Preeclampsia

Complex MONDO:0005081 Pathograph 29 Show in embeddings browser Hypertensive disorder of pregnancy Placental disease

Preeclampsia is a multisystemic pregnancy disorder characterized by new-onset hypertension and often proteinuria after 20 weeks of gestation, which can progress to multi-organ dysfunction including hepatic, renal, and cerebral disease. It complicates 2-8% of pregnancies globally and is a leading cause of maternal and perinatal morbidity and mortality. The pathophysiology involves defective trophoblast invasion and spiral artery remodeling leading to placental ischemia, followed by release of anti-angiogenic factors (sFlt-1, soluble endoglin) that cause widespread maternal endothelial dysfunction. The only definitive treatment is delivery of the fetus and placenta.

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Subtypes

Early-onset preeclampsia (<34 weeks)

Preeclampsia with onset before 34 weeks of gestation. Strongly associated with defective placentation and more severe angiogenic imbalance. Associated with higher rates of maternal and fetal complications, intrauterine growth restriction, and features resembling atherosclerosis.

Show evidence (1 reference)

PMID:35177220 SUPPORT Human clinical

"Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis."

Distinguishes early-onset preeclampsia as having features of vascular pathology resembling atherosclerosis.

Late-onset preeclampsia (>=34 weeks)

Preeclampsia with onset at or after 34 weeks of gestation. The more common form, often associated with less severe placental pathology and thought to result from a mismatch between fetal metabolic demands and maternal cardiovascular supply capacity.

Show evidence (1 reference)

PMID:35177220 SUPPORT Human clinical

Characterizes late-onset preeclampsia as a metabolic crisis from demand-supply mismatch.

HELLP syndrome

Severe variant characterized by hemolysis, elevated liver enzymes, and low platelet count. Represents the severe end of the preeclampsia spectrum and can occur with or without significant hypertension or proteinuria.

Show evidence (1 reference)

PMID:34033373 SUPPORT Human clinical

"This disease represents a spectrum of hypertensive disease in pregnancy, beginning with gestational hypertension and progressing to develop severe features, ultimately leading to its more severe manifestations, such as eclampsia and HELLP syndrome."

Identifies HELLP syndrome as a severe manifestation on the preeclampsia spectrum.

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Mechanistic Hypotheses

Early-Onset Placenta-Dominant Antiangiogenic Model

early_onset_placenta_dominant CANONICAL Early-onset HELLP

Evidence balance 2 support 1 refute

In early-onset preeclampsia, immune maladaptation at the maternal-fetal interface and defective trophoblast invasion produce severe placental malperfusion before clinical disease. Placental hypoxia and stress drive a marked antiangiogenic shift, especially excess sFlt-1 and soluble endoglin with reduced free PlGF, causing maternal endothelial dysfunction and organ-specific renal, hepatic, CNS, and uteroplacental manifestations.

The 2026 OpenScientist hypothesis-search report (kb/hypotheses/Preeclampsia/early_onset_placenta_dominant/openscientist.md) retained this model as strongly supported after reviewing 98 papers. It emphasized convergent support for the antiangiogenic cascade and KIR/HLA-C upstream trigger, while flagging three boundaries: late-onset disease is not primarily explained by this model, HELLP may include a parallel complement microangiopathy branch, and definitive Phase III interventional evidence for targeted sFlt-1 reduction is still missing. The 2026 assessment of that report (assessments/openscientist-assessment-by-claude-opus-5.yaml in the same directory) confirmed the central chain and the subtype boundary but rejected three of the report's supporting arguments. Two of those bear directly on how strongly this model can be scoped to early-onset disease. First, the fetal FLT1 GWAS is not early-onset-specific evidence: the locus is real, but the source reports its association as strongest in late-gestation preeclampsia with normally grown babies, and the report's contrary claim that no subtype-stratified analysis exists is incorrect. Second, the interventional argument rests on one uncontrolled apheresis series rather than two, because the second apheresis study prolonged pregnancy without lowering sFlt-1 at all. Both points are curated as evidence and as a knowledge gap below rather than as a change of status, which remains CANONICAL.

Pathograph links

Immune Maladaptation at Maternal-Fetal Interface -> Defective Trophoblast Invasion and Spiral Artery Remodeling Dysregulated dNK-KIR recognition of fetal trophoblast HLA-C can bias the decidua toward inadequate trophoblast invasion and poor spiral artery transformation.

Defective Trophoblast Invasion and Spiral Artery Remodeling -> Placental Anti-Angiogenic Factor Release Placental ischemia from poor spiral artery remodeling triggers release of anti-angiogenic factors into the maternal circulation.

Defective Trophoblast Invasion and Spiral Artery Remodeling -> HIF-1alpha Stabilization in the Ischemic Placenta Persistent hypoxia from a high-resistance, poorly remodeled uteroplacental circulation stabilizes HIF-1alpha in the placenta.

Defective Trophoblast Invasion and Spiral Artery Remodeling -> NLRP3 Inflammasome Activation and Inflammatory Cascade Placental ischemia and stress arising from defective trophoblast invasion and poor spiral artery remodeling activate pattern recognition receptors and the NLRP3 inflammasome in placental and decidual immune cells.

Defective Trophoblast Invasion and Spiral Artery Remodeling -> Intrauterine growth retardation Poorly remodeled spiral arteries limit uteroplacental perfusion, restricting nutrient and oxygen delivery to the fetus.

HIF-1alpha Stabilization in the Ischemic Placenta -> Placental Anti-Angiogenic Factor Release Sustained HIF-1alpha activity promotes antiangiogenic transcriptional programs, including sFlt-1 upregulation, converting placental ischemia into a systemic angiogenic imbalance.

Placental Anti-Angiogenic Factor Release -> Maternal Endothelial Dysfunction Anti-angiogenic factors in the maternal circulation cause widespread endothelial injury and dysfunction.

NLRP3 Inflammasome Activation and Inflammatory Cascade -> Maternal Endothelial Dysfunction NLRP3-derived inflammatory mediators (IL-1β, IL-18) amplify endothelial activation and dysfunction, synergizing with anti-angiogenic factors to produce systemic inflammation and vascular injury.

NLRP3 Inflammasome Activation and Inflammatory Cascade -> Cytokine-Induced Tissue Factor Expression and Coagulation Cascade Activation DIRECT NLRP3-derived cytokines (IL-1beta, IL-18) join the wider TNF-alpha/IL-6 surge that induces tissue factor on endothelial cells and monocytes, initiating the extrinsic coagulation cascade and establishing the immunothrombotic state.

Cytokine-Induced Tissue Factor Expression and Coagulation Cascade Activation -> Platelet Activation and NET-Amplified Thrombus Propagation DIRECT The same cytokine signal that induces tissue factor promotes platelet activation, and the thrombin generated by the cascade is itself a platelet agonist, so cascade activation and platelet activation propagate together.

Platelet Activation and NET-Amplified Thrombus Propagation -> Microvascular Thrombosis and Maternal Organ Ischemia DIRECT Platelet aggregation on a NET scaffold, with fibrin deposition, produces the microthrombi that occlude the maternal microvasculature.

Microvascular Thrombosis and Maternal Organ Ischemia -> Hepatic Sinusoidal Obstruction and HELLP DIRECT Immunothrombotic microvascular injury with hepatic sinusoidal microthrombi and fibrin deposition causes hepatocyte ischemia and the HELLP phenotype (hemolysis from mechanical destruction of red blood cells by fibrin strands).

Microvascular Thrombosis and Maternal Organ Ischemia -> Thrombocytopenia INDIRECT KNOWN INTERMEDIATES Microvascular thrombosis contributes to HELLP syndrome, of which thrombocytopenia is a defining feature. The intermediate omitted here is the HELLP node itself, which carries its own platelet-consumption account. Intermediates: Hepatic Sinusoidal Obstruction and HELLP

Maternal Endothelial Dysfunction -> Hypertension Reduced nitric oxide bioavailability, increased endothelin-1 and loss of endothelium-dependent vasodilation raise systemic vascular tone, producing the new-onset hypertension that defines the syndrome.

Maternal Endothelial Dysfunction -> Pulmonary edema Increased endothelial permeability, together with the raised afterload and diastolic dysfunction that follow systemic vasoconstriction, allows fluid to leak into the lungs in severe disease.

Maternal Endothelial Dysfunction -> Glomerular Endotheliosis and Proteinuria Systemic antiangiogenic endothelial injury targets glomerular capillaries, producing endotheliosis and proteinuria.

Maternal Endothelial Dysfunction -> Hepatic Sinusoidal Obstruction and HELLP Endothelial injury and prothrombotic inflammation can cause hepatic sinusoidal microthrombi, fibrin deposition, hepatocyte ischemia, and the HELLP phenotype.

Maternal Endothelial Dysfunction -> Cerebrovascular Autoregulation Failure and Eclampsia Cerebral endothelial dysfunction and impaired vascular autoregulation can disrupt the blood-brain barrier, produce vasogenic edema or PRES, and precipitate eclamptic seizures.

Glomerular Endotheliosis and Proteinuria -> Proteinuria Glomerular endothelial swelling and filtration-barrier injury increase urinary protein loss.

Hepatic Sinusoidal Obstruction and HELLP -> Thrombocytopenia Prothrombotic endothelial injury consumes platelets in the HELLP microangiopathy.

Hepatic Sinusoidal Obstruction and HELLP -> Hemolytic anemia Microangiopathic vascular injury fragments erythrocytes and produces hemolysis.

Hepatic Sinusoidal Obstruction and HELLP -> Elevated hepatic transaminases Ischemic hepatocyte injury downstream of sinusoidal obstruction releases transaminases into the circulation.

Cerebrovascular Autoregulation Failure and Eclampsia -> Seizures (eclampsia) Cerebral edema and vascular dysfunction can precipitate eclamptic seizures.

Cerebrovascular Autoregulation Failure and Eclampsia -> Headache Cerebrovascular dysfunction contributes to severe headache in preeclampsia with severe features.

Cerebrovascular Autoregulation Failure and Eclampsia -> Visual disturbances PRES-like posterior cerebral involvement can produce visual symptoms.

Deep research

OpenScientist citations 30 citations 2026-06-03T09:56:04.435262

Show evidence (3 references)

PMID:35177220 SUPPORT Human clinical

Supports modeling early-onset preeclampsia separately from late-onset disease.

PMID:41582793 SUPPORT Human clinical

"In contrast, late-onset preeclampsia exhibited comparatively subtle transcriptional changes, suggestive of a distinct pathophysiological process driven by maternal cardiovascular maladaptation, placental aging, cellular senescence and oxidative stress."

Supports restricting this model to early-onset disease on transcriptomic rather than clinical grounds. The comparison is made within one placental single-cell atlas, so the early-onset and late-onset profiles were measured on the same platform.

PMID:28628106 REFUTE Human clinical

"The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile."

Argues against treating fetal FLT1 genetics as support for an early-onset-specific model. The locus is the strongest genetic evidence that the antiangiogenic axis is causal in preeclampsia at all, but its own stratification points to late-gestation disease with normal fetal growth, which is the presentation this hypothesis explicitly does not claim.

Late-Onset Maternal Constitutional Threshold Model

late_onset_maternal_constitutional ALTERNATIVE Late-onset

Evidence balance 1 support

In late-onset preeclampsia, placental stress and antiangiogenic imbalance can be milder, while maternal cardiovascular, metabolic, renal, or immune susceptibility lowers the threshold for systemic endothelial dysfunction as fetal and placental demands peak near term. This model explains cases with limited placental lesions but clinically important hypertension and end-organ dysfunction.

Pathograph links

Maternal Vascular Susceptibility Threshold -> Maternal Endothelial Dysfunction Maternal vascular, renal, and metabolic comorbidities lower the threshold for systemic endothelial dysfunction as late-pregnancy demand rises.

Placental Anti-Angiogenic Factor Release -> Maternal Endothelial Dysfunction Anti-angiogenic factors in the maternal circulation cause widespread endothelial injury and dysfunction.

Maternal Endothelial Dysfunction -> Glomerular Endotheliosis and Proteinuria Systemic antiangiogenic endothelial injury targets glomerular capillaries, producing endotheliosis and proteinuria.

Glomerular Endotheliosis and Proteinuria -> Proteinuria Glomerular endothelial swelling and filtration-barrier injury increase urinary protein loss.

Cerebrovascular Autoregulation Failure and Eclampsia -> Seizures (eclampsia) Cerebral edema and vascular dysfunction can precipitate eclamptic seizures.

Cerebrovascular Autoregulation Failure and Eclampsia -> Headache Cerebrovascular dysfunction contributes to severe headache in preeclampsia with severe features.

Cerebrovascular Autoregulation Failure and Eclampsia -> Visual disturbances PRES-like posterior cerebral involvement can produce visual symptoms.

Show evidence (1 reference)

PMID:35177220 SUPPORT Human clinical

Supports a late-onset model centered on maternal-fetal demand-supply mismatch.

Discussions and Knowledge Gaps

Which upstream trigger best explains each presentation of preeclampsia: decidual immune maladaptation, abnormal placentation, placental stress, complement/inflammatory injury, or maternal vascular susceptibility?

KNOWLEDGE GAP OPEN preeclampsia_upstream_trigger_heterogeneity

Attached to

pathophysiology#Immune Maladaptation at Maternal-Fetal Interface pathophysiology#Defective Trophoblast Invasion and Spiral Artery Remodeling pathophysiology#Placental Anti-Angiogenic Factor Release pathophysiology#Maternal Vascular Susceptibility Threshold

The antiangiogenic endothelial dysfunction pathway is comparatively well supported, but the initiating biology is heterogeneous. Resolving whether early-onset and late-onset preeclampsia are dominated by distinct upstream triggers would improve subtype-specific biomarker interpretation, preventive trial design, and organ-risk prediction.

Added for monarch-initiative/dismech issue 3667. The OpenScientist hypothesis deep-research report for early_onset_placenta_dominant is available at kb/hypotheses/Preeclampsia/early_onset_placenta_dominant/openscientist.md; treat report-specific citation suggestions as literature leads requiring independent PMID and snippet verification before adding new evidence.

Does micro- and nanoplastic exposure contribute to human preeclampsia, or is the HIF-1alpha/TFRC trophoblast ferroptosis mechanism a property of the rat model that produced it?

HUMAN MODEL MISMATCH OPEN preeclampsia_microplastic_human_evidence_gap

Attached to

pathophysiology#Defective Trophoblast Invasion and Spiral Artery Remodeling environmental#Micro- and nanoplastic particle exposure

Every element of the microplastic-preeclampsia claim except the human endpoint is in place. Plastic particles are demonstrably present in human placental tissue; a rodent model reproduces the maternal syndrome and names an interventionally supported trophoblast mechanism. What no study has done is relate measured placental or maternal plastic burden to preeclampsia in people, and a 2024 systematic review found the human outcome literature essentially empty. The exposure is therefore modelled here with an explicit species caveat rather than as an established contributor. Note the two entries for plastic-derived chemistry in this file sit on opposite footings: the phthalate and bisphenol A entries have human risk estimates but no mechanism, while this one has a mechanism but no human endpoint. Neither gap is filled by the other.

Proposed experiments

Placental polymer burden and ferroptosis markers in preeclamptic versus normotensive placentas

preeclampsia_placental_polymer_burden_case_control

Quantify polymer burden by pyrolysis GC-MS in placentas from preeclamptic and normotensive pregnancies matched for gestational age and delivery mode, paired with the TFRC, iron-handling and lipid-peroxidation readouts the rat model identifies. Matching on gestational age matters because preeclamptic delivery is earlier, and burden may simply track exposure duration.

Would support

pathophysiology#Defective Trophoblast Invasion and Spiral Artery Remodeling

Supporting outcome

Higher polymer burden in preeclamptic placentas, accompanied by the predicted TFRC and lipid-peroxidation shift, in gestational-age-matched comparisons.

Refuting outcome

No burden difference after matching, or a burden difference without the predicted ferroptotic markers, which would place the rat mechanism outside human disease.

Show evidence (2 references)

PMID:38287142 SUPPORT Human clinical

"Cell culture and animal studies have demonstrated potential reproductive toxicity of these particles; however, their association with adverse fertility or pregnancy outcomes in humans is not known."

A systematic review stating the human outcome evidence is absent, which is precisely the mismatch this discussion records.

PMID:40414414 SUPPORT Model organism

"These findings identified PS-MP-induced ferroptosis as a critical mechanism underlying placental dysfunction, highlighting PS-MP as a potential environmental risk factor for PE."

The model-side claim, stated by its authors as potential rather than established, which is the half of the picture that does exist.

Does removing circulating sFlt-1 improve early-onset preeclampsia because sFlt-1 was removed, or do the apheresis modalities that prolong pregnancy work through something else?

KNOWLEDGE GAP OPEN preeclampsia_sflt1_removal_interventional_gap

Attached to

pathophysiology#Placental Anti-Angiogenic Factor Release pathophysiology#Maternal Endothelial Dysfunction mechanistic_hypotheses#early_onset_placenta_dominant

Interventional reversibility is the strongest argument that sFlt-1 excess is causal rather than reactive, and it is the argument this entry's canonical hypothesis leans on hardest. The evidence for it is thinner than it is usually presented. One pilot series of eight women showed that dextran sulfate cellulose apheresis lowers sFlt-1 dose-dependently, reduces proteinuria, stabilises blood pressure, and prolongs pregnancy by 15 to 23 days, but it is uncontrolled and its own authors call for further studies. The second apheresis study, using heparin-mediated extracorporeal LDL precipitation, prolonged pregnancy against historic controls yet did not lower sFlt-1 below baseline and left the sFlt-1/PlGF ratio unaffected, so its authors concluded that lipid lowering or undefined factors mattered more than sFlt-1 reduction. Read together, the two studies establish that apheresis helps and leave open whether sFlt-1 removal is why. No Phase III trial of a targeted sFlt-1 reduction has been completed. This matters for the entry because it sets how much causal weight the antiangiogenic node can carry, and because a therapy chosen on the strength of the wrong mechanism would be optimised against the wrong endpoint.

Proposed experiments

Randomised trial of a selective sFlt-1-lowering intervention with paired angiogenic and lipid monitoring

preeclampsia_targeted_sflt1_reduction_rct

Randomise women with early-onset preeclampsia and a high sFlt-1/PlGF ratio to a selective sFlt-1-lowering intervention or to standard care, with time from randomisation to delivery as the primary outcome. The discriminating feature is the monitoring, not the endpoint: measure sFlt-1, free PlGF, the ratio, and the lipid fractions that the heparin-mediated apheresis study implicated, so that any prolongation can be attributed to the analyte that actually moved. A trial that reports only the clinical outcome would reproduce the present ambiguity.

Would support

pathophysiology#Placental Anti-Angiogenic Factor Release mechanistic_hypotheses#early_onset_placenta_dominant

Supporting outcome

Pregnancy prolongation that tracks the fall in circulating sFlt-1 and in the sFlt-1/PlGF ratio, without a comparable change in the lipid fractions.

Refuting outcome

Prolongation without a sustained fall in sFlt-1, or prolongation that tracks lipid change instead, which would place the benefit of apheresis outside the antiangiogenic mechanism this entry models.

Recorded from the 2026 assessment of the OpenScientist hypothesis report in kb/hypotheses/Preeclampsia/early_onset_placenta_dominant/. The report cited both apheresis studies as convergent support for sFlt-1 removal and stated that a systematic search found no failed sFlt-1-targeted therapy trials; the second of its own citations is the counterexample.

Show evidence (5 references)

PMID:21810665 SUPPORT Human clinical

"Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus."

The positive half of the interventional argument, in which the analyte fell and the syndrome improved together.

PMID:21810665 SUPPORT Human clinical

"This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting."

The authors' own scoping of what an uncontrolled series of eight women establishes, which is that sFlt-1 can be lowered and not yet that lowering it prolongs pregnancy.

