Preeclampsia

Research Summary: Preeclampsia (MONDO:0005081)

This is assigned to @nlharris — skipping autonomous curation. This summary is intended as a research aid for the curator.

Disease Overview

Preeclampsia is a multisystem pregnancy disorder affecting 2–8% of pregnancies worldwide, accounting for >50,000 maternal and >500,000 fetal deaths annually. It is defined by new-onset hypertension (≥140/90 mmHg) developing after 20 weeks of gestation, typically accompanied by proteinuria or evidence of end-organ damage. It is the dominant clinical manifestation in a spectrum that includes gestational hypertension, HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets), and eclampsia (seizures).

The condition is now understood as a vascular disorder unmasked by pregnancy rather than a hypertensive disorder per se — the placenta is the central driver, and delivery is the only definitive cure.

Key ACOG diagnostic update (2019+): Proteinuria is no longer required if severe hypertension coexists with end-organ damage (thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or new-onset headache/visual symptoms).

Pathophysiology: The Two-Stage Model

The dominant framework is a two-stage model (Roberts/Hubel, extensively reviewed):

STAGE 1 (Silent, pre-clinical)         STAGE 2 (Clinical maternal syndrome)
─────────────────────────────           ─────────────────────────────────────
Defective trophoblast invasion   →  →   Anti-angiogenic factors released
+ Failed spiral artery remodeling       into maternal circulation
                   →  →   Endothelial dysfunction (systemic)
                         → Hypertension
                         → Proteinuria (glomerular endotheliosis)
                         → HELLP, eclampsia

This explains the early-onset/late-onset split: early-onset (< 34 wks) is dominated by placental failure (Stage 1); late-onset (≥ 34 wks) by maternal constitutional predisposition and endothelial vulnerability.

Pathophysiology Nodes (Suggested Structure)

Node 1: Defective Trophoblast Invasion and Spiral Artery Remodeling

• Normally, extravillous trophoblasts (EVTs) invade the spiral arteries and replace vascular smooth muscle, transforming them from high-resistance to high-capacitance vessels
• In preeclampsia, this invasion is shallow; spiral arteries remain narrow, tortuous, and high-resistance
• Results in placental ischemia and hypoxia

Key mechanisms: - Impaired uterine NK (uNK) cell tolerance and signaling (KIR/HLA-C interactions at the decidua-trophoblast interface) - HLA-G expressed on EVTs normally dampens NK cytotoxicity; this axis is disrupted in PE - Dysregulated TGF-β, VEGF, and HIF-1α signaling in the decidua

Key cell types: - Extravillous trophoblast (EVT): CL:0000351 (trophoblast) / extravillous subtype - Uterine natural killer cell: CL:0000623 (natural killer cell) — decidual NK cells are CL:0002362 - Decidual stromal cell

Key biological processes: - Trophoblast cell migration / invasion: GO:0001753 (trophoblast giant cell differentiation — verify specificity) - GO:0001570 (vasculogenesis) - GO:0035441 (cell migration involved in vasculogenesis) - Response to hypoxia: GO:0001666

Node 2: Placental Oxidative Stress and sFlt-1 Overproduction

• Ischemic/hypoxic placenta upregulates HIF-1α, triggering massive production of sFlt-1 (soluble VEGF receptor-1, a splice variant of FLT1)
• sFlt-1 is a potent decoy receptor that sequesters circulating VEGF and PlGF (placental growth factor)
• Result: markedly reduced free VEGF/PlGF → anti-angiogenic state in the mother
• Soluble endoglin (sEng), also released by the hypoxic placenta, inhibits TGF-β signaling and amplifies endothelial damage
• The sFlt-1:PlGF ratio is now used clinically (ratio >38 predicts adverse outcomes within 4 weeks; EMA/FDA approved)

Key genes (need OAK verification of HGNC IDs): - FLT1 (hgnc:3738 — verify) — encodes Flt-1; alternative splicing generates sFlt-1 - PGF (hgnc:8982 — verify) — encodes PlGF - ENG (hgnc:3349 — verify) — encodes endoglin; shed as sEng - VEGFA (hgnc:12680 — verify) — primary target sequestered by sFlt-1

Key biological processes: - GO:0001525 — angiogenesis - GO:0048010 — VEGF receptor signaling pathway - GO:0001666 — cellular response to hypoxia - HIF-1 signaling / hypoxia-inducible factor pathway

