi:10.1016/S0140-6736(18)33212-4

22. von Dadelszen P, Payne B, Li J, et al; PIERS Study Group. Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet. 2011;377(9761):219-227. doi:10.1016/S0140-6736(10)61351-7