PMID:29858106 REFUTE Human clinical

"Although H.E.L.P.-apheresis induced a transient peak baseline levels did not change and rather stabilized sFlt-1 levels at pre-apheresis levels throughout treatments, with sFlt-1/PLGF ratio remaining unaffected."

Dissociates the clinical benefit of apheresis from sFlt-1 removal. This study prolonged pregnancy while leaving the analyte and the ratio unchanged, which is why it cannot be counted as interventional support for the antiangiogenic mechanism.

+ 2 more references

Is complement activation in HELLP syndrome an effector pathway independent of the antiangiogenic shift, or is it downstream of it?

KNOWLEDGE GAP OPEN preeclampsia_complement_independence_in_hellp

Attached to

pathophysiology#Hepatic Sinusoidal Obstruction and HELLP pathophysiology#Maternal Endothelial Dysfunction mechanistic_hypotheses#early_onset_placenta_dominant

This entry models HELLP as a liver-specific amplification of the systemic endothelial injury caused by the antiangiogenic shift, and the canonical hypothesis claims HELLP among the subtypes it explains. Complement is the main candidate for a branch that would sit outside that account. The activation itself is not in doubt: a systematic review of 41 studies reports consistent consumption of C3, C4 and factor H alongside raised C4d, Bb, factor D, C3a, C5a and C5b-9 in preeclampsia. What is unresolved is dependence. The only interventional evidence is a single case in which C5 inhibition normalised laboratory parameters and prolonged pregnancy by 17 days, and that report measured no angiogenic factors at all, so it cannot show that the benefit was independent of sFlt-1. Resolving this decides whether complement inhibition belongs alongside or instead of antiangiogenic approaches in HELLP, and whether this entry needs a separate complement branch rather than a note.

Proposed experiments

Complement inhibition in HELLP with serial complement and angiogenic monitoring

preeclampsia_hellp_complement_inhibition_with_angiogenic_monitoring

Treat HELLP syndrome with C5 inhibition against standard care, measuring C3a, C5a and sC5b-9 alongside sFlt-1, free PlGF and their ratio on the same schedule. The design point is that both pathways are tracked in the same patients, so a clinical response can be assigned to one of them rather than inferred. The existing case report failed precisely here: it recorded the clinical result and no angiogenic measurement.

Would support

pathophysiology#Hepatic Sinusoidal Obstruction and HELLP

Supporting outcome

Clinical and laboratory improvement following complement inhibition while sFlt-1 and the sFlt-1/PlGF ratio remain unchanged, which would establish a complement branch acting in parallel to the antiangiogenic shift.

Refuting outcome

Improvement accompanied by a fall in sFlt-1, or no improvement despite complement blockade, either of which would keep complement activation downstream of the antiangiogenic mechanism this entry already models.

Recorded from the 2026 assessment of the OpenScientist hypothesis report in kb/hypotheses/Preeclampsia/early_onset_placenta_dominant/. The report graded the claim SPECULATIVE in its own classification table but described it in its evidence matrix as improvement independent of sFlt-1, which the case report does not establish. The systematic review also warns that complement measurements across this literature suffer from a lack of experimental uniformity and biased cohort selection, so the biomarker signal should not be read as a settled quantitative baseline either.

Show evidence (4 references)

PMID:38983853 SUPPORT Human clinical

"Retrieved results consistently reported C4, C3, and factor H reduction, and increased circulating levels of C4d, Bb, factor D, C3a, C5a, and C5b-9 in PE compared to normal pregnancies, depicting an overall scenario of excessive C activation and aberrant C regulation."

Establishes that complement activation is a consistent finding in preeclampsia across 41 studies, which is what makes the independence question worth asking rather than dismissing.

PMID:38983853 SUPPORT Human clinical

"Moreover, we also discussed emerging pitfalls in C analysis, mainly due to a lack of experimental uniformity and biased cohort selection among different studies and laboratories"

The same review's caveat on its own evidence base, which is why the complement signal is recorded here as an open question rather than as a curated mechanism node.

PMID:23228435 SUPPORT Human clinical

"We describe a patient presenting with severe preeclampsia/HELLP syndrome at 26 weeks gestation that was treated with Eculizumab, a targeted inhibitor of complement protein C5, which resulted in marked clinical improvement and complete normalization of lab parameters."

The whole of the interventional evidence, which is one patient. No angiogenic factors were measured, so the case cannot separate a complement effect from an antiangiogenic one.

+ 1 more reference

Is circulating GDF-15 elevation in preeclampsia a pathogenic driver of the disease, or a compensatory response to placental stress?

KNOWLEDGE GAP OPEN preeclampsia_gdf15_pathogenic_or_compensatory_gap

Attached to

pathophysiology#Placental Anti-Angiogenic Factor Release pathophysiology#Maternal Endothelial Dysfunction

GDF-15 is highly expressed in the placenta and rises in the maternal circulation through gestation, and it is elevated in affected women, particularly in early-onset disease. Whether that elevation drives the placental and endothelial injury or reflects an adaptive response to it determines whether GDF-15 belongs in this entry as a pathophysiology node or only as a biomarker, and how it relates to the angiogenic pathway already modelled here.

Added for monarch-initiative/dismech issue 13414. The source is a review, so the quoted sentence is the review's own statement of an open question, not a primary finding. No node is added for GDF-15 until a primary study addresses the direction of the association.

Show evidence (1 reference)

PMID:42803395 SUPPORT REVIEW SYNTHESIS Other

"key unresolved questions are identified, including whether GDF-15 elevation is pathogenic or compensatory"

The review's own statement that the direction of the GDF-15 association is unresolved, which is the gap this discussion records.

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Pathophysiology

Immune Maladaptation at Maternal-Fetal Interface

Decidual natural killer cells normally interact with fetal extravillous trophoblast HLA-C through maternal KIR receptors and help regulate placental development, trophoblast invasion, and spiral artery remodeling. In susceptible maternal-fetal genotype combinations, especially maternal KIR AA with fetal HLA-C2, excessive inhibitory signaling can reduce dNK activation and impair trophoblast invasion. This upstream immune maladaptation is modeled as an early-onset, placenta-dominant trigger rather than as the established antiangiogenic effector pathway itself.

Early-Onset Placenta-Dominant Antiangiogenic Model

decidual natural killer cell CL:0002343 extravillous trophoblast CL:0008036

maternal-fetal immune tolerance GO:0002507 ↕ DYSREGULATED natural killer cell activation balance GO:0045954 ↕ DYSREGULATED

Downstream

Defective Trophoblast Invasion and Spiral Artery Remodeling Dysregulated dNK-KIR recognition of fetal trophoblast HLA-C can bias the decidua toward inadequate trophoblast invasion and poor spiral artery transformation.

Show evidence (5 references)

PMID:15477349 SUPPORT Human clinical

"We have found that the combination of maternal KIR AA genotype with a fetal HLA-C2 is associated with an increased risk of preeclampsia."

Supports the KIR/HLA-C maternal-fetal genotype interaction as an upstream risk mechanism.

PMID:15477349 SUPPORT Human clinical

"too much inhibition of uNK cells leading to poor trophoblast invasion into the uterine arteries."

Supports the proposed bridge from excessive inhibitory uterine NK signaling to poor trophoblast invasion.

PMID:32309433 SUPPORT Human clinical

"Decidual NK (dNK) cells significantly contribute to the vascular remodeling through the secretion of cytokines and angiogenic mediators in normal placental development."

Review evidence supports the role of decidual NK cells in normal placental vascular remodeling.

+ 2 more references

Maternal Vascular Susceptibility Threshold

Late-onset preeclampsia can be modeled as a threshold phenomenon in which near-term fetal and placental demands interact with maternal cardiovascular, renal, metabolic, or inflammatory susceptibility. In this model, placental antiangiogenic stress can be less severe than in early-onset disease, but maternal endothelial reserve is lower, so hypertension and end-organ dysfunction emerge when physiologic demand exceeds vascular supply.

Late-Onset Maternal Constitutional Threshold Model

blood vessel endothelial cell CL:0000071

endothelial cell activation GO:0042118 ↕ DYSREGULATED blood circulation GO:0008015 ↕ DYSREGULATED vasoconstriction GO:0042310 ↑ INCREASED

Downstream

Maternal Endothelial Dysfunction Maternal vascular, renal, and metabolic comorbidities lower the threshold for systemic endothelial dysfunction as late-pregnancy demand rises.

Show evidence (1 reference)

PMID:30792480 SUPPORT Human clinical

"Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity"

Identifies maternal vascular, renal, and metabolic comorbidities that can reduce endothelial reserve.

PSG2-Mediated TGF-beta/Smad3 Activation

Placenta-derived pregnancy-specific beta-1-glycoprotein 2 (PSG2) is upregulated in preeclamptic placentas and activates the TGF-β/Smad3 signaling pathway in extravillous trophoblasts. This placental-derived mechanism cell-autonomously suppresses trophoblast epithelial-to-mesenchymal transition (EMT) and downregulates matrix metalloproteinases (MMP2/MMP9), thereby reducing trophoblast proliferation, migration, and invasion capacity. This is distinct from the sEng-mediated inhibition of endothelial TGF-beta signaling modeled downstream in the maternal circulation.

extravillous trophoblast CL:0008036

PSG2 hgnc:9519

transforming growth factor beta receptor signaling pathway GO:0007179 ↑ INCREASED SMAD protein signal transduction GO:0060395 ↑ INCREASED

Downstream

Defective Trophoblast Invasion and Spiral Artery Remodeling PSG2-activated TGF-β/Smad3 signaling suppresses epithelial-mesenchymal transition and metalloproteinase expression, reducing trophoblast invasiveness and contributing to defective spiral artery remodeling.

Show evidence (1 reference)

PMID:42573986 SUPPORT In vitro / ex vivo

"Highly expressed PSG2 in PE placentas contributes to PE pathogenesis by activating the TGF-β/Smad3 pathway, thereby inhibiting EMT and MMPs expression and attenuating trophoblast proliferation, migration, and invasion."

Establishes PSG2 upregulation in preeclamptic placentas as a mechanism activating TGF-β/Smad3 signaling.

Defective Trophoblast Invasion and Spiral Artery Remodeling

In normal pregnancy, extravillous trophoblasts invade the uterine decidua and remodel maternal spiral arteries into high-capacitance, low-resistance vessels. In preeclampsia, this invasion is shallow and incomplete, resulting in narrow, high-resistance spiral arteries that fail to adequately perfuse the placenta. The resulting placental ischemia and hypoxia trigger downstream pathological cascades.

Early-Onset Placenta-Dominant Antiangiogenic Model

extravillous trophoblast CL:0008036 decidual natural killer cell CL:0002343

placenta development GO:0001890 ↓ DECREASED spiral artery remodeling GO:0001974 ↓ DECREASED vasculogenesis GO:0001570 ↓ DECREASED epithelial to mesenchymal transition GO:0001837 ↓ DECREASED

Downstream

Placental Anti-Angiogenic Factor Release Placental ischemia from poor spiral artery remodeling triggers release of anti-angiogenic factors into the maternal circulation.

HIF-1alpha Stabilization in the Ischemic Placenta Persistent hypoxia from a high-resistance, poorly remodeled uteroplacental circulation stabilizes HIF-1alpha in the placenta.

NLRP3 Inflammasome Activation and Inflammatory Cascade Placental ischemia and stress arising from defective trophoblast invasion and poor spiral artery remodeling activate pattern recognition receptors and the NLRP3 inflammasome in placental and decidual immune cells.

Intrauterine growth retardation Poorly remodeled spiral arteries limit uteroplacental perfusion, restricting nutrient and oxygen delivery to the fetus.

Show evidence (2 references)

PMID:39062815 SUPPORT Human clinical

"PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia."

Directly describes the defective trophoblast invasion and spiral artery remodeling as the initiating event in preeclampsia.

PMID:35177220 SUPPORT Human clinical

"a growing body of evidence suggests that products of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome."

Supports the concept that placental ischemia (from defective remodeling) drives vascular pathology.

HIF-1alpha Stabilization in the Ischemic Placenta

Tightly controlled hypoxia guides normal trophoblast differentiation and vascular remodeling in early gestation. When hypoxia becomes persistent or excessive, hypoxia-inducible factor 1-alpha (HIF-1alpha) is stabilized rather than degraded, and sustained HIF-1alpha activity becomes the transcriptional link between placental ischemia and the antiangiogenic shift: it drives mitochondrial dysfunction and oxidative stress that amplify placental injury, and it promotes antiangiogenic transcriptional programs including sFlt-1 upregulation. This node is curated from review-level synthesis; no HIF-1alpha perturbation experiment has been performed in human placental tissue, so the edge to antiangiogenic factor release is mechanistically motivated rather than directly demonstrated in humans. It is distinct from the HIF-1alpha/TFRC ferroptosis axis modelled under microplastic exposure, which is a rodent finding about a specific exposure rather than the endogenous ischemic response described here.

Early-Onset Placenta-Dominant Antiangiogenic Model

syncytiotrophoblast CL:0000525 extravillous trophoblast CL:0008036

HIF1A hgnc:4910

cellular response to hypoxia GO:0071456 ↑ INCREASED response to oxidative stress GO:0006979 ↑ INCREASED negative regulation of angiogenesis GO:0016525 ↑ INCREASED

Downstream

Placental Anti-Angiogenic Factor Release Sustained HIF-1alpha activity promotes antiangiogenic transcriptional programs, including sFlt-1 upregulation, converting placental ischemia into a systemic angiogenic imbalance.

Show evidence (2 references)

PMID:41814104 SUPPORT Human clinical

"Sustained HIF-1α activation drives mitochondrial dysfunction and oxidative stress, amplifying placental injury."

Supports the mitochondrial and oxidative-stress content of this node as a consequence of sustained HIF-1alpha activity.

PMID:41814104 SUPPORT Human clinical

"Early-onset preeclampsia is a severe placental disorder driven primarily by impaired uteroplacental perfusion and early placental ischemia."

Scopes this hypoxic-signaling node to early-onset disease, matching the subtype restriction of the hypothesis it belongs to.

Placental Anti-Angiogenic Factor Release

The ischemic placenta releases excess anti-angiogenic factors, primarily soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), into the maternal circulation. sFlt-1 acts as a decoy receptor that sequesters VEGF and PlGF, while sEng inhibits TGF-beta signaling. Together, these factors create a systemic anti-angiogenic state that disrupts normal endothelial function. Levels of sFlt-1 rise and PlGF fall weeks before clinical onset.

Early-Onset Placenta-Dominant Antiangiogenic Model Late-Onset Maternal Constitutional Threshold Model

syncytiotrophoblast CL:0000525

FLT1 hgnc:3763 ENG hgnc:3349

VEGF receptor signaling pathway GO:0048010 ↓ DECREASED angiogenesis GO:0001525 ↓ DECREASED response to hypoxia GO:0001666

VEGF and PlGF ligand binding by soluble FLT1 (decoy receptor) GO:0038085 ↑ INCREASED

Downstream

Maternal Endothelial Dysfunction Anti-angiogenic factors in the maternal circulation cause widespread endothelial injury and dysfunction.

Show evidence (8 references)

PMID:12618519 SUPPORT Human clinical

"we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery."

Landmark paper demonstrating that placental sFlt-1 is upregulated in preeclampsia with systemic elevation.

PMID:12618519 SUPPORT BACKGROUND In vitro / ex vivo

"VEGF and PlGF by binding to them and preventing their interaction with their cell-surface receptors, Flt1 and KDR."

States the molecular function bound on this node: sFlt1 antagonizes VEGF and PlGF by binding them, which is the ligand-binding (decoy-receptor) activity that the excess circulating sFlt1 contributes.

PMID:14764923 SUPPORT Human clinical

"The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia."

Shows that sFlt-1 rises weeks before clinical disease, consistent with placental release preceding symptoms.

+ 5 more references

NLRP3 Inflammasome Activation and Inflammatory Cascade

Dysregulated NOD-like receptor (NLR) signaling, particularly NLRP3 inflammasome activation, contributes to placental and systemic inflammation in preeclampsia. Placental stress from ischemia and poor trophoblast invasion triggers pattern recognition receptors that activate the NLRP3 inflammasome complex (NLRP3, ASC, and pro-caspase-1). Active caspase-1 processes pro-IL-1β and pro-IL-18 into their mature, secreted forms, driving excessive IL-1β and IL-18 release from placental macrophages, trophoblasts, and maternal immune cells. This inflammasome-mediated inflammatory cascade amplifies oxidative stress, endothelial dysfunction, and systemic inflammation, contributing to hypertension and multi-organ involvement in preeclampsia.

Early-Onset Placenta-Dominant Antiangiogenic Model Late-Onset Maternal Constitutional Threshold Model

placental macrophage CL:0000235 extravillous trophoblast CL:0008036 blood vessel endothelial cell CL:0000071

NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED interleukin-1 beta production GO:0032611 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

Maternal Endothelial Dysfunction NLRP3-derived inflammatory mediators (IL-1β, IL-18) amplify endothelial activation and dysfunction, synergizing with anti-angiogenic factors to produce systemic inflammation and vascular injury.

Cytokine-Induced Tissue Factor Expression and Coagulation Cascade Activation NLRP3-derived cytokines (IL-1beta, IL-18) join the wider TNF-alpha/IL-6 surge that induces tissue factor on endothelial cells and monocytes, initiating the extrinsic coagulation cascade and establishing the immunothrombotic state.

Show evidence (1 reference)

PMID:42269339 SUPPORT Human clinical

"This review synthesizes the most recent data on NLRs in PE, focusing on their role in disease genesis, pathogenic processes, biomarker potential, and therapeutic consequences."

Comprehensive review documenting NLRP3 inflammasome role in preeclampsia genesis and pathogenesis.

Cytokine-Induced Tissue Factor Expression and Coagulation Cascade Activation

Systemic pro-inflammatory cytokines from placental ischemia and NLRP3 inflammasome activation (TNF-α, IL-6, IL-1β, IL-17, IFN-γ) stimulate tissue factor expression on endothelial cells and monocytes, triggering the extrinsic coagulation cascade. Impaired anticoagulant pathways (reduced protein C, antithrombin) and suppression of fibrinolysis (elevated plasminogen activator inhibitor-1) hold the resulting thrombin generation and fibrin deposition unopposed. This is the initiating limb of immunothrombosis - the bidirectional interaction in which inflammatory activation promotes thrombosis and thrombotic processes amplify inflammation. Conformance to the thrombogenesis module is supported here because the cited review describes an explicit tissue factor to thrombin to fibrin branch rather than the TTP-type microangiopathy the module's scope note excludes.

Early-Onset Placenta-Dominant Antiangiogenic Model Late-Onset Maternal Constitutional Threshold Model

blood vessel endothelial cell CL:0000071 monocyte CL:0000576

blood coagulation GO:0007596 ↑ INCREASED fibrin clot formation GO:0072378 ↑ INCREASED fibrinolysis GO:0042730 ↓ DECREASED

Downstream

Platelet Activation and NET-Amplified Thrombus Propagation The same cytokine signal that induces tissue factor promotes platelet activation, and the thrombin generated by the cascade is itself a platelet agonist, so cascade activation and platelet activation propagate together.

Show evidence (2 references)

PMID:42381215 SUPPORT Human clinical

"In addition to endothelial dysfunction, increasing attention has focused on the role of thromboinflammation and immunothrombosis in the pathogenesis of pre-eclampsia. Immunothrombosis refers to the bidirectional interaction between immune and coagulation pathways whereby inflammatory activation..."

Defines immunothrombosis as the bidirectional interaction between immune and coagulation pathways in preeclampsia.

PMID:42381215 SUPPORT Human clinical

"Cytokines stimulate tissue factor expression on endothelial cells and monocytes, while simultaneously promoting platelet activation and impairing fibrinolysis."

The tissue factor induction and fibrinolysis suppression this node is named for, quoted from the sentence that states both.