Node 3: Maternal Endothelial Dysfunction and Multi-Organ Injury

• Circulating sFlt-1, sEng, syncytiotrophoblast microparticles, and inflammatory mediators damage the systemic maternal endothelium
• Endothelial activation → reduced NO production, endothelin-1 upregulation → vasoconstriction → hypertension
• Kidney: Glomerular endotheliosis (pathognomonic lesion — swelling of glomerular endothelial cells, effacement of fenestrae) → proteinuria
• Liver: Hepatic sinusoidal obstruction, periportal necrosis → elevated transaminases; capsular distension → epigastric/RUQ pain; HELLP
• Brain: Posterior reversible encephalopathy syndrome (PRES), cerebral edema, seizures (eclampsia) — cerebrovascular autoregulation failure
• Coagulation: Endothelial activation triggers DIC-spectrum, thrombocytopenia (HELLP)
• Placenta: Decidual vasculopathy, infarcts → fetal growth restriction, placental abruption

Key cell types: - Vascular endothelial cell: CL:0000071 (blood vessel endothelial cell) - Glomerular endothelial cell: CL:1000850 (glomerular endothelial cell — verify) - Syncytiotrophoblast: CL:0000525 (syncytiotrophoblast — verify CL ID) - Platelet: CL:0000233

Key biological processes: - GO:0008217 — regulation of blood pressure - GO:0045087 — innate immune response - GO:0042493 — response to drug (for treatment nodes) - Nitric oxide signaling / endothelial NOS pathway - GO:0006954 — inflammatory response - Complement activation: GO:0006956

Clinical Phenotypes (Suggested HPO Terms)

Subtypes

The entry should have at least two main subtypes: - Early-onset (< 34 weeks): Placenta-driven, more severe, higher sFlt-1, more associated with FGR; higher risk - Late-onset (≥ 34 weeks): More maternal constitutional; less placental pathology; more common but generally less severe - HELLP syndrome: Can be considered a severe variant with microangiopathic hemolysis, elevated LFTs, low platelets; may occur without classic hypertension/proteinuria - Superimposed preeclampsia: On a background of chronic hypertension

Treatments

Key Evidence References (Verified PMIDs)

The following PMIDs were confirmed by direct abstract retrieval:

1. PMID:30792480 — Phipps et al. 2019, Nat Rev Nephrology — "Pre-eclampsia: pathogenesis, novel diagnostics and therapies." Comprehensive mechanistic review covering sFlt-1/sEng/PlGF, endothelial dysfunction, renal glomerular endotheliosis, and emerging therapies. Highly recommended as primary reference.

2. PMID:35177220 — Erez et al. 2022, Am J Obstet Gynecol — "Preeclampsia and eclampsia: the conceptual evolution of a syndrome." Covers the historical shift from neurological → vascular conceptualization; early vs. late onset subtypes; role of antiangiogenic factors.

3. PMID:34033373 — Karrar et al. 2024, StatPearls — Comprehensive overview of diagnostic criteria, pathophysiology (uteroplacental ischemia), and management.

4. PMID:32443079 — ACOG Practice Bulletin #222, 2020, Obstet Gynecol — Clinical guideline; the rate of preeclampsia increased 25% between 1987–2004; management thresholds and protocols.

Additional high-priority references to fetch and verify (titles confirmed, PMIDs need just fetch-reference verification):

• Maynard et al. (2003) J Clin Invest — "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia" — The landmark animal model paper establishing sFlt-1 causality.
• Levine et al. (2004) N Engl J Med — "Circulating angiogenic factors and the risk of preeclampsia" — Prospective clinical cohort showing sFlt-1 rises and PlGF falls weeks before clinical PE onset.
• Redman & Sargent (2005) Science — "Latest advances in understanding preeclampsia" — Overview of immune and vascular mechanisms.
• Verlohren et al. (2010/2012) Hypertension — Established the sFlt-1:PlGF ratio clinical cutoff of 38.
• Staff et al. (2019) — Clinical use of angiogenic biomarkers in preeclampsia.

Orphanet / Structured Sources

• Orphanet ORPHA code for pre-eclampsia: likely ORPHA:275555 — run just fetch-reference ORPHA:275555 to verify and check for definition, prevalence, and gene-disease associations that can be cited as ORPHA:275555 evidence items.

Suggested Module Conformance

Preeclampsia does not appear to conform to the existing fibrotic_response or immune_checkpoint_blockade modules. The disease may warrant a future placental_vascular_dysfunction module given the conserved sFlt-1/PlGF anti-angiogenic mechanism also seen in fetal growth restriction, spontaneous preterm birth, and HELLP syndrome.

The complement-driven endothelial damage node could potentially align with modules used in other thrombotic microangiopathy entries (e.g., aHUS) if those are curated.

Long-term Consequences (for progression or outcomes section)

• Women with prior preeclampsia have 2× lifetime risk of cardiovascular disease, 2–4× risk of hypertension, and 2× risk of stroke
• Preterm delivery and FGR are the primary fetal consequences
• Recurrence rate in subsequent pregnancies: 15–25% (higher if early-onset index pregnancy)

Summary generated by Claude Code summarization agent from PubMed abstracts and authoritative review sources. All PMIDs must be verified with just fetch-reference before use as snippets.