Compare the pathophysiology of early versus late onset pre-eclampsia and HELLP syndrome

Clinical overview

Pre-eclampsia is a multisystem, pregnancy-specific disorder of placental origin that manifests as new-onset hypertension after 20 weeks plus evidence of maternal organ dysfunction or uteroplacental compromise. It is not one disease but a spectrum with at least two phenotypes that share a final common pathway of generalised endothelial dysfunction but differ markedly in their roots: an early-onset form (classically delivery before 34 weeks) driven primarily by defective placentation, and a late-onset form (at or after 34 weeks, the great majority of cases) driven more by maternal cardiovascular and metabolic susceptibility meeting a maturing, ageing placenta. HELLP syndrome — Haemolysis, Elevated Liver enzymes, Low Platelets — is a severe variant on the same continuum, dominated by microangiopathic and hepatic injury, that can occur with only modest hypertension.

For the South African registrar this objective is not academic. Hypertensive disorders of pregnancy are consistently among the leading direct causes of maternal death in the Saving Mothers reports of the National Committee on Confidential Enquiry into Maternal Deaths (NCCEMD), and a large share of those deaths are judged avoidable — failures to measure blood pressure, to give magnesium sulphate, to control severe hypertension, or to deliver in time. Understanding why early- and late-onset disease behave differently sharpens prediction, surveillance and the timing of delivery. This chapter compares their pathophysiology and links it to the management you will be examined on; the clinical thresholds and acute drills overlap heavily with hypertension-in-pregnancy.

Core knowledge

Definitions and the diagnostic shift

Pre-eclampsia is new hypertension (≥140/90 mmHg on two occasions, or ≥160/110 once) after 20 weeks, with proteinuria OR maternal organ dysfunction OR uteroplacental dysfunction (e.g. fetal growth restriction). A key conceptual shift, reflected in modern guidance, is that proteinuria is no longer mandatory — renal, hepatic, haematological, neurological or fetal involvement satisfies the diagnosis. The NICE NG133 / ISSHP-aligned position used in the SA NDoH Maternity Guideline (NDoH, 2024) recognises this broadened definition. Eclampsia is pre-eclampsia complicated by generalised tonic–clonic seizures.

The two-stage model — and where the phenotypes diverge

The unifying framework is the two-stage model:

Stage 1 (preclinical, placental): abnormal spiral-artery remodelling → placental malperfusion → release of antiangiogenic and inflammatory factors into the maternal circulation.
Stage 2 (clinical, maternal): circulating factors cause systemic endothelial dysfunction → vasospasm, increased capillary permeability, activation of coagulation, and the multi-organ syndrome we recognise.

Both phenotypes pass through Stage 2 (the same endothelium, the same syndrome), but they reach it differently.

Early-onset pre-eclampsia — a placental disease

In normal pregnancy, extravillous trophoblast invades the decidual and inner myometrial segments of the spiral arteries, replacing their muscular walls so they become flaccid, low-resistance conduits delivering high-volume flow to the intervillous space. In early-onset disease this physiological conversion is shallow and incomplete: the arteries retain muscular tone and responsiveness, producing intermittent perfusion, ischaemia–reperfusion injury, and oxidative and endoplasmic-reticulum stress in the syncytiotrophoblast.

The stressed placenta tips the angiogenic balance. It oversecretes soluble fms-like tyrosine kinase-1 (sFlt-1), a decoy receptor that mops up circulating placental growth factor (PlGF) and vascular endothelial growth factor, and secretes soluble endoglin. The net effect is loss of the VEGF/PlGF signalling that maintains healthy endothelium, especially the fenestrated glomerular and hepatic endothelium. A high sFlt-1/PlGF ratio is the biochemical signature, and the foundation of the PlGF-based tests (NICE DG49) used to rule out pre-eclampsia. Because the lesion is placental and early, early-onset disease is tightly associated with placental insufficiency, fetal growth restriction, oligohydramnios and abnormal umbilical-artery Dopplers (see placental-insufficiency-response and intrauterine-growth-restriction). It is the less common but more dangerous phenotype, carrying higher rates of severe maternal morbidity, HELLP, eclampsia and perinatal loss.