Platelet Activation and NET-Amplified Thrombus Propagation

Activated platelets release pro-inflammatory mediators that amplify endothelial activation and leukocyte recruitment. Neutrophil extracellular traps provide a structural scaffold that enhances platelet aggregation and fibrin deposition, while circulating extracellular vesicles carry tissue factor and inflammatory cytokines to distant vascular sites. Together these make the process self-perpetuating rather than self-limiting, which is what distinguishes immunothrombosis from ordinary hemostasis.

Early-Onset Placenta-Dominant Antiangiogenic Model Late-Onset Maternal Constitutional Threshold Model

platelet CL:0000233 neutrophil CL:0000775

platelet activation GO:0030168 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

Downstream

Microvascular Thrombosis and Maternal Organ Ischemia Platelet aggregation on a NET scaffold, with fibrin deposition, produces the microthrombi that occlude the maternal microvasculature.

Show evidence (1 reference)

PMID:42381215 SUPPORT Human clinical

"Emerging evidence also highlights the role of neutrophil extracellular traps (NETs) and extracellular vesicles in the propagation of immunothrombosis. NETs provide a structural scaffold that enhances platelet aggregation and fibrin deposition, while extracellular vesicles carry tissue factor and..."

Documents how NETs and extracellular vesicles amplify the immunothrombotic cascade.

Microvascular Thrombosis and Maternal Organ Ischemia

Microthrombi form in the microvasculature of critical maternal organs (kidney, liver, brain, placenta), reducing perfusion and exacerbating endothelial injury. This is the point at which the prothrombotic state becomes organ injury, and it is the node from which the severe maternal complications of preeclampsia follow.

Early-Onset Placenta-Dominant Antiangiogenic Model Late-Onset Maternal Constitutional Threshold Model

blood vessel endothelial cell CL:0000071

blood coagulation GO:0007596 ↑ INCREASED

Downstream

Hepatic Sinusoidal Obstruction and HELLP Immunothrombotic microvascular injury with hepatic sinusoidal microthrombi and fibrin deposition causes hepatocyte ischemia and the HELLP phenotype (hemolysis from mechanical destruction of red blood cells by fibrin strands).

Thrombocytopenia Microvascular thrombosis contributes to HELLP syndrome, of which thrombocytopenia is a defining feature. The intermediate omitted here is the HELLP node itself, which carries its own platelet-consumption account.

Show evidence (1 reference)

PMID:42381215 SUPPORT Human clinical

"These alterations create a prothrombotic state characterized by microvascular thrombosis, endothelial injury, and organ ischemia."

The microvascular thrombosis and organ ischemia this node is named for, quoted from the sentence that states both.

Maternal Endothelial Dysfunction

The anti-angiogenic imbalance causes widespread maternal endothelial dysfunction, manifesting as vasoconstriction, increased vascular permeability, and activation of the coagulation cascade. This leads to the clinical features of hypertension, proteinuria (from glomerular endotheliosis), hepatic dysfunction, cerebral edema, and thrombocytopenia. The characteristic renal lesion is glomerular endotheliosis.

Early-Onset Placenta-Dominant Antiangiogenic Model Late-Onset Maternal Constitutional Threshold Model

blood vessel endothelial cell CL:0000071 platelet CL:0000233

innate immune response GO:0045087 inflammatory response GO:0006954 vasodilation GO:0042311 ↓ DECREASED vasoconstriction GO:0042310 ↑ INCREASED

Downstream

Hypertension Reduced nitric oxide bioavailability, increased endothelin-1 and loss of endothelium-dependent vasodilation raise systemic vascular tone, producing the new-onset hypertension that defines the syndrome.

Pulmonary edema Increased endothelial permeability, together with the raised afterload and diastolic dysfunction that follow systemic vasoconstriction, allows fluid to leak into the lungs in severe disease.

Glomerular Endotheliosis and Proteinuria Systemic antiangiogenic endothelial injury targets glomerular capillaries, producing endotheliosis and proteinuria.

Hepatic Sinusoidal Obstruction and HELLP Endothelial injury and prothrombotic inflammation can cause hepatic sinusoidal microthrombi, fibrin deposition, hepatocyte ischemia, and the HELLP phenotype.

Cerebrovascular Autoregulation Failure and Eclampsia Cerebral endothelial dysfunction and impaired vascular autoregulation can disrupt the blood-brain barrier, produce vasogenic edema or PRES, and precipitate eclamptic seizures.

Show evidence (3 references)

PMID:12618519 SUPPORT Model organism

"administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia."

Direct demonstration that sFlt-1 causes the clinical triad of hypertension, proteinuria, and glomerular endotheliosis.

PMID:30792480 SUPPORT Human clinical

"Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia."

Identifies endothelial dysfunction from placental factors as the hallmark of preeclampsia.

PMID:16751767 SUPPORT In vitro / ex vivo

"sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature."

Biochemical/cell-based evidence that sEng disrupts TGF-beta receptor binding and eNOS activation.

Glomerular Endotheliosis and Proteinuria

Antiangiogenic injury to glomerular endothelial cells disrupts the fenestrated filtration barrier, producing glomerular endotheliosis and proteinuria. This renal branch is the most direct organ-specific consequence of the sFlt-1/VEGF/PlGF imbalance.

Early-Onset Placenta-Dominant Antiangiogenic Model Late-Onset Maternal Constitutional Threshold Model

glomerular endothelial cell CL:0002188

glomerular filtration GO:0003094 ↓ DECREASED endothelial cell activation GO:0042118 ↕ DYSREGULATED

Downstream

Proteinuria Glomerular endothelial swelling and filtration-barrier injury increase urinary protein loss.

Show evidence (1 reference)

PMID:12618519 SUPPORT Model organism

"administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia."

Demonstrates the renal lesion and proteinuria after sFlt-1 exposure in pregnant rats.

Hepatic Sinusoidal Obstruction and HELLP

In severe preeclampsia and HELLP syndrome, systemic endothelial injury and inflammatory prothrombotic signaling can be amplified in hepatic sinusoids, where low shear favors microthrombi and fibrin deposition. Sinusoidal obstruction causes ischemic hepatocyte injury, elevated liver enzymes, platelet consumption, and microangiopathic hemolysis.

Early-Onset Placenta-Dominant Antiangiogenic Model

hepatic sinusoidal endothelial cell CL:1000398 platelet CL:0000233

blood coagulation GO:0007596 ↑ INCREASED endothelial cell activation GO:0042118 ↕ DYSREGULATED

Downstream

Thrombocytopenia Prothrombotic endothelial injury consumes platelets in the HELLP microangiopathy.

Hemolytic anemia Microangiopathic vascular injury fragments erythrocytes and produces hemolysis.

Elevated hepatic transaminases Ischemic hepatocyte injury downstream of sinusoidal obstruction releases transaminases into the circulation.

Show evidence (2 references)

PMID:31877439 SUPPORT Human clinical

"The dysfunctional placenta in women developing HELLP initiates a cascade of events that eventually results in liver dysfunction."

Places HELLP liver injury downstream of placental dysfunction.

PMID:31877439 SUPPORT Human clinical

"The latter causes ischemic damage and progressive demise of hepatocytes."

Supports ischemic hepatocyte injury downstream of sinusoidal obstruction.

Cerebrovascular Autoregulation Failure and Eclampsia

Cerebral vascular dysfunction in preeclampsia can include impaired autoregulatory reserve, endothelial injury, blood-brain barrier disruption, and vasogenic edema. This branch connects systemic endothelial dysfunction to headache, visual symptoms, PRES-like edema, seizures, stroke, and eclampsia.

Early-Onset Placenta-Dominant Antiangiogenic Model Late-Onset Maternal Constitutional Threshold Model

cerebral blood vessel endothelial cell CL:2000044

blood circulation GO:0008015 ↕ DYSREGULATED vasoconstriction GO:0042310 ↕ DYSREGULATED endothelial cell activation GO:0042118 ↕ DYSREGULATED

Downstream

Seizures (eclampsia) Cerebral edema and vascular dysfunction can precipitate eclamptic seizures.

Headache Cerebrovascular dysfunction contributes to severe headache in preeclampsia with severe features.

Visual disturbances PRES-like posterior cerebral involvement can produce visual symptoms.

Show evidence (2 references)

PMID:26126779 SUPPORT Human clinical

"Cerebrovascular dysfunction during preeclampsia can lead to cerebral edema, seizures, stroke, and potentially maternal mortality."

Directly links preeclampsia cerebrovascular dysfunction to acute neurologic complications.

PMID:26126779 SUPPORT Human clinical

"PRES can be caused by an acute elevation in blood pressure that overcomes cerebral artery and arteriole vasoconstriction, resulting in a loss of CBF autoregulation, disruption to the blood-brain barrier (BBB), and vasogenic edema formation"

Supports the autoregulatory failure, BBB disruption, and vasogenic edema mechanism for eclampsia/PRES-like manifestations.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 2

Thrombocytopenia HP:0001873

Show evidence (2 references)

PMID:34033373 SUPPORT Human clinical

Human clinical anchor placing HELLP syndrome — of which thrombocytopenia is a defining component — on the preeclampsia spectrum.

PMID:16751767 SUPPORT Model organism

"leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome"

Rat sFlt1/sEng co-administration model reproduces the low-platelet component of HELLP. Model-organism support for the mechanism only; it is not the primary evidence for the human phenotype.

Hemolytic anemia HP:0001878

Show evidence (2 references)

PMID:34033373 SUPPORT Human clinical

Human clinical anchor placing HELLP — whose "H" is microangiopathic hemolysis — within the preeclampsia spectrum.

PMID:16751767 SUPPORT Model organism

"leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome"

Rat model reproduces the hemolysis component of HELLP; model-organism corroboration rather than primary human evidence.

Cardiovascular 1

Hypertension VERY_FREQUENT HP:0000822

Show evidence (2 references)

PMID:34033373 SUPPORT Human clinical

"The parameters for initial identification of hypertension in the context of pregnancy-induced hypertension constituting the "mild range" are specifically defined as a systolic blood pressure (SBP) of 140 mm Hg or more or diastolic blood pressure (DBP) of 90 mm Hg or more on 2 occasions at least..."

Defines the diagnostic blood pressure criteria for preeclampsia.

PMID:32443079 SUPPORT Human clinical

"Hypertensive disorders of pregnancy constitute one of the leading causes of maternal and perinatal mortality worldwide."

Establishes hypertensive disorders as a defining feature of the preeclampsia spectrum.

Eye 1

Visual disturbances Blurred vision HP:0000622

Show evidence (1 reference)

PMID:39247143 SUPPORT Human clinical

"Severe preeclampsia is defined as blood pressure (BP) >160/110 mmHg with warning signs such as headache, blurring of vision, and epigastric pain."

Explicitly identifies blurring of vision as a warning sign of severe preeclampsia.

Genitourinary 1

Proteinuria HP:0000093

Show evidence (1 reference)

PMID:30792480 SUPPORT Human clinical

"The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered."

Identifies proteinuria as a frequent but not universal feature of preeclampsia.

Metabolism 2

Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (2 references)

PMID:31877439 SUPPORT Human clinical

"The latter causes ischemic damage and progressive demise of hepatocytes."

Human literature review supports hepatocyte ischemic injury as the basis of the transaminase elevation seen in severe preeclampsia and HELLP.

PMID:16751767 SUPPORT Model organism

"leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome"

Rat model reproduces the elevated-liver-enzyme component of HELLP; model-organism corroboration rather than primary human evidence.

Pulmonary edema HP:0100598

Pulmonary edema is a recognized severe complication of preeclampsia, resulting from endothelial dysfunction, decreased oncotic pressure, and iatrogenic fluid overload. It is included in ACOG criteria for severe features of preeclampsia.

Show evidence (1 reference)

PMID:42381215 SUPPORT REVIEW SYNTHESIS Human clinical

"Severe disease is associated with higher blood pressure levels, greater degrees of endothelial dysfunction, more extensive coagulation abnormalities, and increased risks of complications such as HELLP syndrome, eclampsia, acute kidney injury, pulmonary edema, and maternal death."

Names pulmonary edema among the complications of severe preeclampsia.

Nervous System 2

Seizures (eclampsia) HP:0001250

Show evidence (1 reference)

PMID:35177220 SUPPORT Human clinical

"once thought to be a disease of the central nervous system, recognized by the occurrence of seizures (ie, eclampsia)"

Eclamptic seizures are the historically defining severe complication of preeclampsia.

Headache HP:0002315

Show evidence (1 reference)

PMID:39247143 SUPPORT Human clinical

"Severe preeclampsia is defined as blood pressure (BP) >160/110 mmHg with warning signs such as headache, blurring of vision, and epigastric pain."

Explicitly identifies headache as a warning sign of severe preeclampsia.

Growth 1

Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:14764923 SUPPORT Human clinical

"Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant."

Links angiogenic factor alterations to small-for-gestational-age infants in preeclampsia.

🧬

Genetic Associations

FLT1 (Risk Factor (FLT1 polymorphisms) and source of the sFlt-1 effector)

Gene: FLT1 hgnc:3763 gene page relationship_type: RISK_FACTOR

Show evidence (4 references)

PMID:28628106 SUPPORT Human clinical

"We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls."

Replaces a general statement that FLT1 polymorphisms matter with the actual genome-wide significant locus, its effect size context, and the fact that it was found in offspring rather than mothers.

PMID:28628106 SUPPORT Human clinical

"This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia."

Ties the genome-wide significant signal to the placental sFlt-1 isoform this entry models as the effector.

PMID:39062815 SUPPORT Human clinical

"Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles."

Identifies FLT1 polymorphisms as playing a critical role in preeclampsia.

+ 1 more reference

PGF (Mechanistic effector (reduced free PlGF protein))

Gene: PGF hgnc:8893 relationship_type: BIOMARKER

Show evidence (1 reference)

PMID:14764923 SUPPORT Human clinical

"Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia."

PlGF reduction is a key predictive feature of preeclampsia.

ENG (Mechanistic effector (placenta-derived soluble endoglin))

Gene: ENG hgnc:3349 gene page relationship_type: BIOMARKER

Show evidence (1 reference)

PMID:16751767 SUPPORT Model organism

"Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia."

Demonstrates the pathogenic role of soluble endoglin (ENG gene product) in severe preeclampsia.

VEGFA (Mechanistic effector (free VEGF sequestered by sFlt-1))

Gene: VEGFA hgnc:12680 gene page relationship_type: BIOMARKER

Show evidence (2 references)

PMID:12618519 SUPPORT Human clinical

"increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF"

Human clinical data showing that sFlt-1 excess sequesters free VEGF in preeclampsia patients.

PMID:12618519 SUPPORT In vitro / ex vivo

"resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF."

In vitro evidence that exogenous VEGF can rescue sFlt-1-induced endothelial dysfunction.

💊

Medical Actions

Delivery

Action: labor induction Ontology label: Induction of Labor NCIT:C92814

Delivery of the fetus and placenta is the only definitive treatment for preeclampsia. Timing depends on gestational age and severity, balancing maternal risk against fetal prematurity. Generally recommended at 37 weeks for preeclampsia without severe features, and earlier if severe features or maternal/fetal deterioration occurs.

Show evidence (1 reference)

PMID:30792480 SUPPORT Human clinical

"which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered."

Identifies delivery as the necessary intervention to prevent progression.

Low-dose aspirin prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: acetylsalicylic acid CHEBI:15365

Low-dose aspirin (150 mg daily) initiated at 11-14 weeks of gestation in women identified as high risk reduces the incidence of preterm preeclampsia by approximately 62%. This is a preventive intervention, not a treatment for established disease.

Mechanism Target:

INHIBITS Platelet Activation and NET-Amplified Thrombus Propagation — Irreversible inhibition of platelet cyclooxygenase-1 reduces thromboxane A2 production, which is the platelet-activation limb of immunothrombosis. This is prophylaxis rather than treatment of established disease, so the edge describes what aspirin acts on, not a reversal of established thrombosis.

Show evidence (1 reference)

PMID:42381215 SUPPORT Human clinical

"Its primary mechanism involves irreversible inhibition of platelet cyclooxygenase‐1, leading to reduced thromboxane A2 production and a shift toward a vasodilatory and antithrombotic state."

Names the platelet target that makes this an inhibitory edge onto the platelet-activation node rather than onto the coagulation cascade.

Show evidence (2 references)

PMID:28657417 SUPPORT Human clinical

"Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004)."

The ASPRE trial demonstrated a 62% reduction in preterm preeclampsia with aspirin 150 mg daily.

PMID:37891152 SUPPORT Other

"In women with a history of vasculo-placental disease, low dose of aspirin (Strong recommendation, Quality of the evidence moderate) at a dosage of 100-160mg per day (Weak recommendation, Quality of the evidence low)"

The French College of Obstetricians and Gynecologists clinical practice guidelines make a Strong recommendation for low-dose aspirin in women with a history of vasculo-placental disease; the specific 100-160 mg per day dosage is graded only a Weak recommendation.

Magnesium sulfate for seizure prevention

Action: Pharmacotherapy NCIT:C15986

Agent: magnesium sulfate CHEBI:32599

Magnesium sulfate is the first-line agent for prevention and treatment of eclamptic seizures. It halves the risk of eclampsia in women with preeclampsia and probably reduces maternal mortality.

Show evidence (1 reference)

PMID:12057549 SUPPORT Human clinical

"Women allocated magnesium sulphate had a 58% lower risk of eclampsia (95% CI 40-71) than those allocated placebo (40, 0.8%, vs 96, 1.9%; 11 fewer women with eclampsia per 1000 women)."

The Magpie trial demonstrated that magnesium sulfate halves eclampsia risk.

Antihypertensive therapy (labetalol)

Action: Pharmacotherapy NCIT:C15986

Agent: labetalol CHEBI:6343

Labetalol is a first-line antihypertensive for acute blood pressure management in severe preeclampsia, used to prevent hypertensive emergencies and stroke.

Show evidence (1 reference)

PMID:39247143 SUPPORT Human clinical

"Nifedipine (C17H18N2O6), labetalol (C19H24N2O3), and hydralazine (C8H8N4) are commonly used drugs, and all are recommended as first-line agents."

Identifies labetalol as a recommended first-line agent for acute hypertensive management in pregnancy.

Antihypertensive therapy (nifedipine)

Action: Pharmacotherapy NCIT:C15986

Agent: nifedipine CHEBI:7565

Nifedipine is an alternative first-line oral antihypertensive for acute severe hypertension in preeclampsia.

Show evidence (1 reference)

PMID:39247143 SUPPORT Human clinical

"oral nifedipine has been proposed as a first-line alternative to intravenous labetalol."

Identifies nifedipine as a first-line alternative antihypertensive for severe preeclampsia.

🌍

Environmental Factors

Gestational phthalate exposure

Phthalate plasticisers are detected in the urine of nearly all pregnant women, and higher gestational concentrations track with a higher rate of preeclampsia. What the human data do not supply is a step: the association is with onset of the syndrome, not with any measured placental or endothelial intermediate, and the strongest series is a nested case-control sample of 50 cases drawn from a preterm-birth study rather than a preeclampsia cohort. A candidate mediator exists - phthalate metabolites track with circulating matrix metalloproteinases, the enzymes that execute spiral artery remodeling - but that was measured in a different cohort with no preeclampsia endpoint, so it supports plausibility rather than the chain.

Show evidence (1 reference)

PMID:27177253 SUPPORT Human clinical

"Urinary concentrations of BPA and several phthalate metabolites were significantly associated with increased risk of preeclampsia."

Establishes the exposure-disease association in a longitudinally sampled pregnancy cohort, which is what makes phthalates an environmental factor for this entry.

