Pre-eclampsia pathogenesis
Hypertensive disorders of pregnancy: pathogenesis of pre-eclampsia, eclampsia and HELLP
Pre-eclampsia is a placental disease that becomes a maternal endothelial disease: poorly remodelled spiral arteries make the placenta ischaemic, and it releases anti-angiogenic factors that injure endothelium throughout the mother's body. Every sign, from hypertension and proteinuria to fits, liver pain and haemolysis, follows from that endothelial damage. CPSP asks the two-stage mechanism, the mediators, organ pathology and risk factors.
Definitions
| Disorder | Features |
|---|---|
| Chronic hypertension | BP 140/90 or more before pregnancy or before 20 weeks |
| Gestational hypertension | New hypertension after 20 weeks without proteinuria or organ dysfunction |
| Pre-eclampsia | New hypertension after 20 weeks with proteinuria (300 mg or more per 24 hours) or maternal organ or uteroplacental dysfunction |
| Severe features | BP 160/110 or more, headache, visual disturbance, epigastric pain, low platelets, rising creatinine, pulmonary oedema |
| Eclampsia | Generalised fits in a woman with pre-eclampsia |
| HELLP | Haemolysis, Elevated Liver enzymes, Low Platelets; a severe variant, sometimes with little hypertension |
- Pre-eclampsia before 20 weeks suggests a hydatidiform mole: the large trophoblast mass sheds excess anti-angiogenic factors.
- Oedema alone is no longer a diagnostic criterion, as it is common in normal pregnancy.
Stage 1: the placenta
- In normal pregnancy, extravillous cytotrophoblast invades the spiral arteries in two waves, replacing smooth muscle and elastic tissue with fibrinoid so they become wide, flaccid, low-resistance channels reaching the inner third of the myometrium, unresponsive to vasoconstrictors.
- In pre-eclampsia remodelling is confined to the decidual segments; myometrial segments keep their muscular walls, so flow is low, pulsatile and intermittent. The resulting ischaemia–reperfusion causes oxidative stress in the placenta. (Excess invasion, by contrast, gives placenta accreta.)
- Uterine artery Doppler at 20–24 weeks shows a high pulsatility index and a persistent early diastolic notch (high resistance), predicting pre-eclampsia and growth restriction.
- Acute atherosis of unremodelled decidual arteries: fibrinoid necrosis, lipid-laden foamy macrophages and perivascular lymphocytes; it leads to thrombosis and placental infarcts.
- Immune maladaptation to paternal antigens contributes: risk is higher in first pregnancies, with a new partner, after short cohabitation, barrier contraception, and donor oocyte or sperm pregnancies.
Stage 2: the maternal syndrome
- The stressed placenta releases sFlt-1 (soluble VEGF receptor 1), which traps VEGF and placental growth factor (PlGF), and soluble endoglin, which binds TGF-β and impairs endothelial NO production (highest in HELLP). A high sFlt-1:PlGF ratio supports the diagnosis; PlGF itself falls.
- Loss of VEGF signalling damages fenestrated endothelium (glomerulus, liver, choroid plexus) and causes generalised endothelial dysfunction:
| Change | Effect |
|---|---|
| Less prostacyclin and NO, more thromboxane A2 and endothelin | Vasoconstriction, platelet activation |
| Loss of the normal refractoriness to angiotensin II | Exaggerated pressor response |
| Capillary leak | Oedema with reduced plasma volume and a rising haematocrit |
| Platelet activation and consumption | Thrombocytopenia, microthrombi, DIC |
- The low intravascular volume is why diuretics are avoided and why the haematocrit rises rather than falls.
Organ pathology
| Organ | Lesion | Clinical result |
|---|---|---|
| Kidney | Glomerular endotheliosis: swollen endothelial cells occluding capillary lumens | Proteinuria, reduced GFR, raised uric acid and creatinine, oliguria |
| Brain | Loss of autoregulation, vasogenic oedema mainly in parieto-occipital white matter (posterior reversible encephalopathy), vasospasm, haemorrhage | Headache, visual disturbance, eclamptic fits; intracerebral haemorrhage is a leading cause of death |
| Liver | Periportal haemorrhagic necrosis and fibrin deposition; oedema stretching the capsule | Epigastric and right upper quadrant pain, raised ALT, subcapsular haematoma, rupture |
| Blood | Fibrin strands in small vessels shear red cells | Microangiopathic haemolysis: schistocytes, high LDH, low haptoglobin, negative DAT |
| Lungs | Capillary leak, low oncotic pressure, sometimes LV dysfunction | Pulmonary oedema |
| Placenta and fetus | Infarcts, acute atherosis, abruption | Growth restriction, oligohydramnios, abnormal Doppler, fetal death |
- HELLP: haemolysis from microangiopathy, liver enzyme rise from periportal necrosis, low platelets from consumption; it can progress to DIC and liver rupture.
