Preeclampsia

Definition

Preeclampsia is a hypertensive disorder of pregnancy defined by new-onset hypertension (≥140/90 mmHg) after 20 weeks' gestation accompanied by proteinuria and/or organ damage (hepatic, renal, haematological, neurological, or utero-placental). It is increasingly recognised as a heterogeneous disease with distinct clinical phenotypes (early vs late onset; placental vs maternal) likely reflecting different underlying pathological mechanisms. Preeclampsia is among the most severe immediate complications of pregnancy and one of the strongest independent risk factors for lifetime CVD in the affected individual.

Key Concepts

Pathophysiology

Spiral Artery Failure (Core Mechanism):

• Normal pregnancy: uterine spiral arteries undergo profound remodeling (dilation) by endovascular trophoblast and uterine natural killer cells, creating a high-flow, low-resistance utero-placental bed
• Preeclampsia: failed spiral artery remodeling — smooth muscle is retained → turbulent high-velocity jets (1–2 m/s, 10–20× normal) enter intervillous space → villous architectural damage, echogenic cystic lesions, ischemia-reperfusion injury, oxidative stress sources/ht-pregnancy-aha-2022 (rating: high)

Angiogenic Imbalance:

• Placental ischemia → ↑soluble fms-like tyrosine kinase 1 (sFlt-1) — antiangiogenic factor
• sFlt-1 neutralizes proangiogenic placental growth factor (PlGF) and vascular endothelial growth factor (VEGF)
• → systemic endothelial dysfunction → hypertension, glomerulopathy, proteinuria
• sFlt-1/PlGF ratio: elevated particularly in early/severe preeclampsia; useful for risk stratification (incorporated into therapeutic trials but not yet standard of care in the US) sources/ht-pregnancy-aha-2022 (rating: high)

Glomerular Pathology:

• Podocyturia: urinary loss of glomerular podocytes documented before clinical preeclampsia diagnosis
• Endotheliosis: characteristic glomerular capillary swelling; underlies decreased GFR (~30% lower than in normal pregnancy)
• Glomerular filtration is further reduced by both decreased renal blood flow and the ultrafiltration coefficient

Haemodynamic and Metabolic Changes:

• Preeclampsia: overfilled, vasoconstricted circulation (not true hypovolemia) — suppressed plasma renin, high BP, decreased GFR, edema
• ↑insulin resistance, ↑TG, ↑cholesterol, ↑LDL-C — all more pronounced than in normal pregnancy
• Exaggerated hypercoagulability: ↑thrombin, fibrinogen; ↓protein S; ↓fibrinolysis

Senescence:

• Senescence-associated secretory phenotype (SASP) may impair placental angiogenesis and contribute to sFlt-1 excess; metformin shown to have senomorphic (anti-senescence) effects in experimental models

Clinical Phenotypes — Heterogeneity

• Both mechanisms coexist with varying contributions in individual patients; strict separation is artificial
• Early-onset preeclampsia: CVD risk is highest — aHR 4.9 (3.0–7.8) for subsequent CVD events sources/ht-pregnancy-aha-2022 (rating: high)

Risk Factors (Table 3 from Source)

High-risk (aspirin COR 1 if ≥1 factor):

• Prior preeclampsia: RR 8.4
• Chronic stage 2 hypertension (≥140/90): RR 5.1
• Pregestational diabetes: RR 3.7
• Multifetal pregnancy: RR 2.9
• Antiphospholipid syndrome: RR 2.8
• SLE: RR 2.5
• Chronic kidney disease: OR 10.4

Moderate-risk (aspirin if ≥2 factors):

• Age >35: RR 1.2; prepregnancy BMI >30: aOR 3.7
• First-degree family history: RR 2.9
• Black race: aHR 1.6 (early-onset HR 2.2)
• Low socioeconomic status: aOR 4.91; nulliparity: RR 2.1; prior adverse pregnancy outcome