Mechanism Target:

PREDISPOSES Defective Trophoblast Invasion and Spiral Artery Remodeling — Drawn to the placental node because that is where preeclampsia risk is thought to be set, not because any step was demonstrated. The cited hazard ratios are for onset of the syndrome; nothing between exposure and trophoblast behaviour was measured. The intermediates are marked unknown deliberately - the matrix metalloproteinase finding below is the leading candidate, not an established link, and it points the opposite way from the MMP2/MMP9 suppression this file models as the invasion defect.

Show evidence (2 references)

PMID:27177253 SUPPORT INDIRECT Human clinical

"We found consistent associations between DEHP metabolites and preeclampsia across pregnancy, with a potential heightened risk associated with concentrations later in pregnancy."

Quantifies the exposure-outcome relationship across gestation. It establishes risk of the syndrome without evidence for the placental step this edge points at, so the link to the node is inferred.

PMID:36113809 SUPPORT INDIRECT Human clinical

"significant associations between mono-n-butyl phthalate (MBP) and higher MMP1 by 7.86 % (95 % CI: 0.49, 15.76) and between mono oxononyl phthalate (MONP) and higher MMP2 by 8.30 % (95 % CI: 2.22, 14.75)"

Supplies the candidate mediator - phthalate exposure altering the matrix metalloproteinases that remodel spiral arteries. Indirect because this cohort measured circulating biomarkers, not preeclampsia or placental MMP expression, so the mediation is inferred rather than shown. The direction is also unresolved and is the most informative thing about this citation: the reported association is with *higher* MMP1 and MMP2, whereas this entry models defective trophoblast invasion as MMP2/MMP9 *suppression* (the PSG2 node). Whether a systemic rise in circulating metalloproteinases is compatible with local suppression at the invading trophoblast front is not addressed by either source.

PREDISPOSES Placental Anti-Angiogenic Factor Release — The better-supported of the two phthalate edges, because here the outcome measured is this node itself rather than the syndrome. In the same birth cohort, oxidised DEHP metabolites tracked with falling placental growth factor and a rising sFlt-1 to PlGF ratio across gestation - the exact angiogenic imbalance this node describes. What remains unknown is the step between the plasticiser and the trophoblast that secretes these factors, so the intermediates stay marked unknown.

Show evidence (1 reference)

PMID:25913709 SUPPORT Human clinical

"oxidized di-2-ethylhexyl phthalate (DEHP) metabolites were associated with decreases in PlGF as well as increases in the sFlt-1 to PlGF ratio"

Measures the node's own output - PlGF and the sFlt-1/PlGF ratio - against exposure, which is what makes this edge land on a mechanism rather than on the diagnosis.

Gestational bisphenol A exposure

Bisphenol A, the polycarbonate and epoxy-resin monomer that shares a source pathway with phthalates, showed a comparable association with preeclampsia onset in the same cohort. It is curated as a distinct exposure because the two chemicals have different sources and different modes of action, and because BPA's obstetric evidence base is inconsistent across endpoints - the analogous meta-analysis for gestational diabetes is null. No mechanism exists at the level of the angiogenic factors that define the maternal syndrome, and that is where its single edge is drawn.

Show evidence (1 reference)

PMID:27177253 SUPPORT Human clinical

"an interquartile range increase of urinary concentrations of BPA (1.53; 95% CI: 1.04, 2.25) and MEP (monoethyl phthalate) (1.72; 95% CI: 1.28, 2.30) at 10 weeks gestation was associated with onset of preeclampsia"

Reports the BPA hazard ratio for preeclampsia onset with an early-gestation exposure window, which is the whole basis for listing BPA here.

Mechanism Target:

PREDISPOSES Placental Anti-Angiogenic Factor Release — BPA tracked with higher circulating sFlt-1 and a higher sFlt-1 to PlGF ratio across gestation in the same cohort that produced its preeclampsia hazard ratio, which puts the exposure and this node in the same population rather than in two unrelated studies. It is still an association between a urinary exposure biomarker and a plasma factor, with no placental step measured.

Show evidence (1 reference)

PMID:25913709 SUPPORT Human clinical

"BPA, however, was associated with increased sFlt-1 as well as the sFlt-1 to PlGF ratio in both crude and adjusted models."

Associates BPA exposure with the anti-angiogenic shift this node names, which is the mechanism-level claim the hazard-ratio paper cannot make.

Micro- and nanoplastic particle exposure

Polystyrene microplastics reproduce a preeclampsia-like syndrome in pregnant rats - hypertension, proteinuria, and shifted angiogenic factor expression - through a defined trophoblast mechanism. There is no human counterpart: no study has related the plastic burden measurable in human placentas to preeclampsia risk, so this exposure rests entirely on a rodent model at experimental doses. Listed because the mechanism it names, ferroptotic trophoblast injury upstream of failed spiral artery remodeling, is testable in human tissue and would matter if it held; see the human-model mismatch discussion.

Show evidence (1 reference)

PMID:40414414 SUPPORT Model organism

"Pregnant rats were exposed to PS-MP, which induced PE-like symptoms including elevated blood pressure, increased proteinuria, and altered expression of angiogenic factors."

Establishes that the exposure produces the maternal syndrome in an animal model, which is the only outcome evidence this entry has.

Mechanism Target:

TRIGGERS Defective Trophoblast Invasion and Spiral Artery Remodeling — The rodent chain runs from particle exposure through HIF-1alpha/TFRC activation to iron overload, oxidative stress and trophoblast ferroptosis, and lands on impaired trophoblast migration, invasion and angiogenesis - this node's content. Ferroptosis inhibition rescues those defects, which is what makes the intermediates known rather than assumed. The species and dose gap to human exposure is unaddressed.

Show evidence (2 references)

PMID:40414414 SUPPORT Model organism

"PS-MP triggered ferroptosis in placental trophoblast cells by activating the HIF-1α/TFRC axis, resulting in iron overload and oxidative stress"

Names the intermediate steps that make this an indirect edge with known mechanism rather than an unexplained association.

PMID:40414414 SUPPORT Model organism

"PS-MP exposure impaired trophoblast migration, invasion, and angiogenesis; these effects were ameliorated by ferroptosis inhibition"

The rescue arm: blocking the proposed intermediate restores the trophoblast behaviour this node describes, tying the exposure to the node causally within the model.

🔬

Biochemical Markers

Elevated sFlt-1 (Elevated)

Context: diagnostic biomarker

Show evidence (1 reference)

PMID:14764923 SUPPORT Human clinical

"At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001)."

Quantifies the elevation of sFlt-1 in preeclampsia versus controls.

Decreased PlGF (Decreased)

Context: diagnostic biomarker

Show evidence (1 reference)

PMID:14764923 SUPPORT Human clinical

"The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01)"

Shows that PlGF depression begins early in the second trimester before clinical disease.

Elevated sFlt-1/PlGF ratio (Elevated)

Context: diagnostic biomarker

Show evidence (4 references)

PMID:31188674 SUPPORT Human clinical

"An sFlt-1/PlGF ratio of ≤38 had a negative predictive value of 98.6% (95% CI, 97.2%-99.4%) for ruling out preeclampsia within 1 week, with 76.5% sensitivity and 82.1% specificity."

Quantifies the rule-out performance of the ratio in a prospective multicenter cohort of women with suspected preeclampsia.

PMID:31188674 SUPPORT Human clinical

"The positive predictive value of a ratio of >38 for ruling in preeclampsia within 4 weeks was 30.3% (95% CI, 23.0%-38.5%), with 62.0% sensitivity and 83.9% specificity."

Records the asymmetry that matters clinically. The same cutoff that excludes disease reliably confirms it poorly, so the ratio should not be read as a positive diagnostic test.

PMID:42041953 SUPPORT Human clinical

"Within preeclampsia, the renal-dominant phenotype showed the highest ratio (66.0 ± 22.5), followed by hepatic (55.9 ± 18.2) and hematologic phenotypes (52.0 ± 16.8)."

Shows the ratio varying with organ-damage pattern within preeclampsia, the renal branch carrying the largest imbalance. This is a cross-sectional association in 68 cases, not a demonstration that the imbalance determines the organ pattern.

+ 1 more reference

Elevated senescence-associated secretory phenotype factors (Elevated)

Context: early predictive biomarker

Show evidence (2 references)

PMID:39440423 SUPPORT Human clinical

"We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis."

Identifies the two specific circulating SASP factors this record names and establishes that they precede diagnosis.

PMID:39440423 SUPPORT Human clinical

"Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester."

Places the elevation in the first trimester, earlier than the sFlt-1 rise recorded elsewhere in this section, which is what makes these markers candidates for a parallel rather than purely downstream process.

Elevated soluble endoglin (Elevated)

Context: diagnostic biomarker

Show evidence (1 reference)

PMID:16751767 SUPPORT Human clinical

"We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery."

Identifies elevated sEng as correlating with disease severity.

📈

Progression

Postpartum long-term cardiovascular risk

Age: Years to decades after affected pregnancy

A pregnancy affected by preeclampsia is followed by persistently elevated maternal vascular risk, including later hypertension, ischemic heart disease, stroke, cardiovascular death, and heart failure. This progression item records the long-term sequelae without assuming that acute pregnancy endothelial injury is the only cause; shared antecedent vascular susceptibility may also contribute.

Show evidence (2 references)

PMID:17975258 SUPPORT Human clinical

"The relative risks (95% confidence intervals) for hypertension were 3.70 (2.70 to 5.05) after 14.1 years weighted mean follow-up, for ischaemic heart disease 2.16 (1.86 to 2.52) after 11.7 years, for stroke 1.81 (1.45 to 2.27) after 10.4 years"

Quantifies the long-term post-preeclampsia risks for hypertension, ischemic heart disease, and stroke.

PMID:28228456 SUPPORT Human clinical

"Preeclampsia is associated with a 4-fold increase in future incident heart failure and a 2-fold increased risk in coronary heart disease, stroke, and death because of coronary heart or cardiovascular disease."

Confirms elevated future heart failure, coronary disease, stroke, and cardiovascular mortality risks.

📊

Prevalence

Pregnancies worldwide

Period prevalence 2000.0–8000.0 per 100,000 >1 in 1,000

Proportion of pregnancies complicated by preeclampsia (2-8%), i.e. 2,000-8,000 per 100,000 pregnancies. Modeled as a period prevalence over the pregnancy episode rather than a population point prevalence.

Show evidence (1 reference)

PMID:32443079 SUPPORT Human clinical

"It has been estimated that preeclampsia complicates 2-8% of pregnancies globally"

ACOG Practice Bulletin 222 provides the global 2-8% per-pregnancy estimate asserted in the entry description.

📊

Related Datasets

Vascular endothelial growth factor receptors 1 and 3 mediate placental trophoblast leptin production in preeclampsia, inducing vascular dysfunction geo:GSE324111

Heightened soluble FMS-like tyrosine kinase-1 (sFlt-1) level is a hallmark of preeclampsia patients and induces a state of angiogenic imbalance by sequestering free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). The receptors for VEGF and PlGF, membrane-bound VEGFR, are expressed in placental trophoblast cells, but their functions in this cell type are largely unknown. Placenta production of leptin significantly increases in preeclampsia, and we recently showed leptin induces placental and vascular endothelial dysfunction in pregnancy. We hypothesized that inappropriately high sFlt-1 in preeclampsia leads to an increase in trophoblast leptin production.

human BULK RNA SEQ n=6

PMID:42422950

Identified by GEO DataSets index search for Preeclampsia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Differences in miRNAs profile in pregnant women with preeclampsia compared with healthy pregnant women geo:GSE309563

Individualized outcome prediction classifiers were successfully constructed through expression profiling of a total of 800 human miRNAs in serum samples of 12 pregnant women (4 samples from severe preeclampsia pregnancies, 4 samples from mild preeclampsia pregnancies and 4 samples from healthy pregnancies)

human MICROARRAY n=12

PMID:42135755

Racial discrepancies in placental gene expressions between Black and White healthy and preeclampsia patients of equivalent BMI and blood pressure in a Southeastern USA cohort geo:GSE303840

Preeclampsia is a devastating hypertensive disorder of pregnancy that afflicts between 5-10% of pregnancies in the US, with a higher prevalence in the southern regions of the United States. Black pregnant women are disproportionally at higher risk for preeclampsia onset and severity of disease than other racial groups, including White women. Although this has been recognized in the maternal fetal medicine literature for many years, the underlying mechanism(s) for this racial disparity are unclear. One confounding issue with many studies of racial discrepancies in pregnant women is differences in comorbidities between racial groups.

human BULK RNA SEQ n=24

Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Uzbeks (DNA samples from the Institute of Immunology, Uzbek Academy of Sciences, Tashkent, Uzbekistan; Republic Specialized Scientific Practical Medical Centre of Obstetrics and Gynecology, Tashkent, Uzbekistan) ega:EGAS00001000416

Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls.

human

PMID:33239696

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Preeclampsia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Kazakhs (DNA samples from the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan; Gulnara Svyatova, Principal Investigator ega:EGAS00001000417

human

PMID:33239696

Preeclampsia InterPregGen Consortium: GWAS meta-analysis summary statistics for European fetal preeclampsia cases versus controls and GWAS genotype data for European fetal preeclampsia cases ega:EGAS00001001048

human

PMID:28628106

Maternal blood lipidomics associated with severe preeclampsia metabolomics_workbench:ST001360

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Preeclampsia"). Retrieved 2026-08-02.

Integrative Exposomic, Transcriptomic, Epigenomic Analyses of Human Placental Samples Links Understudied Chemicals to Preeclampsia metabolomics_workbench:ST002151

Molecular Signatures of Preeclampsia and Gestational Diabetes Mellitus Utilizing Multi-Omics Analyses, Part 2 massive:MSV000085361

The application of multi-omic evaluations, multi-dimensional analysis methods, and new cheminformatics-based visualization tools to provide an in depth understanding of the molecular changes taking place in preeclampsia (PRE) and gestational diabetes mellitus (GDM) patients. Since PRE and GDM are two prevalent pregnancy complications that result in adverse health effects for both the mother and fetus during pregnancy and later in life, a better understanding of each is essential.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Preeclampsia"). Retrieved 2026-08-02.

{ }

Source YAML

click to show

name: Preeclampsia
creation_date: "2026-05-13T00:00:00Z"
category: Complex
synonyms:
- Pre-eclampsia
- Toxemia of pregnancy
- Pregnancy-induced hypertension with proteinuria
description: >
  Preeclampsia is a multisystemic pregnancy disorder characterized by new-onset
  hypertension and often proteinuria after 20 weeks of gestation, which can
  progress to multi-organ dysfunction including hepatic, renal, and cerebral
  disease. It complicates 2-8% of pregnancies globally and is a leading cause
  of maternal and perinatal morbidity and mortality. The pathophysiology involves
  defective trophoblast invasion and spiral artery remodeling leading to placental
  ischemia, followed by release of anti-angiogenic factors (sFlt-1, soluble
  endoglin) that cause widespread maternal endothelial dysfunction. The only
  definitive treatment is delivery of the fetus and placenta.
disease_term:
  preferred_term: preeclampsia
  term:
    id: MONDO:0005081
    label: preeclampsia
parents:
- Hypertensive disorder of pregnancy
- Placental disease
has_subtypes:
- name: Early-onset
  display_name: Early-onset preeclampsia (<34 weeks)
  description: >
    Preeclampsia with onset before 34 weeks of gestation. Strongly associated
    with defective placentation and more severe angiogenic imbalance. Associated
    with higher rates of maternal and fetal complications, intrauterine growth
    restriction, and features resembling atherosclerosis.
  evidence:
  - reference: PMID:35177220
    reference_title: "Preeclampsia and eclampsia: the conceptual evolution of a syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis."
    explanation: Distinguishes early-onset preeclampsia as having features of vascular pathology resembling atherosclerosis.
- name: Late-onset
  display_name: Late-onset preeclampsia (>=34 weeks)
  description: >
    Preeclampsia with onset at or after 34 weeks of gestation. The more common
    form, often associated with less severe placental pathology and thought to
    result from a mismatch between fetal metabolic demands and maternal
    cardiovascular supply capacity.
  evidence:
  - reference: PMID:35177220
    reference_title: "Preeclampsia and eclampsia: the conceptual evolution of a syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis."
    explanation: Characterizes late-onset preeclampsia as a metabolic crisis from demand-supply mismatch.
- name: HELLP
  display_name: HELLP syndrome
  description: >
    Severe variant characterized by hemolysis, elevated liver enzymes, and low
    platelet count. Represents the severe end of the preeclampsia spectrum and
    can occur with or without significant hypertension or proteinuria.
  evidence:
  - reference: PMID:34033373
    reference_title: "Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disease represents a spectrum of hypertensive disease in pregnancy, beginning with gestational hypertension and progressing to develop severe features, ultimately leading to its more severe manifestations, such as eclampsia and HELLP syndrome."
    explanation: Identifies HELLP syndrome as a severe manifestation on the preeclampsia spectrum.
prevalence:
- population: Pregnancies worldwide
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_low: 2000.0
  rate_high: 8000.0
  notes: >-
    Proportion of pregnancies complicated by preeclampsia (2-8%), i.e. 2,000-8,000
    per 100,000 pregnancies. Modeled as a period prevalence over the pregnancy
    episode rather than a population point prevalence.
  evidence:
  - reference: PMID:32443079
    reference_title: "Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It has been estimated that preeclampsia complicates 2-8% of pregnancies globally"
    explanation: ACOG Practice Bulletin 222 provides the global 2-8% per-pregnancy estimate asserted in the entry description.
progression:
- phase: Postpartum long-term cardiovascular risk
  age_range: Years to decades after affected pregnancy
  notes: >
    A pregnancy affected by preeclampsia is followed by persistently elevated
    maternal vascular risk, including later hypertension, ischemic heart
    disease, stroke, cardiovascular death, and heart failure. This progression
    item records the long-term sequelae without assuming that acute pregnancy
    endothelial injury is the only cause; shared antecedent vascular
    susceptibility may also contribute.
  evidence:
  - reference: PMID:17975258
    reference_title: "Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The relative risks (95% confidence intervals) for hypertension were 3.70 (2.70 to 5.05) after 14.1 years weighted mean follow-up, for ischaemic heart disease 2.16 (1.86 to 2.52) after 11.7 years, for stroke 1.81 (1.45 to 2.27) after 10.4 years"
    explanation: Quantifies the long-term post-preeclampsia risks for hypertension, ischemic heart disease, and stroke.
  - reference: PMID:28228456
    reference_title: "Preeclampsia and Future Cardiovascular Health: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Preeclampsia is associated with a 4-fold increase in future incident heart failure and a 2-fold increased risk in coronary heart disease, stroke, and death because of coronary heart or cardiovascular disease."
    explanation: Confirms elevated future heart failure, coronary disease, stroke, and cardiovascular mortality risks.
mechanistic_hypotheses:
- hypothesis_group_id: early_onset_placenta_dominant
  hypothesis_label: Early-Onset Placenta-Dominant Antiangiogenic Model
  status: CANONICAL
  applies_to_subtypes:
  - Early-onset
  - HELLP
  description: >
    In early-onset preeclampsia, immune maladaptation at the maternal-fetal
    interface and defective trophoblast invasion produce severe placental
    malperfusion before clinical disease. Placental hypoxia and stress drive a
    marked antiangiogenic shift, especially excess sFlt-1 and soluble endoglin
    with reduced free PlGF, causing maternal endothelial dysfunction and
    organ-specific renal, hepatic, CNS, and uteroplacental manifestations.
  notes: >
    The 2026 OpenScientist hypothesis-search report
    (kb/hypotheses/Preeclampsia/early_onset_placenta_dominant/openscientist.md)
    retained this model as strongly supported after reviewing 98 papers. It
    emphasized convergent support for the antiangiogenic cascade and KIR/HLA-C
    upstream trigger, while flagging three boundaries: late-onset disease is not
    primarily explained by this model, HELLP may include a parallel complement
    microangiopathy branch, and definitive Phase III interventional evidence for
    targeted sFlt-1 reduction is still missing.