Late-onset pre-eclampsia — a maternal/placental mismatch

Late-onset disease, the majority of cases, often arises in a placenta that was normally implanted. Here the problem is a supply–demand mismatch: as term approaches, a large or senescent placenta outgrows its perfusion, or — more importantly — a maternal constitution predisposed to endothelial and metabolic dysfunction (chronic hypertension, obesity, insulin resistance, dyslipidaemia, pre-existing renal or vascular disease, older age) reaches the threshold at which the normal cardiovascular stress of late pregnancy unmasks disease. The angiogenic imbalance is usually milder (a lower sFlt-1/PlGF rise), fetal growth is more often normal or even large, and umbilical Dopplers are frequently normal. Conceptually: early-onset is placenta failing the mother; late-onset is mother failing the placenta. This distinction is real but a continuum, not a clean dichotomy — overlap is common and should not breed complacency, because late-onset disease still kills.

Figure J20.1 — Early- and late-onset pre-eclampsia reach the same endothelial syndrome through different placental and maternal pathways.

HELLP syndrome — the microangiopathic extreme

HELLP sits within the severe end of the spectrum and is best understood as endothelial injury concentrated in the hepatic microcirculation with systemic microangiopathic haemolysis. Fibrin deposition in hepatic sinusoids causes periportal/focal hepatocellular necrosis, raising transaminases and distending Glisson's capsule (the source of right-upper-quadrant/epigastric pain). Red cells are sheared through damaged microvasculature → microangiopathic haemolytic anaemia (schistocytes, raised LDH and bilirubin, low haptoglobin). Platelets are consumed at sites of endothelial injury → thrombocytopenia. Classic laboratory criteria (Tennessee): LDH ≥600 U/L, AST/ALT elevated (often ≥70 U/L), platelets <100 ×10⁹/L. HELLP can present with normal or only mildly raised blood pressure and minimal proteinuria, which is exactly why it is missed. It overlaps clinically with acute fatty liver of pregnancy and the thrombotic microangiopathies (TTP/HUS), and may be complicated by DIC, abruption, hepatic infarction or subcapsular liver haematoma with rupture.

HELLP syndrome microangiopathy infographic

Figure J20.2 — HELLP syndrome as hepatic microangiopathy with haemolysis, liver-enzyme rise, platelet consumption and delivery-focused stabilisation.

Feature	Early-onset PE	Late-onset PE	HELLP
Onset	<34 weeks	≥34 weeks (most cases)	Often near term; can be early
Primary driver	Defective placentation (Stage 1)	Maternal cardiometabolic susceptibility / mismatch	Severe endothelial + hepatic microangiopathy
sFlt-1/PlGF	Markedly raised	Mildly raised / variable	Raised
Fetal growth	FGR common	Often normal / LGA	Variable; FGR if early
Uterine/umbilical Doppler	Often abnormal	Often normal	Variable
Maternal risk	Highest	Lower but not benign	Very high

Assessment

History and risk stratification

Identify high-risk factors (any one): prior pre-eclampsia, chronic hypertension, chronic kidney disease, diabetes (type 1 or 2), and autoimmune disease (SLE, antiphospholipid syndrome). And moderate-risk factors (two or more): first pregnancy, age ≥40, BMI ≥35 kg/m², family history, multiple pregnancy, and pregnancy interval >10 years. These guide aspirin prophylaxis (NICE NG133). Ask specifically about headache, visual disturbance, epigastric/right-upper-quadrant pain, vomiting, and reduced fetal movements — symptoms of severe disease and impending eclampsia or HELLP. In the SA setting, integrate HIV status and antiretroviral history and any history of substance use, and remember the high background of chronic hypertension that predisposes to superimposed and late-onset disease.

Examination

Blood pressure with a correctly sized cuff, repeated; document severe-range (≥160/110).
Reflexes and clonus, level of consciousness — neurological irritability precedes eclampsia.
Epigastric/RUQ tenderness — hepatic involvement / HELLP.
Oedema (non-specific), crepitations and oxygen saturation — pulmonary oedema is a leading cause of death.
Symphysis–fundal height and fetal assessment.