- Eclampsia can occur antenatally, in labour or within days postpartum; magnesium sulphate (NMDA block, cerebral vasodilatation) prevents and treats fits.
Risk factors
- First pregnancy or new partner; previous pre-eclampsia; family history.
- Multiple pregnancy and molar pregnancy (large placental mass).
- Chronic hypertension, renal disease, diabetes, obesity, antiphospholipid syndrome, SLE.
- Maternal age over 40, long interval between pregnancies, IVF.
Prevention
- Low-dose aspirin started before 16 weeks in high-risk women preferentially inhibits platelet thromboxane A2 (platelets cannot make new COX) while endothelial prostacyclin recovers, restoring the balance.
- Calcium supplements reduce risk where dietary calcium is low.
- Delivery of the placenta is the only cure; the disease usually resolves within days.
Remember Shallow spiral artery invasion makes an ischaemic placenta; sFlt-1 and soluble endoglin turn that into endothelial damage in every maternal organ.
Exam trap In pre-eclampsia oedema hides a contracted plasma volume; the haematocrit rises.
Exam trap Hypertension and proteinuria before 20 weeks should prompt a search for a molar pregnancy.
Test yourself on this topic
5 of the 12 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A woman with HELLP syndrome has a falling haemoglobin, raised LDH, low haptoglobin and fragmented red cells on the blood film. Her direct antiglobulin test is negative. What is the mechanism of the haemolysis?
Answer: Red cells shear on fibrin in damaged vessels
HELLP syndrome is a severe form of pre-eclampsia with widespread endothelial injury. Platelets and fibrin are deposited on the damaged endothelium of small vessels, and red cells forced through these meshes are cut into fragments (schistocytes). This microangiopathic haemolysis is intravascular, raising LDH and lowering haptoglobin. It is not antibody-mediated, so the direct antiglobulin test is negative.
HELLP haemolysis
- Endothelial injury
- Fibrin and platelets in small vessels
- Red cells fragmented (schistocytes)
- DAT negative, high LDH
Remember Fragments on the film in HELLP: microangiopathy.
Exam trap A negative antiglobulin test points away from an immune cause.
Why the other options are wrong
- Complement attack on antibody-coated red cells Antibody-mediated haemolysis gives a positive antiglobulin test.
- Oxidant damage from G6PD deficiency Would give bite and blister cells after an oxidant stress.
- Splenic removal of spherocytes Spherocytes suggest hereditary or autoimmune haemolysis.
- Osmotic lysis from hyponatraemia Not a cause of fragmented cells.
A woman had an uncomplicated first pregnancy. She remarries and develops pre-eclampsia in her first pregnancy with her new husband after only a few months of marriage. What best explains her increased risk?
Answer: Little prior exposure to his antigens
Pre-eclampsia is partly an immune maladaptation between the mother and the fetal (paternal) antigens on trophoblast. Repeated exposure to a partner's antigens, for example through prolonged sexual cohabitation before conception, seems to induce tolerance that supports normal placentation. A new partner, a short period of exposure, barrier contraception and pregnancy by donor gametes all increase the risk. This explains why a woman's risk can return with a change of partner.
Primipaternity and pre-eclampsia
- Immune maladaptation to paternal antigens
- Risk up with a new partner
- Short cohabitation, barrier methods
- Donor oocyte or sperm pregnancies
Remember New father, new risk.
Exam trap Multiparity protects only when the partner is the same.
Why the other options are wrong
- Greater maternal age at this pregnancy Older age adds some risk, but not the key factor here.
- Higher parity Multiparity usually lowers the risk.
- Previous normal placentation Previous normal placentation lowers the risk with the same partner.
- Reduced maternal plasma volume A consequence, not a cause, of pre-eclampsia.