    The 2026 assessment of that report
    (assessments/openscientist-assessment-by-claude-opus-5.yaml in the same
    directory) confirmed the central chain and the subtype boundary but rejected
    three of the report's supporting arguments. Two of those bear directly on
    how strongly this model can be scoped to early-onset disease. First, the
    fetal FLT1 GWAS is not early-onset-specific evidence: the locus is real, but
    the source reports its association as strongest in late-gestation
    preeclampsia with normally grown babies, and the report's contrary claim
    that no subtype-stratified analysis exists is incorrect. Second, the
    interventional argument rests on one uncontrolled apheresis series rather
    than two, because the second apheresis study prolonged pregnancy without
    lowering sFlt-1 at all. Both points are curated as evidence and as a
    knowledge gap below rather than as a change of status, which remains
    CANONICAL.
  evidence:
  - reference: PMID:35177220
    reference_title: "Preeclampsia and eclampsia: the conceptual evolution of a syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis."
    explanation: Supports modeling early-onset preeclampsia separately from late-onset disease.
  - reference: PMID:41582793
    reference_title: "[Types of Preeclampsia According to Placental Single Cell RNA Sequencing, Type 1 and Type 2 Levels - Insights and Clinical Implications]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, late-onset preeclampsia exhibited comparatively subtle transcriptional changes, suggestive of a distinct pathophysiological process driven by maternal cardiovascular maladaptation, placental aging, cellular senescence and oxidative stress."
    explanation: >-
      Supports restricting this model to early-onset disease on transcriptomic
      rather than clinical grounds. The comparison is made within one placental
      single-cell atlas, so the early-onset and late-onset profiles were
      measured on the same platform.
  - reference: PMID:28628106
    reference_title: "Variants in the fetal genome near FLT1 are associated with risk of preeclampsia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile."
    explanation: >-
      Argues against treating fetal FLT1 genetics as support for an
      early-onset-specific model. The locus is the strongest genetic evidence
      that the antiangiogenic axis is causal in preeclampsia at all, but its own
      stratification points to late-gestation disease with normal fetal growth,
      which is the presentation this hypothesis explicitly does not claim.
- hypothesis_group_id: late_onset_maternal_constitutional
  hypothesis_label: Late-Onset Maternal Constitutional Threshold Model
  status: ALTERNATIVE
  applies_to_subtypes:
  - Late-onset
  description: >
    In late-onset preeclampsia, placental stress and antiangiogenic imbalance
    can be milder, while maternal cardiovascular, metabolic, renal, or immune
    susceptibility lowers the threshold for systemic endothelial dysfunction
    as fetal and placental demands peak near term. This model explains cases
    with limited placental lesions but clinically important hypertension and
    end-organ dysfunction.
  evidence:
  - reference: PMID:35177220
    reference_title: "Preeclampsia and eclampsia: the conceptual evolution of a syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis."
    explanation: Supports a late-onset model centered on maternal-fetal demand-supply mismatch.
pathophysiology:
- name: Immune Maladaptation at Maternal-Fetal Interface
  description: >
    Decidual natural killer cells normally interact with fetal extravillous
    trophoblast HLA-C through maternal KIR receptors and help regulate
    placental development, trophoblast invasion, and spiral artery remodeling.
    In susceptible maternal-fetal genotype combinations, especially maternal
    KIR AA with fetal HLA-C2, excessive inhibitory signaling can reduce dNK
    activation and impair trophoblast invasion. This upstream immune
    maladaptation is modeled as an early-onset, placenta-dominant trigger
    rather than as the established antiangiogenic effector pathway itself.
  cell_types:
  - preferred_term: decidual natural killer cell
    term:
      id: CL:0002343
      label: decidual natural killer cell, human
  - preferred_term: extravillous trophoblast
    term:
      id: CL:0008036
      label: extravillous trophoblast
  biological_processes:
  - preferred_term: maternal-fetal immune tolerance
    term:
      id: GO:0002507
      label: tolerance induction
    modifier: DYSREGULATED
  - preferred_term: natural killer cell activation balance
    term:
      id: GO:0045954
      label: positive regulation of natural killer cell mediated cytotoxicity
    modifier: DYSREGULATED
  downstream:
  - target: Defective Trophoblast Invasion and Spiral Artery Remodeling
    description: Dysregulated dNK-KIR recognition of fetal trophoblast HLA-C can bias the decidua toward inadequate trophoblast invasion and poor spiral artery transformation.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:15477349
      reference_title: "Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, the conclusion is that the interaction between maternal KIR on uNK cells and fetal HLA class I molecules on trophoblast has a physiological function in regulating the development of the placenta"
      explanation: Places maternal KIR and fetal trophoblast HLA interactions upstream of placental development.
  evidence:
  - reference: PMID:15477349
    reference_title: "Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have found that the combination of maternal KIR AA genotype with a fetal HLA-C2 is associated with an increased risk of preeclampsia."
    explanation: Supports the KIR/HLA-C maternal-fetal genotype interaction as an upstream risk mechanism.
  - reference: PMID:15477349
    reference_title: "Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "too much inhibition of uNK cells leading to poor trophoblast invasion into the uterine arteries."
    explanation: Supports the proposed bridge from excessive inhibitory uterine NK signaling to poor trophoblast invasion.
  - reference: PMID:32309433
    reference_title: "The Roles of Uterine Natural Killer (NK) Cells and KIR/HLA-C Combination in the Development of Preeclampsia: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decidual NK (dNK) cells significantly contribute to the vascular remodeling through the secretion of cytokines and angiogenic mediators in normal placental development."
    explanation: Review evidence supports the role of decidual NK cells in normal placental vascular remodeling.
  - reference: PMID:24091323
    reference_title: "Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Activation of KIR2DS1+ dNK by HLA-C2 stimulated production of soluble products including GM-CSF, detected by intracellular FACS and ELISA. We demonstrated that GM-CSF enhanced migration of primary trophoblast and JEG-3 trophoblast cells in vitro."
    explanation: >-
      Supplies the soluble mediator this node was previously missing. The
      protective arm of the KIR/HLA-C system works through GM-CSF secreted by
      activated decidual NK cells, which enhances trophoblast migration; a KIR
      AA genotype lacking the activating receptor cannot produce that signal.
  - reference: PMID:20972337
    reference_title: "Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother"
    explanation: >-
      Sharpens the genotype combination this node describes. The risk is not
      carried by maternal KIR AA with any fetal C2, but specifically by a fetal
      C2 dose exceeding the mother's, which points to a paternally inherited
      allogeneic effect rather than a shared maternal-fetal genotype.
- name: Maternal Vascular Susceptibility Threshold
  description: >
    Late-onset preeclampsia can be modeled as a threshold phenomenon in which
    near-term fetal and placental demands interact with maternal cardiovascular,
    renal, metabolic, or inflammatory susceptibility. In this model, placental
    antiangiogenic stress can be less severe than in early-onset disease, but
    maternal endothelial reserve is lower, so hypertension and end-organ
    dysfunction emerge when physiologic demand exceeds vascular supply.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: endothelial cell activation
    term:
      id: GO:0042118
      label: endothelial cell activation
    modifier: DYSREGULATED
  - preferred_term: blood circulation
    term:
      id: GO:0008015
      label: blood circulation
    modifier: DYSREGULATED
  - preferred_term: vasoconstriction
    term:
      id: GO:0042310
      label: vasoconstriction
    modifier: INCREASED
  downstream:
  - target: Maternal Endothelial Dysfunction
    description: Maternal vascular, renal, and metabolic comorbidities lower the threshold for systemic endothelial dysfunction as late-pregnancy demand rises.
    hypothesis_groups:
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:35177220
      reference_title: "Preeclampsia and eclampsia: the conceptual evolution of a syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis."
      explanation: Supports linking late-onset disease to a maternal demand-supply threshold model.
  evidence:
  - reference: PMID:30792480
    reference_title: "Pre-eclampsia: pathogenesis, novel diagnostics and therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity"
    explanation: Identifies maternal vascular, renal, and metabolic comorbidities that can reduce endothelial reserve.
- name: PSG2-Mediated TGF-beta/Smad3 Activation
  biological_scale: MOLECULAR
  description: >
    Placenta-derived pregnancy-specific beta-1-glycoprotein 2 (PSG2) is upregulated
    in preeclamptic placentas and activates the TGF-β/Smad3 signaling pathway in
    extravillous trophoblasts. This placental-derived mechanism cell-autonomously
    suppresses trophoblast epithelial-to-mesenchymal transition (EMT) and
    downregulates matrix metalloproteinases (MMP2/MMP9), thereby reducing
    trophoblast proliferation, migration, and invasion capacity. This is distinct
    from the sEng-mediated inhibition of endothelial TGF-beta signaling modeled
    downstream in the maternal circulation.
  cell_types:
  - preferred_term: extravillous trophoblast
    term:
      id: CL:0008036
      label: extravillous trophoblast
  genes:
  - preferred_term: PSG2
    term:
      id: hgnc:9519
      label: PSG2
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  - preferred_term: SMAD protein signal transduction
    term:
      id: GO:0060395
      label: SMAD protein signal transduction
    modifier: INCREASED
  downstream:
  - target: Defective Trophoblast Invasion and Spiral Artery Remodeling
    description: PSG2-activated TGF-β/Smad3 signaling suppresses epithelial-mesenchymal transition and metalloproteinase expression, reducing trophoblast invasiveness and contributing to defective spiral artery remodeling.
    evidence:
    - reference: PMID:42573986
      reference_title: "PSG2 Impairs Human Trophoblast Function in Preeclampsia by Activating TGF-β/Smad3 to Suppress EMT and MMP2/9 Expression."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mechanistically, PSG2 activated the TGF-β/Smad3 signaling pathway, and the TGFBR1 inhibitor SB431542 effectively reversed PSG2-mediated inhibition of EMT, MMP2/MMP9 expression, and trophoblast functional impairment."
      explanation: Directly demonstrates PSG2-TGF-β/Smad3 activation suppresses EMT and MMPs, impairing trophoblast function.
  evidence:
  - reference: PMID:42573986
    reference_title: "PSG2 Impairs Human Trophoblast Function in Preeclampsia by Activating TGF-β/Smad3 to Suppress EMT and MMP2/9 Expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Highly expressed PSG2 in PE placentas contributes to PE pathogenesis by activating the TGF-β/Smad3 pathway, thereby inhibiting EMT and MMPs expression and attenuating trophoblast proliferation, migration, and invasion."
    explanation: Establishes PSG2 upregulation in preeclamptic placentas as a mechanism activating TGF-β/Smad3 signaling.
- name: Defective Trophoblast Invasion and Spiral Artery Remodeling
  conforms_to: "deep_placentation_defect#Failure of Spiral Artery Physiological Transformation"
  description: >
    In normal pregnancy, extravillous trophoblasts invade the uterine decidua
    and remodel maternal spiral arteries into high-capacitance, low-resistance
    vessels. In preeclampsia, this invasion is shallow and incomplete, resulting
    in narrow, high-resistance spiral arteries that fail to adequately perfuse
    the placenta. The resulting placental ischemia and hypoxia trigger downstream
    pathological cascades.
  cell_types:
  - preferred_term: extravillous trophoblast
    term:
      id: CL:0008036
      label: extravillous trophoblast
  - preferred_term: decidual natural killer cell
    term:
      id: CL:0002343
      label: decidual natural killer cell, human
  biological_processes:
  - preferred_term: placenta development
    term:
      id: GO:0001890
      label: placenta development
    modifier: DECREASED
  - preferred_term: spiral artery remodeling
    term:
      id: GO:0001974
      label: blood vessel remodeling
    modifier: DECREASED
    description: >-
      The module's defining process for this conformance target. GO has no
      spiral-artery-specific remodeling term, so the specificity is carried in
      preferred_term.
  - preferred_term: vasculogenesis
    term:
      id: GO:0001570
      label: vasculogenesis
    modifier: DECREASED
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: DECREASED
  downstream:
  - target: Placental Anti-Angiogenic Factor Release
    description: Placental ischemia from poor spiral artery remodeling triggers release of anti-angiogenic factors into the maternal circulation.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:39062815
      reference_title: "A Narrative Review on the Pathophysiology of Preeclampsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation."
      explanation: Directly describes the causal chain from defective trophoblast invasion through placental hypoxia to anti-angiogenic factor release.
  - target: HIF-1alpha Stabilization in the Ischemic Placenta
    description: Persistent hypoxia from a high-resistance, poorly remodeled uteroplacental circulation stabilizes HIF-1alpha in the placenta.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:41814104
      reference_title: "HIF-1α mediated placental ischemic signaling in the development of early-onset preeclampsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Persistent or excessive hypoxia stabilizes HIF-1α, leading to defective trophoblast invasion, impaired spiral artery remodeling, and progressive placental ischemia."
      explanation: Places HIF-1alpha stabilization downstream of the sustained hypoxia produced by impaired spiral artery remodeling.
  - target: NLRP3 Inflammasome Activation and Inflammatory Cascade
    description: Placental ischemia and stress arising from defective trophoblast invasion and poor spiral artery remodeling activate pattern recognition receptors and the NLRP3 inflammasome in placental and decidual immune cells.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:42269339
      reference_title: "NLRs and preeclampsia: Advances in etiology, pathogenesis, and therapeutic targeting, highlighting NLRP3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Key characteristics of PE include dysregulated NLR activity, excessive inflammation, oxidative stress, endothelial dysfunction, and impaired trophoblast invasion."
      explanation: Links impaired trophoblast invasion and dysregulated NLR (NLRP3) activity as co-occurring core features of preeclampsia, supporting placental invasion failure upstream of inflammasome activation.
  - target: Intrauterine growth retardation
    description: Poorly remodeled spiral arteries limit uteroplacental perfusion, restricting nutrient and oxygen delivery to the fetus.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:29422210
      reference_title: "Pathophysiology of placental-derived fetal growth restriction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Placental-related fetal growth restriction arises primarily due to deficient remodeling of the uterine spiral arteries supplying the placenta during early pregnancy."
      explanation: Names deficient spiral artery remodeling as the primary cause of placental fetal growth restriction, which is this edge.
    - reference: PMID:29422210
      reference_title: "Pathophysiology of placental-derived fetal growth restriction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The changes are more severe in cases of growth restriction associated with preeclampsia compared to those with growth restriction alone"
      explanation: Places growth restriction that accompanies preeclampsia on the same placental pathway, with more severe placental changes than growth restriction alone.
  evidence:
  - reference: PMID:39062815
    reference_title: "A Narrative Review on the Pathophysiology of Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia."
    explanation: Directly describes the defective trophoblast invasion and spiral artery remodeling as the initiating event in preeclampsia.
  - reference: PMID:35177220
    reference_title: "Preeclampsia and eclampsia: the conceptual evolution of a syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a growing body of evidence suggests that products of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome."
    explanation: Supports the concept that placental ischemia (from defective remodeling) drives vascular pathology.
- name: HIF-1alpha Stabilization in the Ischemic Placenta
  biological_scale: MOLECULAR
  description: >
    Tightly controlled hypoxia guides normal trophoblast differentiation and
    vascular remodeling in early gestation. When hypoxia becomes persistent or
    excessive, hypoxia-inducible factor 1-alpha (HIF-1alpha) is stabilized
    rather than degraded, and sustained HIF-1alpha activity becomes the
    transcriptional link between placental ischemia and the antiangiogenic
    shift: it drives mitochondrial dysfunction and oxidative stress that
    amplify placental injury, and it promotes antiangiogenic transcriptional
    programs including sFlt-1 upregulation. This node is curated from
    review-level synthesis; no HIF-1alpha perturbation experiment has been
    performed in human placental tissue, so the edge to antiangiogenic factor
    release is mechanistically motivated rather than directly demonstrated in
    humans. It is distinct from the HIF-1alpha/TFRC ferroptosis axis modelled
    under microplastic exposure, which is a rodent finding about a specific
    exposure rather than the endogenous ischemic response described here.
  cell_types:
  - preferred_term: syncytiotrophoblast
    term:
      id: CL:0000525
      label: syncytiotrophoblast cell
  - preferred_term: extravillous trophoblast
    term:
      id: CL:0008036
      label: extravillous trophoblast
  genes:
  - preferred_term: HIF1A
    term:
      id: hgnc:4910
      label: HIF1A
  biological_processes:
  - preferred_term: cellular response to hypoxia
    term:
      id: GO:0071456
      label: cellular response to hypoxia
    modifier: INCREASED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: negative regulation of angiogenesis
    term:
      id: GO:0016525
      label: negative regulation of angiogenesis
    modifier: INCREASED
  downstream:
  - target: Placental Anti-Angiogenic Factor Release
    description: Sustained HIF-1alpha activity promotes antiangiogenic transcriptional programs, including sFlt-1 upregulation, converting placental ischemia into a systemic angiogenic imbalance.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:41814104
      reference_title: "HIF-1α mediated placental ischemic signaling in the development of early-onset preeclampsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At the transcriptional level, HIF-1α promotes antiangiogenic programs, including sFlt-1 upregulation, resulting in systemic angiogenic imbalance and maternal endothelial dysfunction."
      explanation: States the transcriptional step from stabilized HIF-1alpha to sFlt-1 overproduction and systemic angiogenic imbalance that this edge represents.
  evidence:
  - reference: PMID:41814104
    reference_title: "HIF-1α mediated placental ischemic signaling in the development of early-onset preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sustained HIF-1α activation drives mitochondrial dysfunction and oxidative stress, amplifying placental injury."
    explanation: Supports the mitochondrial and oxidative-stress content of this node as a consequence of sustained HIF-1alpha activity.
  - reference: PMID:41814104
    reference_title: "HIF-1α mediated placental ischemic signaling in the development of early-onset preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early-onset preeclampsia is a severe placental disorder driven primarily by impaired uteroplacental perfusion and early placental ischemia."
    explanation: Scopes this hypoxic-signaling node to early-onset disease, matching the subtype restriction of the hypothesis it belongs to.
- name: Placental Anti-Angiogenic Factor Release
  description: >
    The ischemic placenta releases excess anti-angiogenic factors, primarily
    soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng),
    into the maternal circulation. sFlt-1 acts as a decoy receptor that
    sequesters VEGF and PlGF, while sEng inhibits TGF-beta signaling. Together,
    these factors create a systemic anti-angiogenic state that disrupts normal
    endothelial function. Levels of sFlt-1 rise and PlGF fall weeks before
    clinical onset.
  cell_types:
  - preferred_term: syncytiotrophoblast
    term:
      id: CL:0000525
      label: syncytiotrophoblast cell
  genes:
  - preferred_term: FLT1
    term:
      id: hgnc:3763
      label: FLT1
  - preferred_term: ENG
    term:
      id: hgnc:3349
      label: ENG
  molecular_functions:
  - preferred_term: VEGF and PlGF ligand binding by soluble FLT1 (decoy receptor)
    modifier: INCREASED
    term:
      id: GO:0038085
      label: vascular endothelial growth factor binding
  biological_processes:
  - preferred_term: VEGF receptor signaling pathway
    term:
      id: GO:0048010
      label: vascular endothelial growth factor receptor signaling pathway
    modifier: DECREASED
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: DECREASED
  - preferred_term: response to hypoxia
    term:
      id: GO:0001666
      label: response to hypoxia
  downstream:
  - target: Maternal Endothelial Dysfunction
    description: Anti-angiogenic factors in the maternal circulation cause widespread endothelial injury and dysfunction.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:12618519
      reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF"
      explanation: Human clinical observation showing sFlt-1 elevation associates with decreased free VEGF and PlGF.
    - reference: PMID:12618519
      reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF."
      explanation: In vitro demonstration that endothelial dysfunction from sFlt-1 excess is reversible with VEGF/PlGF.
  evidence:
  - reference: PMID:12618519
    reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery."
    explanation: Landmark paper demonstrating that placental sFlt-1 is upregulated in preeclampsia with systemic elevation.
  - reference: PMID:12618519
    reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: IN_VITRO
    snippet: "VEGF and PlGF by binding to them and preventing their interaction with their cell-surface receptors, Flt1 and KDR."