Investigations

Urine dipstick → protein:creatinine ratio (≥30 mg/mmol is significant) — but its absence does not exclude PE.
Full blood count (platelets, haemoglobin, evidence of haemolysis on film/schistocytes).
Liver enzymes (AST/ALT), LDH, bilirubin — for HELLP.
Urea, creatinine and electrolytes — renal involvement; baseline before magnesium.
Uric acid — supportive, not diagnostic.
Coagulation profile if HELLP, abruption or DIC suspected.
PlGF-based testing / sFlt-1:PlGF ratio (NICE DG49) where available — strong negative predictive value to rule out PE in the short term; not yet standard in most SA public-sector settings, so do not rely on it.
Fetal assessment: ultrasound for growth and liquor, umbilical-artery (and where indicated MCA/ductus venosus) Doppler, and CTG — see ctg-interpretation and fetal-monitoring-methods. Abnormal Dopplers and growth restriction point to the early-onset placental phenotype.

Management

Management has three simultaneous aims: control severe hypertension, prevent/treat seizures, and effect delivery at the right time and place. Delivery is the only cure; everything else buys time and reduces harm. SA practice follows the NDoH Maternity Guideline (NDoH, 2024) with magnesium and antihypertensives on the EML.

Emergency drill — severe hypertension and eclampsia

SEVERE HYPERTENSION (≥160/110 mmHg) IS AN EMERGENCY — TREAT WITHIN MINUTES, AIM <150/100. Acute control (SA EML / NICE NG133):

Oral nifedipine (immediate-release, not sublingual) 10 mg, repeat at intervals per protocol; OR

IV labetalol boluses titrated (avoid in asthma); OR

IV hydralazine boluses. Recheck BP every few minutes during titration. Avoid precipitous drops that compromise placental perfusion.

ECLAMPSIA / SEIZURE PROPHYLAXIS — MAGNESIUM SULPHATE IS FIRST-LINE (MAGPIE; NICE NG133; SA NDoH).

Loading dose 4 g IV over 5–10 minutes, then maintenance 1 g/hour IV (or the IM regimen where infusion pumps are unavailable), continued for 24 hours after delivery or after the last seizure.

Treat recurrent seizures with a further 2 g IV bolus.

Monitor for toxicity clinically: respiratory rate, deep tendon reflexes (loss of patellar reflex is an early sign), and urine output. Reduce/withhold and check levels in renal impairment.

Antidote: calcium gluconate 10% 10 mL IV for magnesium toxicity (respiratory depression) — keep it drawn up.

General seizure care: left lateral, protect airway, oxygen, do not leave the patient; control BP, then deliver.

Severe pre-eclampsia emergency management ladder infographic

Figure J20.3 — Severe pre-eclampsia emergency ladder for urgent BP control, magnesium sulphate safety, transfer stabilisation and delivery timing.

Antenatal management before delivery

Antihypertensive maintenance: oral labetalol, nifedipine, or methyldopa (methyldopa avoided in depression). Aim to keep BP controlled, not normalised.
Expectant management of early-onset disease (remote from term, stable mother, reassuring fetus) in a regional/tertiary unit to gain fetal maturity — but only while maternal and fetal surveillance stay reassuring.
Antenatal corticosteroids for fetal lung maturity if delivery before 34 (and selectively to ~36) weeks is anticipated (RCOG GTG74) — see preterm-birth-and-pprom.
Magnesium sulphate for fetal neuroprotection when very preterm delivery is planned, in addition to its maternal anticonvulsant role.
Fluids: restrict (risk of pulmonary oedema); strict input/output.

Timing and place of delivery

Delivery is curative. At ≥37 weeks, deliver. For severe disease, deliver once the mother is stabilised regardless of gestation. For early-onset disease before 34 weeks, expectant management in a unit with neonatal capacity is reasonable only while safe — deteriorating maternal organ function, uncontrollable hypertension, eclampsia, HELLP, abruption, or a non-reassuring fetus mandates delivery.
Mode: vaginal birth is not contraindicated; caesarean for obstetric indications or when induction is inappropriate. Beware regional anaesthesia with thrombocytopenia (HELLP) — check platelets.
Level of care: severe pre-eclampsia, eclampsia and HELLP belong at regional or tertiary level; stabilise (control BP, load magnesium) before transfer, communicate early, and never delay magnesium or antihypertensives while awaiting transport. This is a recurrent avoidable-death theme in Saving Mothers.