The ischaemic placenta in pre-eclampsia releases a soluble receptor into the maternal blood. It traps VEGF and placental growth factor, causing widespread endothelial dysfunction. Which factor is this?
Answer: sFlt-1
Soluble fms-like tyrosine kinase-1 (sFlt-1) is a circulating splice variant of the VEGF receptor. It binds VEGF and placental growth factor so they cannot act on endothelium, where they normally maintain fenestrations and nitric oxide production. The resulting endothelial dysfunction produces hypertension, proteinuria and the other features of pre-eclampsia. A high sFlt-1 to PlGF ratio is used clinically to support the diagnosis.
sFlt-1 in pre-eclampsia
- Released by ischaemic placenta
- Traps VEGF and PlGF
- Causes endothelial dysfunction
- High sFlt-1:PlGF ratio
Remember The placenta soaks up the growth factors the endothelium needs.
Exam trap PlGF falls while sFlt-1 rises; the ratio is the useful marker.
Why the other options are wrong
- Soluble endoglin Also anti-angiogenic, but it traps TGF-beta, not VEGF.
- Endothelin-1 Raised downstream, but not the placental trap for VEGF.
- Thromboxane A2 A vasoconstrictor raised in pre-eclampsia, but not a soluble receptor.
- Prostacyclin A vasodilator that is reduced in pre-eclampsia.
At 16 weeks, a woman with a confirmed complete hydatidiform mole has a BP of 160/105 mmHg and 3+ proteinuria. Why can pre-eclampsia appear so early in a molar pregnancy?
Answer: Excess trophoblast shedding anti-angiogenic factors
Pre-eclampsia is driven by the placenta, not the fetus, so a complete mole with no fetus can still cause it. The mass of abnormal trophoblast is large and poorly perfused, and it releases large amounts of anti-angiogenic factors such as sFlt-1 and soluble endoglin. These cause maternal endothelial dysfunction weeks earlier than usual. Pre-eclampsia before 20 weeks should therefore prompt a search for a mole, multiple pregnancy or other cause of a large placental mass.
Early-onset pre-eclampsia
- Pre-eclampsia < 20 weeks is unusual
- Think molar pregnancy
- Large trophoblast mass
- Excess anti-angiogenic factors
Remember The placenta, not the fetus, causes pre-eclampsia.
Exam trap Do not diagnose ordinary pre-eclampsia before 20 weeks without excluding a mole.
Why the other options are wrong
- Very high hCG stimulating the adrenal cortex hCG does not drive adrenal hypertension.
- Molar tissue secreting renin Not the mechanism of molar pre-eclampsia.
- The fetus producing vasopressor amines There is no fetus in a complete mole.
- Molar hyperthyroidism raising systolic pressure Thyrotoxicosis can occur with moles but does not cause proteinuria.
Histology of the placental bed after delivery in a woman with severe early-onset pre-eclampsia shows decidual spiral arteries with fibrinoid necrosis of the wall, clusters of lipid-laden foamy macrophages and a perivascular lymphocytic infiltrate. What is this lesion called?
Answer: Acute atherosis
Acute atherosis is the characteristic vascular lesion of the placental bed in pre-eclampsia. Non-remodelled decidual spiral arteries develop fibrinoid necrosis, accumulate lipid-laden macrophages in the intima and are surrounded by lymphocytes, resembling an early atherosclerotic plaque. The lesion narrows the vessels and may thrombose, causing placental infarcts. It is also seen in fetal growth restriction and some cases of antiphospholipid syndrome.
Acute atherosis
- Unremodelled decidual arteries
- Fibrinoid necrosis of wall
- Foamy macrophages in intima
- Leads to infarcts
Remember Foamy macrophages in spiral arteries: acute atherosis.
Exam trap Despite the name, it is a pregnancy lesion of decidual vessels, not true atherosclerosis.
Why the other options are wrong
- Hyaline arteriolosclerosis A lesion of hypertension and diabetes in systemic arterioles.
- Thromboangiitis obliterans Affects limb vessels of young male smokers.
- Giant cell arteritis Affects the temporal artery in older adults.
- Monckeberg medial sclerosis Medial calcification of muscular arteries in the elderly.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: General pathology in obstetrics, Hypertensive disorders of pregnancy: pre-eclampsia, eclampsia and HELLP pathogenesis
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