    explanation: >-
      States the molecular function bound on this node: sFlt1 antagonizes VEGF
      and PlGF by binding them, which is the ligand-binding (decoy-receptor)
      activity that the excess circulating sFlt1 contributes.
  - reference: PMID:14764923
    reference_title: "Circulating angiogenic factors and the risk of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia."
    explanation: Shows that sFlt-1 rises weeks before clinical disease, consistent with placental release preceding symptoms.
  - reference: PMID:14764923
    reference_title: "Circulating angiogenic factors and the risk of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia."
    explanation: Confirms the predictive anti-angiogenic imbalance pattern.
  - reference: PMID:16751767
    reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "sEng inhibits formation of capillary tubes in vitro"
    explanation: In vitro evidence that soluble endoglin has anti-angiogenic effects.
  - reference: PMID:16751767
    reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth."
    explanation: Rat model demonstrates that sEng synergizes with sFlt-1 to produce severe preeclampsia including HELLP syndrome.
  - reference: PMID:39062815
    reference_title: "A Narrative Review on the Pathophysiology of Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation."
    explanation: Summarizes the anti-angiogenic cascade from placental hypoxia to endothelial dysfunction.
  - reference: PMID:40253080
    reference_title: "Placenta at single-cell resolution in early and late preeclampsia: insights and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key findings in early-onset preeclampsia included disrupted syncytiotrophoblast and extravillous trophoblast angiogenic signaling, characterized by an up-regulation of FLT1 and down-regulation of PGF, consistent with an angiogenic imbalance."
    explanation: >-
      Locates the antiangiogenic shift in the specific placental cell types this
      node names, rather than inferring it from circulating protein levels. The
      other evidence here measures sFlt-1 and PlGF in maternal blood; this is
      the transcriptional counterpart in syncytiotrophoblast and extravillous
      trophoblast.
- name: NLRP3 Inflammasome Activation and Inflammatory Cascade
  description: >
    Dysregulated NOD-like receptor (NLR) signaling, particularly NLRP3 inflammasome
    activation, contributes to placental and systemic inflammation in preeclampsia.
    Placental stress from ischemia and poor trophoblast invasion triggers pattern
    recognition receptors that activate the NLRP3 inflammasome complex (NLRP3,
    ASC, and pro-caspase-1). Active caspase-1 processes pro-IL-1β and pro-IL-18
    into their mature, secreted forms, driving excessive IL-1β and IL-18 release
    from placental macrophages, trophoblasts, and maternal immune cells. This
    inflammasome-mediated inflammatory cascade amplifies oxidative stress,
    endothelial dysfunction, and systemic inflammation, contributing to hypertension
    and multi-organ involvement in preeclampsia.
  cell_types:
  - preferred_term: placental macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: extravillous trophoblast
    term:
      id: CL:0008036
      label: extravillous trophoblast
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
    modifier: INCREASED
  - preferred_term: interleukin-1 beta production
    term:
      id: GO:0032611
      label: interleukin-1 beta production
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  downstream:
  - target: Maternal Endothelial Dysfunction
    description: NLRP3-derived inflammatory mediators (IL-1β, IL-18) amplify endothelial activation and dysfunction, synergizing with anti-angiogenic factors to produce systemic inflammation and vascular injury.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:42269339
      reference_title: "NLRs and preeclampsia: Advances in etiology, pathogenesis, and therapeutic targeting, highlighting NLRP3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recent studies underscore the important contribution of NOD-like receptors (NLRs), particularly the NLRP3 inflammasome, to PE development."
      explanation: Directly establishes NLRP3 inflammasome as a key contributor to preeclampsia development.
    - reference: PMID:42269339
      reference_title: "NLRs and preeclampsia: Advances in etiology, pathogenesis, and therapeutic targeting, highlighting NLRP3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Key characteristics of PE include dysregulated NLR activity, excessive inflammation, oxidative stress, endothelial dysfunction, and impaired trophoblast invasion."
      explanation: Links dysregulated NLRs to excessive inflammation, oxidative stress, and endothelial dysfunction—the hallmarks of preeclampsia pathophysiology.
  - target: Cytokine-Induced Tissue Factor Expression and Coagulation Cascade Activation
    description: NLRP3-derived cytokines (IL-1beta, IL-18) join the wider TNF-alpha/IL-6 surge that induces tissue factor on endothelial cells and monocytes, initiating the extrinsic coagulation cascade and establishing the immunothrombotic state.
    causal_link_type: DIRECT
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The cytokine surge characteristic of pre‐eclampsia—primarily involving TNF‐α, IL‐6, and IL‐1β—induces the expression of tissue factor on endothelial cells and circulating monocytes."
      explanation: Names IL-1beta among the cytokines that induce tissue factor expression, placing inflammasome-derived cytokine output upstream of coagulation activation.
  evidence:
  - reference: PMID:42269339
    reference_title: "NLRs and preeclampsia: Advances in etiology, pathogenesis, and therapeutic targeting, highlighting NLRP3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review synthesizes the most recent data on NLRs in PE, focusing on their role in disease genesis, pathogenic processes, biomarker potential, and therapeutic consequences."
    explanation: Comprehensive review documenting NLRP3 inflammasome role in preeclampsia genesis and pathogenesis.
- name: Cytokine-Induced Tissue Factor Expression and Coagulation Cascade Activation
  description: >
    Systemic pro-inflammatory cytokines from placental ischemia and NLRP3
    inflammasome activation (TNF-α, IL-6, IL-1β, IL-17, IFN-γ) stimulate tissue
    factor expression on endothelial cells and monocytes, triggering the
    extrinsic coagulation cascade. Impaired anticoagulant pathways (reduced
    protein C, antithrombin) and suppression of fibrinolysis (elevated
    plasminogen activator inhibitor-1) hold the resulting thrombin generation
    and fibrin deposition unopposed. This is the initiating limb of
    immunothrombosis - the bidirectional interaction in which inflammatory
    activation promotes thrombosis and thrombotic processes amplify
    inflammation. Conformance to the thrombogenesis module is supported here
    because the cited review describes an explicit tissue factor to thrombin to
    fibrin branch rather than the TTP-type microangiopathy the module's scope
    note excludes.
  biological_scale: MOLECULAR
  conforms_to: "thrombogenesis#Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation"
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  - preferred_term: fibrin clot formation
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
    modifier: INCREASED
  - preferred_term: fibrinolysis
    term:
      id: GO:0042730
      label: fibrinolysis
    modifier: DECREASED
  downstream:
  - target: Platelet Activation and NET-Amplified Thrombus Propagation
    description: >-
      The same cytokine signal that induces tissue factor promotes platelet
      activation, and the thrombin generated by the cascade is itself a platelet
      agonist, so cascade activation and platelet activation propagate together.
    causal_link_type: DIRECT
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cytokines stimulate tissue factor expression on endothelial cells and monocytes, while simultaneously promoting platelet activation and impairing fibrinolysis. This phenomenon, referred to as immunothrombosis, represents a convergence of immune and coagulation mechanisms, where the body's attempt to contain inflammation paradoxically causes microvascular thrombi and vascular obstruction."
      explanation: >-
        States that the same cytokine signal drives tissue factor expression and
        platelet activation, which is the edge asserted here.
  evidence:
  - reference: PMID:42381215
    reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to endothelial dysfunction, increasing attention has focused on the role of thromboinflammation and immunothrombosis in the pathogenesis of pre-eclampsia. Immunothrombosis refers to the bidirectional interaction between immune and coagulation pathways whereby inflammatory activation promotes thrombosis and thrombotic processes amplify inflammation."
    explanation: Defines immunothrombosis as the bidirectional interaction between immune and coagulation pathways in preeclampsia.
  - reference: PMID:42381215
    reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cytokines stimulate tissue factor expression on endothelial cells and monocytes, while simultaneously promoting platelet activation and impairing fibrinolysis."
    explanation: >-
      The tissue factor induction and fibrinolysis suppression this node is named
      for, quoted from the sentence that states both.
- name: Platelet Activation and NET-Amplified Thrombus Propagation
  description: >
    Activated platelets release pro-inflammatory mediators that amplify
    endothelial activation and leukocyte recruitment. Neutrophil extracellular
    traps provide a structural scaffold that enhances platelet aggregation and
    fibrin deposition, while circulating extracellular vesicles carry tissue
    factor and inflammatory cytokines to distant vascular sites. Together these
    make the process self-perpetuating rather than self-limiting, which is what
    distinguishes immunothrombosis from ordinary hemostasis.
  biological_scale: CELLULAR
  conforms_to: "thrombogenesis#Platelet Adhesion, Activation, and Aggregation"
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: platelet activation
    term:
      id: GO:0030168
      label: platelet activation
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Microvascular Thrombosis and Maternal Organ Ischemia
    description: >-
      Platelet aggregation on a NET scaffold, with fibrin deposition, produces
      the microthrombi that occlude the maternal microvasculature.
    causal_link_type: DIRECT
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "NETs provide a structural scaffold that enhances platelet aggregation and fibrin deposition, while extracellular vesicles carry tissue factor and inflammatory cytokines, amplifying both coagulation and endothelial damage at distant vascular sites"
      explanation: >-
        Describes the platelet-plus-fibrin thrombus this edge carries into the
        microvascular occlusion node.
  evidence:
  - reference: PMID:42381215
    reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emerging evidence also highlights the role of neutrophil extracellular traps (NETs) and extracellular vesicles in the propagation of immunothrombosis. NETs provide a structural scaffold that enhances platelet aggregation and fibrin deposition, while extracellular vesicles carry tissue factor and inflammatory cytokines, amplifying both coagulation and endothelial damage at distant vascular sites"
    explanation: Documents how NETs and extracellular vesicles amplify the immunothrombotic cascade.
- name: Microvascular Thrombosis and Maternal Organ Ischemia
  description: >
    Microthrombi form in the microvasculature of critical maternal organs
    (kidney, liver, brain, placenta), reducing perfusion and exacerbating
    endothelial injury. This is the point at which the prothrombotic state
    becomes organ injury, and it is the node from which the severe maternal
    complications of preeclampsia follow.
  biological_scale: TISSUE
  conforms_to: "thrombogenesis#Thrombotic Vascular Occlusion and Ischemic Tissue Injury"
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  downstream:
  - target: Hepatic Sinusoidal Obstruction and HELLP
    description: Immunothrombotic microvascular injury with hepatic sinusoidal microthrombi and fibrin deposition causes hepatocyte ischemia and the HELLP phenotype (hemolysis from mechanical destruction of red blood cells by fibrin strands).
    causal_link_type: DIRECT
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These alterations create a prothrombotic state characterized by microvascular thrombosis, endothelial injury, and organ ischemia. The concept of immunothrombosis provides an important mechanistic framework for understanding how inflammatory and coagulation pathways converge to drive disease progression and contribute to complications such as HELLP syndrome, disseminated intravascular coagulation, placental infarction, and adverse fetal outcomes"
      explanation: Links immunothrombosis directly to HELLP syndrome pathogenesis via microvascular thrombosis and organ ischemia.
  - target: Thrombocytopenia
    description: >-
      Microvascular thrombosis contributes to HELLP syndrome, of which
      thrombocytopenia is a defining feature. The intermediate omitted here is
      the HELLP node itself, which carries its own platelet-consumption account.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatic Sinusoidal Obstruction and HELLP
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "microthrombi reduce perfusion, exacerbate endothelial injury, and contribute to the development of severe complications such as HELLP syndrome, eclampsia, and multi-organ dysfunction"
      explanation: >-
        The quote states that microthrombi contribute to HELLP syndrome, of
        which thrombocytopenia is a defining component. It does not describe
        platelet consumption; this review's only mention of thrombocytopenia is
        heparin-induced thrombocytopenia as an LMWH risk, so no consumptive
        mechanism is claimed here.
  evidence:
  - reference: PMID:42381215
    reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These alterations create a prothrombotic state characterized by microvascular thrombosis, endothelial injury, and organ ischemia."
    explanation: >-
      The microvascular thrombosis and organ ischemia this node is named for,
      quoted from the sentence that states both.
- name: Maternal Endothelial Dysfunction
  description: >
    The anti-angiogenic imbalance causes widespread maternal endothelial
    dysfunction, manifesting as vasoconstriction, increased vascular
    permeability, and activation of the coagulation cascade. This leads to
    the clinical features of hypertension, proteinuria (from glomerular
    endotheliosis), hepatic dysfunction, cerebral edema, and
    thrombocytopenia. The characteristic renal lesion is glomerular
    endotheliosis.
  cell_types:
  - preferred_term: blood vessel endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: innate immune response
    term:
      id: GO:0045087
      label: innate immune response
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: vasodilation
    term:
      id: GO:0042311
      label: vasodilation
    modifier: DECREASED
  - preferred_term: vasoconstriction
    term:
      id: GO:0042310
      label: vasoconstriction
    modifier: INCREASED
  downstream:
  - target: Hypertension
    description: >-
      Reduced nitric oxide bioavailability, increased endothelin-1 and loss of
      endothelium-dependent vasodilation raise systemic vascular tone, producing
      the new-onset hypertension that defines the syndrome.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "In pre-eclampsia, endothelial cells undergo profound functional alterations characterized by reduced nitric oxide bioavailability, increased endothelin-1 production, enhanced oxidative stress, expression of adhesion molecules, and increased vascular permeability."
      explanation: Lists the endothelial changes in preeclampsia that the next sentence of the review connects to hypertension.
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "These changes promote vasoconstriction, hypertension, tissue hypoperfusion, and multiorgan dysfunction."
      explanation: States that those endothelial changes produce vasoconstriction and hypertension, which is this edge.
    - reference: PMID:12618519
      reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia."
      explanation: Experimental support in rats that the antiangiogenic endothelial insult is sufficient to cause hypertension.
    - reference: PMID:16751767
      reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "induces vascular permeability and hypertension in vivo"
      explanation: The second antiangiogenic factor, soluble endoglin, also produces hypertension and vascular permeability in vivo.
  - target: Pulmonary edema
    description: >-
      Increased endothelial permeability, together with the raised afterload and
      diastolic dysfunction that follow systemic vasoconstriction, allows fluid
      to leak into the lungs in severe disease.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Cardiac adaptations to these vascular changes include increased afterload, diastolic dysfunction, and myocardial stress, which can manifest clinically as hypertension, pulmonary edema, or acute heart failure in severe cases."
      explanation: Traces pulmonary edema to the cardiac consequences of the endothelial and vascular changes this node describes.
  - target: Glomerular Endotheliosis and Proteinuria
    description: Systemic antiangiogenic endothelial injury targets glomerular capillaries, producing endotheliosis and proteinuria.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:12618519
      reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia."
      explanation: Directly links sFlt-1-driven endothelial dysfunction to the renal lesion and proteinuria.
  - target: Hepatic Sinusoidal Obstruction and HELLP
    description: Endothelial injury and prothrombotic inflammation can cause hepatic sinusoidal microthrombi, fibrin deposition, hepatocyte ischemia, and the HELLP phenotype.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:31877439
      reference_title: "The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Particularly in microcirculations with extremely low shear forces, such as in the hepatic sinusoids, this will facilitate microthrombi formation and fibrin deposition eventually resulting in obstruction of the sinusoids similar as in SOS."
      explanation: Supports the liver-specific endothelial microvascular mechanism for HELLP-related hepatic injury.
  - target: Cerebrovascular Autoregulation Failure and Eclampsia
    description: Cerebral endothelial dysfunction and impaired vascular autoregulation can disrupt the blood-brain barrier, produce vasogenic edema or PRES, and precipitate eclamptic seizures.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:26126779
      reference_title: "Cerebrovascular Dysfunction in Preeclamptic Pregnancies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cerebrovascular dysfunction during preeclampsia can lead to cerebral edema, seizures, stroke, and potentially maternal mortality."
      explanation: Supports a CNS-specific downstream branch from endothelial/cerebrovascular dysfunction to eclampsia-related complications.
  evidence:
  - reference: PMID:12618519
    reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia."
    explanation: Direct demonstration that sFlt-1 causes the clinical triad of hypertension, proteinuria, and glomerular endotheliosis.
  - reference: PMID:30792480
    reference_title: "Pre-eclampsia: pathogenesis, novel diagnostics and therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia."
    explanation: Identifies endothelial dysfunction from placental factors as the hallmark of preeclampsia.
  - reference: PMID:16751767
    reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature."
    explanation: Biochemical/cell-based evidence that sEng disrupts TGF-beta receptor binding and eNOS activation.
- name: Glomerular Endotheliosis and Proteinuria
  description: >
    Antiangiogenic injury to glomerular endothelial cells disrupts the
    fenestrated filtration barrier, producing glomerular endotheliosis and
    proteinuria. This renal branch is the most direct organ-specific
    consequence of the sFlt-1/VEGF/PlGF imbalance.
  cell_types:
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  biological_processes:
  - preferred_term: glomerular filtration
    term:
      id: GO:0003094
      label: glomerular filtration
    modifier: DECREASED
  - preferred_term: endothelial cell activation
    term:
      id: GO:0042118
      label: endothelial cell activation
    modifier: DYSREGULATED
  downstream:
  - target: Proteinuria
    description: Glomerular endothelial swelling and filtration-barrier injury increase urinary protein loss.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:12618519
      reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia."
      explanation: In rats, the same antiangiogenic insult produces glomerular endotheliosis together with proteinuria.
  evidence:
  - reference: PMID:12618519
    reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia."
    explanation: Demonstrates the renal lesion and proteinuria after sFlt-1 exposure in pregnant rats.
- name: Hepatic Sinusoidal Obstruction and HELLP
  description: >
    In severe preeclampsia and HELLP syndrome, systemic endothelial injury and
    inflammatory prothrombotic signaling can be amplified in hepatic sinusoids,
    where low shear favors microthrombi and fibrin deposition. Sinusoidal
    obstruction causes ischemic hepatocyte injury, elevated liver enzymes,
    platelet consumption, and microangiopathic hemolysis.
  cell_types:
  - preferred_term: hepatic sinusoidal endothelial cell
    term:
      id: CL:1000398
      label: endothelial cell of hepatic sinusoid
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  - preferred_term: endothelial cell activation
    term:
      id: GO:0042118
      label: endothelial cell activation
    modifier: DYSREGULATED
  downstream:
  - target: Thrombocytopenia
    description: Prothrombotic endothelial injury consumes platelets in the HELLP microangiopathy.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:19245695
      reference_title: "The HELLP syndrome: clinical issues and management. A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Platelets are activated, and adhere to damaged vascular endothelial cells, resulting in increased platelet turnover with shorter lifespan"
      explanation: Explains the low platelet count of HELLP as consumption of platelets on damaged endothelium.
  - target: Hemolytic anemia
    description: Microangiopathic vascular injury fragments erythrocytes and produces hemolysis.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:19245695
      reference_title: "The HELLP syndrome: clinical issues and management. A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Red cell fragmentation caused by high-velocity passage through damaged endothelium"
      explanation: Attributes the hemolysis of HELLP to red cells fragmenting as they pass through damaged endothelium.
  - target: Elevated hepatic transaminases
    description: Ischemic hepatocyte injury downstream of sinusoidal obstruction releases transaminases into the circulation.
    hypothesis_groups:
    - early_onset_placenta_dominant
    evidence:
    - reference: PMID:31877439