HELLP-specific points

Manage as severe pre-eclampsia: stabilise, magnesium, control BP, deliver.
Platelets may need transfusion before surgery/regional block if very low or bleeding.
Watch for DIC, abruption, acute kidney injury, pulmonary oedema, and subcapsular liver haematoma — sudden shoulder-tip/RUQ pain with shock suggests rupture (a surgical emergency; see shock-management).
Steroids for HELLP improve laboratory parameters but not maternal/perinatal outcomes — do not use solely to treat HELLP.

Prevention and postnatal care

Low-dose aspirin 75–150 mg from 12 weeks until delivery for women at high or moderate risk (NICE NG133; SA NDoH) — the single most effective preventive intervention, most effective against early-onset disease.
Calcium supplementation in low-calcium-intake populations reduces pre-eclampsia (WHO) — relevant to many SA patients.
Postnatal: hypertension can worsen for several days; continue monitoring and treatment, continue magnesium 24 h post-delivery, watch for late eclampsia and pulmonary oedema, and arrange follow-up. Counsel on recurrence risk and long-term cardiovascular/renal risk, and on contraception — see postpartum-contraception.

Red flags / pitfalls

"No proteinuria, so it's not pre-eclampsia." Wrong — the modern definition does not require proteinuria. HELLP especially can present with little proteinuria and only modestly raised BP.
Treating BP but forgetting magnesium — seizure prophylaxis is separate from BP control. Both are needed in severe disease.
Sublingual nifedipine — causes uncontrolled hypotension; use immediate-release oral nifedipine.
Fluid overload — over-zealous IV fluids cause fatal pulmonary oedema; pre-eclamptic women are intravascularly deplete but leaky. Restrict and monitor.
Missing HELLP in a woman with epigastric pain and vomiting attributed to "gastritis" — always check platelets, LDH and transaminases.
Regional anaesthesia with unchecked platelets in HELLP — risk of spinal/epidural haematoma.
Delaying delivery in unstable severe disease to chase fetal maturity — maternal deterioration overrides gestation.
Failing to stabilise before transfer — load magnesium and control BP first; this is a documented avoidable-death pattern.
Forgetting the postnatal window — late eclampsia and pulmonary oedema occur after delivery; do not relax surveillance.
Assuming late-onset disease is benign — it is the commonest phenotype and still causes maternal death.

Evidence anchors

South African National Integrated Maternal and Perinatal Care Guideline (NDoH, 2024) — SA obstetric source of truth for diagnosis, magnesium and antihypertensive protocols, levels of care and referral.
Saving Mothers / NCCEMD triennial reports — hypertensive disorders among the leading direct causes of avoidable maternal death in South Africa.
NICE NG133 — Hypertension in pregnancy: diagnosis and management (2019) — diagnostic criteria, low-dose aspirin 75–150 mg from 12 weeks, labetalol/nifedipine/methyldopa, magnesium sulphate for severe disease/eclampsia (MAGPIE), broadened definition without mandatory proteinuria.
NICE DG49 — PlGF-based testing (sFlt-1/PlGF ratio) to help rule out pre-eclampsia.
RCOG GTG74 — Antenatal corticosteroids for anticipated preterm delivery.
WHO — calcium supplementation for prevention of pre-eclampsia in low-intake populations; WHO recommendations on prevention and treatment of pre-eclampsia/eclampsia.
South African EML — Hospital Level (Adults) — magnesium sulphate, nifedipine, labetalol, hydralazine, calcium gluconate antidote.

Note (hedged, standard teaching not line-itemed in verified sources): the two-stage placental model, sFlt-1/PlGF/soluble endoglin angiogenic mechanism, the early- vs late-onset 34-week split, and the Tennessee HELLP laboratory criteria are textbook canon stated cautiously here and not attributed to a specific cited guideline.