Other: white coat HT RR 2.4; gestational DM aOR 1.6; recovered AKI aOR 2.9; ART RR 1.8; oocyte donation OR 4.3; migraine OR 2.1
Protective: cohabitation >12 months; smoking (inverse, mechanism unclear)

Prevention

• Low-dose aspirin (81–150 mg/day from 12–16 weeks): reduces preeclampsia and related adverse outcomes by 10–20% in high-risk women sources/ht-pregnancy-aha-2022 (rating: high); optimal dose not formally established
• Exercise: reduces gestational HT by ~30%, preeclampsia by ~40% (meta-analysis)
• Dietary interventions: 44-RCT meta-analysis — reduce gestational weight gain and improve pregnancy outcomes
• Pravastatin: experimental evidence promising (pilot trial); fetal safety concern; growing consensus that hydrophilic statins may be safe but unproven sources/prepregnancy-aha-2023 (rating: high)
• Metformin: reduces sFlt-1/soluble endoglin in endothelial tissue; senomorphic mechanism; clinical studies suggest reduction in gestational HT in GDM and possible preeclampsia prevention
• Prepregnancy CVH optimization: preconception health as upstream prevention — see concepts/Prepregnancy-Cardiovascular-Health

Diagnosis and BP Management

• Two BP readings ≥140/90 mmHg ≥4 hours apart after 20 weeks + proteinuria and/or organ damage
• Severe features include: uncontrollable BP ≥160/110 mmHg; severe headache; visual disturbances; pulmonary edema; thrombocytopenia <100k; elevated creatinine; markedly elevated liver enzymes
• Neurological manifestations (headache, visual disturbances, seizures) share pathophysiology with posterior reversible encephalopathy syndrome (PRES) — women with preeclampsia may develop intracerebral hemorrhage at lower SBP (150–170 mmHg) than nonpregnant patients
• Magnesium sulfate — mainstay of seizure prevention (eclampsia); ongoing role in postpartum preeclampsia
• Antihypertensive treatment — see concepts/Hypertensive-Disorders-of-Pregnancy for pharmacotherapy; timing/target BP under active debate (ACOG ≥160/110 vs international ≥140/90 mmHg)
• fullPIERS model (Preeclampsia Integrated Estimate of Risk): predicts adverse maternal outcomes in admitted preeclampsia patients; variables: gestational age, chest pain/dyspnea, O2 saturation, platelet count, creatinine, AST; BP does not independently predict adverse maternal outcomes in this multivariate model — BP is the only element for which an easy intervention is possible sources/cv-pregnancy-aha-2020 (rating: high)

Cerebrovascular Complications

• Cerebrovascular risk is highest in third trimester and first 6 weeks postpartum (puerperium); combined stroke rate 30 per 100,000 pregnancies; ischemic stroke 12.2/100k; ICH 12.2/100k; CVT 9.1/100k sources/cv-pregnancy-aha-2020 (rating: high)
• ICH: risk factors in preeclampsia include preeclampsia/eclampsia itself, age >35, Black race, preexisting or gestational hypertension, coagulopathy, tobacco use; women with preeclampsia may develop ICH at lower SBP (150–170 mmHg) than nonpregnant patients
• CVT (cerebral venous thrombosis): predominantly puerperium-associated (not pregnancy itself); anticoagulant choice guided by stage of pregnancy and breastfeeding status
• RCVS (reversible cerebral vasoconstriction syndrome): thunderclap headache reaching peak intensity within ≤1 minute; associated with preeclampsia/eclampsia; treatment: calcium channel blockade (nifedipine) and magnesium sulfate
• PRES (posterior reversible encephalopathy syndrome): secondary to dysfunctional cerebral autoregulation; presents with headache (less encephalopathy than in nonpregnant patients); treatment: BP management
• RCVS and PRES can co-occur and manifest with convexity subarachnoid hemorrhage
• Thrombolysis for AIS: relative contraindication in pregnancy but should be considered when stroke is disabling sources/cv-pregnancy-aha-2020 (rating: high)