      reference_title: "The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The latter causes ischemic damage and progressive demise of hepatocytes."
      explanation: Places hepatocyte ischemic injury, the source of the transaminase rise, downstream of sinusoidal obstruction.
  evidence:
  - reference: PMID:31877439
    reference_title: "The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The dysfunctional placenta in women developing HELLP initiates a cascade of events that eventually results in liver dysfunction."
    explanation: Places HELLP liver injury downstream of placental dysfunction.
  - reference: PMID:31877439
    reference_title: "The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter causes ischemic damage and progressive demise of hepatocytes."
    explanation: Supports ischemic hepatocyte injury downstream of sinusoidal obstruction.
- name: Cerebrovascular Autoregulation Failure and Eclampsia
  description: >
    Cerebral vascular dysfunction in preeclampsia can include impaired
    autoregulatory reserve, endothelial injury, blood-brain barrier disruption,
    and vasogenic edema. This branch connects systemic endothelial dysfunction
    to headache, visual symptoms, PRES-like edema, seizures, stroke, and
    eclampsia.
  cell_types:
  - preferred_term: cerebral blood vessel endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  biological_processes:
  - preferred_term: blood circulation
    term:
      id: GO:0008015
      label: blood circulation
    modifier: DYSREGULATED
  - preferred_term: vasoconstriction
    term:
      id: GO:0042310
      label: vasoconstriction
    modifier: DYSREGULATED
  - preferred_term: endothelial cell activation
    term:
      id: GO:0042118
      label: endothelial cell activation
    modifier: DYSREGULATED
  downstream:
  - target: Seizures (eclampsia)
    description: Cerebral edema and vascular dysfunction can precipitate eclamptic seizures.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:26126779
      reference_title: "Cerebrovascular Dysfunction in Preeclamptic Pregnancies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Cerebrovascular dysfunction during preeclampsia can lead to cerebral edema, seizures, stroke, and potentially maternal mortality."
      explanation: Names seizures as a consequence of cerebrovascular dysfunction in preeclampsia.
  - target: Headache
    description: Cerebrovascular dysfunction contributes to severe headache in preeclampsia with severe features.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:26126779
      reference_title: "Cerebrovascular Dysfunction in Preeclamptic Pregnancies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "PRES is a clinical-radiologic diagnosis associated with neuroimaging findings of cerebral edema without evidence of cerebral infarct and is clinically associated with headache, visual disturbances, encephalopathy and seizures"
      explanation: Links the PRES-type cerebral edema of this node to headache.
  - target: Visual disturbances
    description: PRES-like posterior cerebral involvement can produce visual symptoms.
    hypothesis_groups:
    - early_onset_placenta_dominant
    - late_onset_maternal_constitutional
    evidence:
    - reference: PMID:26126779
      reference_title: "Cerebrovascular Dysfunction in Preeclamptic Pregnancies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "PRES is a clinical-radiologic diagnosis associated with neuroimaging findings of cerebral edema without evidence of cerebral infarct and is clinically associated with headache, visual disturbances, encephalopathy and seizures"
      explanation: Links the PRES-type cerebral edema of this node to visual disturbances.
  evidence:
  - reference: PMID:26126779
    reference_title: "Cerebrovascular Dysfunction in Preeclamptic Pregnancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebrovascular dysfunction during preeclampsia can lead to cerebral edema, seizures, stroke, and potentially maternal mortality."
    explanation: Directly links preeclampsia cerebrovascular dysfunction to acute neurologic complications.
  - reference: PMID:26126779
    reference_title: "Cerebrovascular Dysfunction in Preeclamptic Pregnancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PRES can be caused by an acute elevation in blood pressure that overcomes cerebral artery and arteriole vasoconstriction, resulting in a loss of CBF autoregulation, disruption to the blood-brain barrier (BBB), and vasogenic edema formation"
    explanation: Supports the autoregulatory failure, BBB disruption, and vasogenic edema mechanism for eclampsia/PRES-like manifestations.
phenotypes:
- name: Hypertension
  category: Clinical
  description: >
    New-onset hypertension after 20 weeks of gestation, defined as systolic
    blood pressure >=140 mmHg or diastolic >=90 mmHg on two occasions at
    least 4 hours apart. Severe-range hypertension is >=160/110 mmHg.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Maternal hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:34033373
    reference_title: "Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The parameters for initial identification of hypertension in the context of pregnancy-induced hypertension constituting the \"mild range\" are specifically defined as a systolic blood pressure (SBP) of 140 mm Hg or more or diastolic blood pressure (DBP) of 90 mm Hg or more on 2 occasions at least 4 hours apart"
    explanation: Defines the diagnostic blood pressure criteria for preeclampsia.
  - reference: PMID:32443079
    reference_title: "Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertensive disorders of pregnancy constitute one of the leading causes of maternal and perinatal mortality worldwide."
    explanation: Establishes hypertensive disorders as a defining feature of the preeclampsia spectrum.
- name: Proteinuria
  category: Clinical
  description: >
    New-onset proteinuria, typically >=300 mg per 24-hour urine collection or
    protein/creatinine ratio >=0.3 mg/mg (30 mg/mmol). While historically required for
    diagnosis, current guidelines recognize preeclampsia can occur without
    proteinuria if other signs of end-organ dysfunction are present.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:30792480
    reference_title: "Pre-eclampsia: pathogenesis, novel diagnostics and therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered."
    explanation: Identifies proteinuria as a frequent but not universal feature of preeclampsia.
- name: Thrombocytopenia
  category: Clinical
  description: >
    Low platelet count, particularly prominent in HELLP syndrome. Reflects
    endothelial activation and consumptive coagulopathy.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:34033373
    reference_title: "Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disease represents a spectrum of hypertensive disease in pregnancy, beginning with gestational hypertension and progressing to develop severe features, ultimately leading to its more severe manifestations, such as eclampsia and HELLP syndrome."
    explanation: >-
      Human clinical anchor placing HELLP syndrome — of which thrombocytopenia
      is a defining component — on the preeclampsia spectrum.
  - reference: PMID:16751767
    reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome"
    explanation: >-
      Rat sFlt1/sEng co-administration model reproduces the low-platelet
      component of HELLP. Model-organism support for the mechanism only; it is
      not the primary evidence for the human phenotype.
- name: Elevated hepatic transaminases
  category: Clinical
  description: >
    Elevated circulating hepatic transaminase concentrations reflecting liver
    involvement, a criterion for severe features and a component of HELLP
    syndrome.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:31877439
    reference_title: "The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter causes ischemic damage and progressive demise of hepatocytes."
    explanation: >-
      Human literature review supports hepatocyte ischemic injury as the basis of
      the transaminase elevation seen in severe preeclampsia and HELLP.
  - reference: PMID:16751767
    reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome"
    explanation: >-
      Rat model reproduces the elevated-liver-enzyme component of HELLP;
      model-organism corroboration rather than primary human evidence.
  reports_on:
  - target: Hepatic Sinusoidal Obstruction and HELLP
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Hepatic sinusoidal obstruction and ischemia injure hepatocytes, increasing circulating transaminases.
- name: Seizures (eclampsia)
  category: Clinical
  description: >
    New-onset tonic-clonic seizures in a woman with preeclampsia, defining
    the transition to eclampsia. Represents a severe neurological complication
    that can occur antepartum, intrapartum, or postpartum.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35177220
    reference_title: "Preeclampsia and eclampsia: the conceptual evolution of a syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "once thought to be a disease of the central nervous system, recognized by the occurrence of seizures (ie, eclampsia)"
    explanation: Eclamptic seizures are the historically defining severe complication of preeclampsia.
- name: Headache
  category: Clinical
  description: >
    Severe, persistent headache that is a warning sign for severe preeclampsia
    and eclampsia, indicating cerebral involvement.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:39247143
    reference_title: "A Comparative Study of Oral Nifedipine and Intravenous Labetalol for Acute Hypertensive Management in Pregnancy: Assessing Feto-Maternal Outcomes in a Hospital-based Randomized Control Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe preeclampsia is defined as blood pressure (BP) >160/110 mmHg with warning signs such as headache, blurring of vision, and epigastric pain."
    explanation: Explicitly identifies headache as a warning sign of severe preeclampsia.
- name: Visual disturbances
  category: Clinical
  description: >
    Blurred vision and other visual disturbances are warning signs of severe
    preeclampsia, reflecting cerebral edema and vasospasm.
  phenotype_term:
    preferred_term: Blurred vision
    term:
      id: HP:0000622
      label: Blurred vision
  evidence:
  - reference: PMID:39247143
    reference_title: "A Comparative Study of Oral Nifedipine and Intravenous Labetalol for Acute Hypertensive Management in Pregnancy: Assessing Feto-Maternal Outcomes in a Hospital-based Randomized Control Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe preeclampsia is defined as blood pressure (BP) >160/110 mmHg with warning signs such as headache, blurring of vision, and epigastric pain."
    explanation: Explicitly identifies blurring of vision as a warning sign of severe preeclampsia.
- name: Intrauterine growth retardation
  category: Clinical
  description: >
    Fetal growth restriction due to impaired uteroplacental perfusion from
    defective spiral artery remodeling. More common in early-onset preeclampsia.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:14764923
    reference_title: "Circulating angiogenic factors and the risk of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant."
    explanation: Links angiogenic factor alterations to small-for-gestational-age infants in preeclampsia.
- name: Hemolytic anemia
  category: Clinical
  subtype: HELLP
  description: >
    Microangiopathic hemolytic anemia as part of HELLP syndrome, reflecting
    erythrocyte destruction in damaged microvasculature.
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:34033373
    reference_title: "Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disease represents a spectrum of hypertensive disease in pregnancy, beginning with gestational hypertension and progressing to develop severe features, ultimately leading to its more severe manifestations, such as eclampsia and HELLP syndrome."
    explanation: >-
      Human clinical anchor placing HELLP — whose "H" is microangiopathic
      hemolysis — within the preeclampsia spectrum.
  - reference: PMID:16751767
    reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome"
    explanation: >-
      Rat model reproduces the hemolysis component of HELLP; model-organism
      corroboration rather than primary human evidence.
- name: Pulmonary edema
  category: Clinical
  description: >
    Pulmonary edema due to increased vascular permeability and fluid overload,
    a severe complication of preeclampsia.
  phenotype_term:
    preferred_term: Pulmonary edema
    term:
      id: HP:0100598
      label: Pulmonary edema
  evidence:
  - reference: PMID:42381215
    reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Severe disease is associated with higher blood pressure levels, greater degrees of endothelial dysfunction, more extensive coagulation abnormalities, and increased risks of complications such as HELLP syndrome, eclampsia, acute kidney injury, pulmonary edema, and maternal death."
    explanation: Names pulmonary edema among the complications of severe preeclampsia.
  notes: >
    Pulmonary edema is a recognized severe complication of preeclampsia,
    resulting from endothelial dysfunction, decreased oncotic pressure,
    and iatrogenic fluid overload. It is included in ACOG criteria for
    severe features of preeclampsia.
biochemical:
- name: Elevated sFlt-1
  presence: Elevated
  context: diagnostic biomarker
  notes: >
    Elevated circulating soluble fms-like tyrosine kinase 1 (sFlt-1/sVEGFR1),
    a decoy VEGF receptor produced by the ischemic placenta that sequesters
    VEGF and PlGF, disrupting endothelial function.
  evidence:
  - reference: PMID:14764923
    reference_title: "Circulating angiogenic factors and the risk of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001)."
    explanation: Quantifies the elevation of sFlt-1 in preeclampsia versus controls.
- name: Decreased PlGF
  presence: Decreased
  context: diagnostic biomarker
  notes: >
    Reduced circulating free placental growth factor (PlGF), sequestered by
    excess sFlt-1. Low PlGF precedes clinical onset and is an early predictive
    biomarker.
  evidence:
  - reference: PMID:14764923
    reference_title: "Circulating angiogenic factors and the risk of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01)"
    explanation: Shows that PlGF depression begins early in the second trimester before clinical disease.
- name: Elevated sFlt-1/PlGF ratio
  presence: Elevated
  context: diagnostic biomarker
  notes: >
    The ratio of circulating sFlt-1 to free PlGF is the form in which the
    angiogenic imbalance is measured clinically, and it behaves differently from
    either analyte alone: it is far better at excluding preeclampsia than at
    predicting it. At a cutoff of 38, the negative predictive value for ruling
    out preeclampsia within one week is about 99%, while the positive predictive
    value for ruling it in within four weeks is only about 30%, so a low ratio is
    informative and a high ratio mostly identifies a group worth watching.
    Within established preeclampsia the ratio also tracks with which organ system
    is involved, being highest in renal-dominant disease, though that gradient
    comes from one retrospective cohort and discriminates the renal phenotype
    only moderately.
  evidence:
  - reference: PMID:31188674
    reference_title: "Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Asian Women With Suspected Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An sFlt-1/PlGF ratio of ≤38 had a negative predictive value of 98.6% (95% CI, 97.2%-99.4%) for ruling out preeclampsia within 1 week, with 76.5% sensitivity and 82.1% specificity."
    explanation: Quantifies the rule-out performance of the ratio in a prospective multicenter cohort of women with suspected preeclampsia.
  - reference: PMID:31188674
    reference_title: "Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Asian Women With Suspected Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The positive predictive value of a ratio of >38 for ruling in preeclampsia within 4 weeks was 30.3% (95% CI, 23.0%-38.5%), with 62.0% sensitivity and 83.9% specificity."
    explanation: >-
      Records the asymmetry that matters clinically. The same cutoff that
      excludes disease reliably confirms it poorly, so the ratio should not be
      read as a positive diagnostic test.
  - reference: PMID:42041953
    reference_title: "Angiogenic Imbalance Defines Multisystem Phenotypes of Preeclampsia: A Phenotype-Oriented Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within preeclampsia, the renal-dominant phenotype showed the highest ratio (66.0 ± 22.5), followed by hepatic (55.9 ± 18.2) and hematologic phenotypes (52.0 ± 16.8)."
    explanation: >-
      Shows the ratio varying with organ-damage pattern within preeclampsia, the
      renal branch carrying the largest imbalance. This is a cross-sectional
      association in 68 cases, not a demonstration that the imbalance determines
      the organ pattern.
  - reference: PMID:42041953
    reference_title: "Angiogenic Imbalance Defines Multisystem Phenotypes of Preeclampsia: A Phenotype-Oriented Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sFlt-1/PlGF ratio demonstrated moderate discrimination for the renal phenotype (AUC = 0.69)."
    explanation: >-
      Bounds the previous item. The same study that reports the organ gradient
      reports only moderate discrimination for the renal phenotype, so the
      gradient is real but is not a phenotype classifier.
- name: Elevated senescence-associated secretory phenotype factors
  presence: Elevated
  context: early predictive biomarker
  notes: >
    Syncytiotrophoblast nuclei in early-onset preeclampsia carry senescent
    transcriptomic states with a senescence-associated secretory phenotype, and
    two of the secreted factors, PAI-1 and activin A, are already raised in
    maternal blood in the first trimester, well before clinical diagnosis. This
    is curated as a measurement rather than as a mechanism node: the source
    establishes that placental senescence occurs and that its secreted markers
    are predictive, but not that SASP secretion causes the maternal syndrome.
  evidence:
  - reference: PMID:39440423
    reference_title: "Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis."
    explanation: Identifies the two specific circulating SASP factors this record names and establishes that they precede diagnosis.
  - reference: PMID:39440423
    reference_title: "Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester."
    explanation: >-
      Places the elevation in the first trimester, earlier than the sFlt-1 rise
      recorded elsewhere in this section, which is what makes these markers
      candidates for a parallel rather than purely downstream process.
- name: Elevated soluble endoglin
  presence: Elevated
  context: diagnostic biomarker
  notes: >
    Elevated circulating soluble endoglin (sEng), a TGF-beta coreceptor
    released by the placenta that inhibits TGF-beta signaling and impairs
    eNOS activation, contributing to endothelial dysfunction.
  evidence:
  - reference: PMID:16751767
    reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery."
    explanation: Identifies elevated sEng as correlating with disease severity.
genetic:
- name: FLT1
  gene_term:
    preferred_term: FLT1
    term:
      id: hgnc:3763
      label: FLT1
  association: Risk Factor (FLT1 polymorphisms) and source of the sFlt-1 effector
  relationship_type: RISK_FACTOR
  notes: >
    Encodes fms-like tyrosine kinase 1 (VEGFR1). Alternative splicing produces
    the soluble isoform sFlt-1, which is overexpressed by the preeclamptic
    placenta and acts as a decoy receptor sequestering VEGF and PlGF.
    Polymorphisms in FLT1 are associated with preeclampsia susceptibility. The
    risk variant is carried in the fetal rather than the maternal genome, which
    is the strongest genetic argument that placental sFlt-1 overproduction is
    causal rather than reactive. Note the association reported for that locus
    was strongest in late-gestation preeclampsia with normally grown offspring,
    so it is evidence for the antiangiogenic axis in preeclampsia generally and
    not specifically for the early-onset subtype.
  evidence:
  - reference: PMID:28628106
    reference_title: "Variants in the fetal genome near FLT1 are associated with risk of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls."
    explanation: >-
      Replaces a general statement that FLT1 polymorphisms matter with the
      actual genome-wide significant locus, its effect size context, and the
      fact that it was found in offspring rather than mothers.
  - reference: PMID:28628106
    reference_title: "Variants in the fetal genome near FLT1 are associated with risk of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia."
    explanation: Ties the genome-wide significant signal to the placental sFlt-1 isoform this entry models as the effector.
  - reference: PMID:39062815
    reference_title: "A Narrative Review on the Pathophysiology of Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles."
    explanation: Identifies FLT1 polymorphisms as playing a critical role in preeclampsia.
  - reference: PMID:12618519
    reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia"
    explanation: Demonstrates sFlt-1 (FLT1 gene product) upregulation in preeclamptic placentas.
- name: PGF
  gene_term:
    preferred_term: PGF
    term:
      id: hgnc:8893
      label: PGF
  association: Mechanistic effector (reduced free PlGF protein)
  relationship_type: BIOMARKER
  notes: >
    Encodes placental growth factor (PlGF), a VEGF family member essential for
    placental angiogenesis. Free PlGF levels are reduced in preeclampsia due
    to sequestration by excess sFlt-1, and low PlGF is an early biomarker.
  evidence:
  - reference: PMID:14764923
    reference_title: "Circulating angiogenic factors and the risk of preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia."
    explanation: PlGF reduction is a key predictive feature of preeclampsia.
- name: ENG
  gene_term:
    preferred_term: ENG
    term:
      id: hgnc:3349
      label: ENG
  association: Mechanistic effector (placenta-derived soluble endoglin)
  relationship_type: BIOMARKER
  notes: >
    Encodes endoglin, a TGF-beta coreceptor. The soluble form (sEng) is
    elevated in preeclampsia and synergizes with sFlt-1 to induce severe
    disease including HELLP syndrome in animal models.
  evidence:
  - reference: PMID:16751767
    reference_title: "Soluble endoglin contributes to the pathogenesis of preeclampsia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia."
    explanation: Demonstrates the pathogenic role of soluble endoglin (ENG gene product) in severe preeclampsia.
- name: VEGFA
  gene_term:
    preferred_term: VEGFA
    term:
      id: hgnc:12680
      label: VEGFA
  association: Mechanistic effector (free VEGF sequestered by sFlt-1)
  relationship_type: BIOMARKER
  notes: >
    Encodes vascular endothelial growth factor A, a key mediator of
    angiogenesis and endothelial homeostasis. Sequestration of free VEGF by
    excess sFlt-1 in preeclampsia contributes to endothelial dysfunction.
  evidence:
  - reference: PMID:12618519
    reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF"
    explanation: Human clinical data showing that sFlt-1 excess sequesters free VEGF in preeclampsia patients.
  - reference: PMID:12618519
    reference_title: "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF."