Biomarkers

• sFlt-1/PlGF ratio: elevated early in placental preeclampsia; not yet routine clinical practice in US
• Podocyturia: detectable before clinical diagnosis; research context
• Angiogenesis markers (PlGF alone): incorporated into risk prediction algorithms in several European trials

Postpartum Preeclampsia

• De novo postpartum preeclampsia (delayed-onset): can occur without antepartum diagnosis
• Prevalence of postpartum HT: up to 50% in women with prior preeclampsia at 6–12 weeks
• sFlt-1/PlGF ratio rate of rise predicts persistent postpartum hypertension independently
• Role of magnesium sulfate in postpartum seizure prevention: undefined

Long-Term Sequelae

Preeclampsia survivors carry markedly elevated lifetime CVD risk independently of traditional risk factors:

• Hypertension: OR 11.6; aHR 4.5; onset 10 years earlier
• Heart failure: aHR 2.1; RR 4.2
• Coronary heart disease: aHR 2.1; RR 2.5
• Stroke: aHR 1.9
• Vascular dementia: aHR 2.4
• ESKD: RR 6.6
• Early-onset preeclampsia (<34 wks): CVD aHR 4.9 sources/ht-pregnancy-aha-2022 (rating: high)

Contradictions / Open Questions

• Causality of HDP → CVD: Whether preeclampsia causes accelerated CVD or reveals preexisting susceptibility remains unresolved. ~1/3 of the HDP-CVD association persists beyond traditional risk factors, suggesting a disease-specific pathogenic mechanism sources/ht-pregnancy-aha-2022 (rating: high)
• Placental vs maternal preeclampsia boundary: The distinction is clinically useful but mechanistically oversimplistic — both processes contribute in most cases; no validated bedside tool to classify individual cases
• sFlt-1/PlGF ratio in clinical practice: Predictive but not yet standard of care in the US; optimal threshold and clinical integration undefined
• Aspirin dose: 81–150 mg/day tested across trials; optimal dose not determined; some evidence that 150 mg more effective (ASPRE trial) but not yet reflected in US guidelines
• Pravastatin and metformin safety: Growing biological rationale and pilot data, but fetal safety unproven; no recommendation yet outside of clinical trials
• Postpartum magnesium: Duration and criteria for magnesium sulfate continuation postpartum undefined
• fullPIERS vs BP as outcome predictor: fullPIERS found BP does not independently predict adverse maternal outcomes in multivariate analysis — yet BP control remains the primary actionable intervention; this apparent paradox reflects that BP may be a mediator rather than an independent predictor in a model that captures the multisystem disease state more holistically sources/cv-pregnancy-aha-2020 (rating: high)

Connections

• Related to concepts/Hypertensive-Disorders-of-Pregnancy — preeclampsia is the most severe HDP subtype
• Related to concepts/Adverse-Pregnancy-Outcomes — preeclampsia is associated with all other APOs (preterm birth, SGA, GDM)
• Related to concepts/Prepregnancy-Cardiovascular-Health — prepregnancy CVH directly influences preeclampsia risk
• Related to entities/Maternal-Health-Disparities — Black race aHR 1.6 for preeclampsia; higher severity and mortality
• Related to entities/Heart-Failure — peripartum cardiomyopathy aOR 3.3; long-term HF risk aHR 2.1
• Related to entities/Hypertension — preeclampsia as strongest predictor of future hypertension (OR 11.6)
• Related to concepts/LQTS-Pregnancy-Management — overlapping maternal CVH and arrhythmia risk context
• Related to concepts/Cardio-Obstetrics — immediate cardio-obstetrics team involvement required for severe preeclampsia; fullPIERS for admission risk stratification
• Related to entities/Peripartum-Cardiomyopathy — preeclampsia aOR 3.3 for PPCM; shared placental vascular dysfunction pathway

Sources

• sources/cv-pregnancy-aha-2020
• sources/ht-pregnancy-aha-2022
• sources/prepregnancy-aha-2023