    explanation: In vitro evidence that exogenous VEGF can rescue sFlt-1-induced endothelial dysfunction.
environmental:
- name: Gestational phthalate exposure
  exposure_term:
    preferred_term: exposure to phthalate
    term:
      id: ECTO:9000522
      label: exposure to phthalate
  description: >-
    Phthalate plasticisers are detected in the urine of nearly all pregnant
    women, and higher gestational concentrations track with a higher rate of
    preeclampsia. What the human data do not supply is a step: the association
    is with onset of the syndrome, not with any measured placental or
    endothelial intermediate, and the strongest series is a nested case-control
    sample of 50 cases drawn from a preterm-birth study rather than a
    preeclampsia cohort. A candidate mediator exists - phthalate metabolites
    track with circulating matrix metalloproteinases, the enzymes that execute
    spiral artery remodeling - but that was measured in a different cohort with
    no preeclampsia endpoint, so it supports plausibility rather than the chain.
  evidence:
  - reference: PMID:27177253
    reference_title: Urinary Concentrations of Bisphenol A and Phthalate Metabolites Measured during Pregnancy and Risk of Preeclampsia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urinary concentrations of BPA and several phthalate metabolites were significantly associated with increased risk of preeclampsia."
    explanation: >-
      Establishes the exposure-disease association in a longitudinally sampled
      pregnancy cohort, which is what makes phthalates an environmental factor
      for this entry.
  influences_mechanisms:
  - target: Defective Trophoblast Invasion and Spiral Artery Remodeling
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn to the placental node because that is where preeclampsia risk is
      thought to be set, not because any step was demonstrated. The cited
      hazard ratios are for onset of the syndrome; nothing between exposure and
      trophoblast behaviour was measured. The intermediates are marked unknown
      deliberately - the matrix metalloproteinase finding below is the leading
      candidate, not an established link, and it points the opposite way from
      the MMP2/MMP9 suppression this file models as the invasion defect.
    evidence:
    - reference: PMID:27177253
      reference_title: Urinary Concentrations of Bisphenol A and Phthalate Metabolites Measured during Pregnancy and Risk of Preeclampsia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We found consistent associations between DEHP metabolites and preeclampsia across pregnancy, with a potential heightened risk associated with concentrations later in pregnancy."
      explanation: >-
        Quantifies the exposure-outcome relationship across gestation. It
        establishes risk of the syndrome without evidence for the placental
        step this edge points at, so the link to the node is inferred.
    - reference: PMID:36113809
      reference_title: Associations of urinary phthalate metabolites and inflammatory biomarkers among pregnant women in Puerto Rico.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "significant associations between mono-n-butyl phthalate (MBP) and higher MMP1 by 7.86 % (95 % CI: 0.49, 15.76) and between mono oxononyl phthalate (MONP) and higher MMP2 by 8.30 % (95 % CI: 2.22, 14.75)"
      explanation: >-
        Supplies the candidate mediator - phthalate exposure altering the matrix
        metalloproteinases that remodel spiral arteries. Indirect because this
        cohort measured circulating biomarkers, not preeclampsia or placental
        MMP expression, so the mediation is inferred rather than shown. The
        direction is also unresolved and is the most informative thing about
        this citation: the reported association is with *higher* MMP1 and MMP2,
        whereas this entry models defective trophoblast invasion as MMP2/MMP9
        *suppression* (the PSG2 node). Whether a systemic rise in circulating
        metalloproteinases is compatible with local suppression at the
        invading trophoblast front is not addressed by either source.
  - target: Placental Anti-Angiogenic Factor Release
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The better-supported of the two phthalate edges, because here the outcome
      measured is this node itself rather than the syndrome. In the same birth
      cohort, oxidised DEHP metabolites tracked with falling placental growth
      factor and a rising sFlt-1 to PlGF ratio across gestation - the exact
      angiogenic imbalance this node describes. What remains unknown is the step
      between the plasticiser and the trophoblast that secretes these factors,
      so the intermediates stay marked unknown.
    evidence:
    - reference: PMID:25913709
      reference_title: Phthalate metabolites and bisphenol-A in association with circulating angiogenic biomarkers across pregnancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "oxidized di-2-ethylhexyl phthalate (DEHP) metabolites were associated with decreases in PlGF as well as increases in the sFlt-1 to PlGF ratio"
      explanation: >-
        Measures the node's own output - PlGF and the sFlt-1/PlGF ratio - against
        exposure, which is what makes this edge land on a mechanism rather than
        on the diagnosis.
- name: Gestational bisphenol A exposure
  exposure_term:
    preferred_term: exposure to bisphenol A
    term:
      id: ECTO:9000057
      label: exposure to bisphenol A
  description: >-
    Bisphenol A, the polycarbonate and epoxy-resin monomer that shares a source
    pathway with phthalates, showed a comparable association with preeclampsia
    onset in the same cohort. It is curated as a distinct exposure because the
    two chemicals have different sources and different modes of action, and
    because BPA's obstetric evidence base is inconsistent across endpoints -
    the analogous meta-analysis for gestational diabetes is null. No mechanism
    exists at the level of the angiogenic factors that define the maternal
    syndrome, and that is where its single edge is drawn.
  evidence:
  - reference: PMID:27177253
    reference_title: Urinary Concentrations of Bisphenol A and Phthalate Metabolites Measured during Pregnancy and Risk of Preeclampsia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an interquartile range increase of urinary concentrations of BPA (1.53; 95% CI: 1.04, 2.25) and MEP (monoethyl phthalate) (1.72; 95% CI: 1.28, 2.30) at 10 weeks gestation was associated with onset of preeclampsia"
    explanation: >-
      Reports the BPA hazard ratio for preeclampsia onset with an early-gestation
      exposure window, which is the whole basis for listing BPA here.
  influences_mechanisms:
  - target: Placental Anti-Angiogenic Factor Release
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      BPA tracked with higher circulating sFlt-1 and a higher sFlt-1 to PlGF
      ratio across gestation in the same cohort that produced its preeclampsia
      hazard ratio, which puts the exposure and this node in the same population
      rather than in two unrelated studies. It is still an association between a
      urinary exposure biomarker and a plasma factor, with no placental step
      measured.
    evidence:
    - reference: PMID:25913709
      reference_title: Phthalate metabolites and bisphenol-A in association with circulating angiogenic biomarkers across pregnancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "BPA, however, was associated with increased sFlt-1 as well as the sFlt-1 to PlGF ratio in both crude and adjusted models."
      explanation: >-
        Associates BPA exposure with the anti-angiogenic shift this node names,
        which is the mechanism-level claim the hazard-ratio paper cannot make.
- name: Micro- and nanoplastic particle exposure
  exposure_term:
    preferred_term: exposure to microplastic particle
    term:
      id: ECTO:7000061
      label: exposure to microplastic particle
  description: >-
    Polystyrene microplastics reproduce a preeclampsia-like syndrome in pregnant
    rats - hypertension, proteinuria, and shifted angiogenic factor expression -
    through a defined trophoblast mechanism. There is no human counterpart: no
    study has related the plastic burden measurable in human placentas to
    preeclampsia risk, so this exposure rests entirely on a rodent model at
    experimental doses. Listed because the mechanism it names, ferroptotic
    trophoblast injury upstream of failed spiral artery remodeling, is testable
    in human tissue and would matter if it held; see the human-model mismatch
    discussion.
  evidence:
  - reference: PMID:40414414
    reference_title: Microplastic exposure induces preeclampsia-like symptoms via HIF-1α/TFRC-mediated ferroptosis in placental trophoblast cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pregnant rats were exposed to PS-MP, which induced PE-like symptoms including elevated blood pressure, increased proteinuria, and altered expression of angiogenic factors."
    explanation: >-
      Establishes that the exposure produces the maternal syndrome in an animal
      model, which is the only outcome evidence this entry has.
  influences_mechanisms:
  - target: Defective Trophoblast Invasion and Spiral Artery Remodeling
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The rodent chain runs from particle exposure through HIF-1alpha/TFRC
      activation to iron overload, oxidative stress and trophoblast ferroptosis,
      and lands on impaired trophoblast migration, invasion and angiogenesis -
      this node's content. Ferroptosis inhibition rescues those defects, which is
      what makes the intermediates known rather than assumed. The species and
      dose gap to human exposure is unaddressed.
    evidence:
    - reference: PMID:40414414
      reference_title: Microplastic exposure induces preeclampsia-like symptoms via HIF-1α/TFRC-mediated ferroptosis in placental trophoblast cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "PS-MP triggered ferroptosis in placental trophoblast cells by activating the HIF-1α/TFRC axis, resulting in iron overload and oxidative stress"
      explanation: >-
        Names the intermediate steps that make this an indirect edge with known
        mechanism rather than an unexplained association.
    - reference: PMID:40414414
      reference_title: Microplastic exposure induces preeclampsia-like symptoms via HIF-1α/TFRC-mediated ferroptosis in placental trophoblast cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "PS-MP exposure impaired trophoblast migration, invasion, and angiogenesis; these effects were ameliorated by ferroptosis inhibition"
      explanation: >-
        The rescue arm: blocking the proposed intermediate restores the trophoblast
        behaviour this node describes, tying the exposure to the node causally
        within the model.
treatments:
- name: Delivery
  description: >
    Delivery of the fetus and placenta is the only definitive treatment for
    preeclampsia. Timing depends on gestational age and severity, balancing
    maternal risk against fetal prematurity. Generally recommended at 37 weeks
    for preeclampsia without severe features, and earlier if severe features
    or maternal/fetal deterioration occurs.
  treatment_term:
    preferred_term: labor induction
    term:
      id: NCIT:C92814
      label: Induction of Labor
  evidence:
  - reference: PMID:30792480
    reference_title: "Pre-eclampsia: pathogenesis, novel diagnostics and therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered."
    explanation: Identifies delivery as the necessary intervention to prevent progression.
- name: Low-dose aspirin prophylaxis
  description: >
    Low-dose aspirin (150 mg daily) initiated at 11-14 weeks of gestation
    in women identified as high risk reduces the incidence of preterm
    preeclampsia by approximately 62%. This is a preventive intervention,
    not a treatment for established disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetylsalicylic acid
      term:
        id: CHEBI:15365
        label: acetylsalicylic acid
  evidence:
  - reference: PMID:28657417
    reference_title: "Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004)."
    explanation: The ASPRE trial demonstrated a 62% reduction in preterm preeclampsia with aspirin 150 mg daily.
  - reference: PMID:37891152
    reference_title: "[Preeclampsia: Guidelines for clinical practice from the French College of Obstetricians and Gynecologists]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In women with a history of vasculo-placental disease, low dose of aspirin (Strong recommendation, Quality of the evidence moderate) at a dosage of 100-160mg per day (Weak recommendation, Quality of the evidence low)"
    explanation: The French College of Obstetricians and Gynecologists clinical practice guidelines make a Strong recommendation for low-dose aspirin in women with a history of vasculo-placental disease; the specific 100-160 mg per day dosage is graded only a Weak recommendation.
  target_mechanisms:
  - target: Platelet Activation and NET-Amplified Thrombus Propagation
    treatment_effect: INHIBITS
    description: >-
      Irreversible inhibition of platelet cyclooxygenase-1 reduces thromboxane
      A2 production, which is the platelet-activation limb of immunothrombosis.
      This is prophylaxis rather than treatment of established disease, so the
      edge describes what aspirin acts on, not a reversal of established
      thrombosis.
    evidence:
    - reference: PMID:42381215
      reference_title: "The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Its primary mechanism involves irreversible inhibition of platelet cyclooxygenase‐1, leading to reduced thromboxane A2 production and a shift toward a vasodilatory and antithrombotic state."
      explanation: >-
        Names the platelet target that makes this an inhibitory edge onto the
        platelet-activation node rather than onto the coagulation cascade.
- name: Magnesium sulfate for seizure prevention
  description: >
    Magnesium sulfate is the first-line agent for prevention and treatment
    of eclamptic seizures. It halves the risk of eclampsia in women with
    preeclampsia and probably reduces maternal mortality.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: magnesium sulfate
      term:
        id: CHEBI:32599
        label: magnesium sulfate
  evidence:
  - reference: PMID:12057549
    reference_title: "Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Women allocated magnesium sulphate had a 58% lower risk of eclampsia (95% CI 40-71) than those allocated placebo (40, 0.8%, vs 96, 1.9%; 11 fewer women with eclampsia per 1000 women)."
    explanation: The Magpie trial demonstrated that magnesium sulfate halves eclampsia risk.
- name: Antihypertensive therapy (labetalol)
  description: >
    Labetalol is a first-line antihypertensive for acute blood pressure
    management in severe preeclampsia, used to prevent hypertensive emergencies
    and stroke.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: labetalol
      term:
        id: CHEBI:6343
        label: labetalol
  evidence:
  - reference: PMID:39247143
    reference_title: "A Comparative Study of Oral Nifedipine and Intravenous Labetalol for Acute Hypertensive Management in Pregnancy: Assessing Feto-Maternal Outcomes in a Hospital-based Randomized Control Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nifedipine (C17H18N2O6), labetalol (C19H24N2O3), and hydralazine (C8H8N4) are commonly used drugs, and all are recommended as first-line agents."
    explanation: Identifies labetalol as a recommended first-line agent for acute hypertensive management in pregnancy.
- name: Antihypertensive therapy (nifedipine)
  description: >
    Nifedipine is an alternative first-line oral antihypertensive for acute
    severe hypertension in preeclampsia.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nifedipine
      term:
        id: CHEBI:7565
        label: nifedipine
  evidence:
  - reference: PMID:39247143
    reference_title: "A Comparative Study of Oral Nifedipine and Intravenous Labetalol for Acute Hypertensive Management in Pregnancy: Assessing Feto-Maternal Outcomes in a Hospital-based Randomized Control Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "oral nifedipine has been proposed as a first-line alternative to intravenous labetalol."
    explanation: Identifies nifedipine as a first-line alternative antihypertensive for severe preeclampsia.
discussions:
- discussion_id: preeclampsia_upstream_trigger_heterogeneity
  prompt: >
    Which upstream trigger best explains each presentation of preeclampsia:
    decidual immune maladaptation, abnormal placentation, placental stress,
    complement/inflammatory injury, or maternal vascular susceptibility?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Immune Maladaptation at Maternal-Fetal Interface
  - pathophysiology#Defective Trophoblast Invasion and Spiral Artery Remodeling
  - pathophysiology#Placental Anti-Angiogenic Factor Release
  - pathophysiology#Maternal Vascular Susceptibility Threshold
  rationale: >
    The antiangiogenic endothelial dysfunction pathway is comparatively well
    supported, but the initiating biology is heterogeneous. Resolving whether
    early-onset and late-onset preeclampsia are dominated by distinct upstream
    triggers would improve subtype-specific biomarker interpretation,
    preventive trial design, and organ-risk prediction.
  notes: >-
    Added for monarch-initiative/dismech issue 3667. The OpenScientist
    hypothesis deep-research report for
    early_onset_placenta_dominant is available at
    kb/hypotheses/Preeclampsia/early_onset_placenta_dominant/openscientist.md;
    treat report-specific citation suggestions as literature leads requiring
    independent PMID and snippet verification before adding new evidence.
- discussion_id: preeclampsia_microplastic_human_evidence_gap
  prompt: >-
    Does micro- and nanoplastic exposure contribute to human preeclampsia, or is
    the HIF-1alpha/TFRC trophoblast ferroptosis mechanism a property of the rat
    model that produced it?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Defective Trophoblast Invasion and Spiral Artery Remodeling
  - environmental#Micro- and nanoplastic particle exposure
  rationale: >-
    Every element of the microplastic-preeclampsia claim except the human
    endpoint is in place. Plastic particles are demonstrably present in human
    placental tissue; a rodent model reproduces the maternal syndrome and names
    an interventionally supported trophoblast mechanism. What no study has done
    is relate measured placental or maternal plastic burden to preeclampsia in
    people, and a 2024 systematic review found the human outcome literature
    essentially empty. The exposure is therefore modelled here with an explicit
    species caveat rather than as an established contributor. Note the two
    entries for plastic-derived chemistry in this file sit on opposite footings:
    the phthalate and bisphenol A entries have human risk estimates but no
    mechanism, while this one has a mechanism but no human endpoint. Neither gap
    is filled by the other.
  proposed_experiments:
  - experiment_id: preeclampsia_placental_polymer_burden_case_control
    name: Placental polymer burden and ferroptosis markers in preeclamptic versus normotensive placentas
    description: >-
      Quantify polymer burden by pyrolysis GC-MS in placentas from preeclamptic
      and normotensive pregnancies matched for gestational age and delivery mode,
      paired with the TFRC, iron-handling and lipid-peroxidation readouts the rat
      model identifies. Matching on gestational age matters because preeclamptic
      delivery is earlier, and burden may simply track exposure duration.
    would_support:
    - pathophysiology#Defective Trophoblast Invasion and Spiral Artery Remodeling
    supporting_outcome:
    - >-
      Higher polymer burden in preeclamptic placentas, accompanied by the
      predicted TFRC and lipid-peroxidation shift, in gestational-age-matched
      comparisons.
    refuting_outcome:
    - >-
      No burden difference after matching, or a burden difference without the
      predicted ferroptotic markers, which would place the rat mechanism outside
      human disease.
  evidence:
  - reference: PMID:38287142
    reference_title: "Exposure to microplastics and human reproductive outcomes: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cell culture and animal studies have demonstrated potential reproductive toxicity of these particles; however, their association with adverse fertility or pregnancy outcomes in humans is not known."
    explanation: >-
      A systematic review stating the human outcome evidence is absent, which is
      precisely the mismatch this discussion records.
  - reference: PMID:40414414
    reference_title: Microplastic exposure induces preeclampsia-like symptoms via HIF-1α/TFRC-mediated ferroptosis in placental trophoblast cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings identified PS-MP-induced ferroptosis as a critical mechanism underlying placental dysfunction, highlighting PS-MP as a potential environmental risk factor for PE."
    explanation: >-
      The model-side claim, stated by its authors as potential rather than
      established, which is the half of the picture that does exist.
- discussion_id: preeclampsia_sflt1_removal_interventional_gap
  prompt: >-
    Does removing circulating sFlt-1 improve early-onset preeclampsia because
    sFlt-1 was removed, or do the apheresis modalities that prolong pregnancy
    work through something else?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Placental Anti-Angiogenic Factor Release
  - pathophysiology#Maternal Endothelial Dysfunction
  - mechanistic_hypotheses#early_onset_placenta_dominant
  rationale: >-
    Interventional reversibility is the strongest argument that sFlt-1 excess is
    causal rather than reactive, and it is the argument this entry's canonical
    hypothesis leans on hardest. The evidence for it is thinner than it is
    usually presented. One pilot series of eight women showed that dextran
    sulfate cellulose apheresis lowers sFlt-1 dose-dependently, reduces
    proteinuria, stabilises blood pressure, and prolongs pregnancy by 15 to 23
    days, but it is uncontrolled and its own authors call for further studies.
    The second apheresis study, using heparin-mediated extracorporeal LDL
    precipitation, prolonged pregnancy against historic controls yet did not
    lower sFlt-1 below baseline and left the sFlt-1/PlGF ratio unaffected, so
    its authors concluded that lipid lowering or undefined factors mattered more
    than sFlt-1 reduction. Read together, the two studies establish that
    apheresis helps and leave open whether sFlt-1 removal is why. No Phase III
    trial of a targeted sFlt-1 reduction has been completed. This matters for
    the entry because it sets how much causal weight the antiangiogenic node can
    carry, and because a therapy chosen on the strength of the wrong mechanism
    would be optimised against the wrong endpoint.
  notes: >-
    Recorded from the 2026 assessment of the OpenScientist hypothesis report in
    kb/hypotheses/Preeclampsia/early_onset_placenta_dominant/. The report cited
    both apheresis studies as convergent support for sFlt-1 removal and stated
    that a systematic search found no failed sFlt-1-targeted therapy trials; the
    second of its own citations is the counterexample.
  proposed_experiments:
  - experiment_id: preeclampsia_targeted_sflt1_reduction_rct
    experiment_design: INTERVENTIONAL_TRIAL
    name: Randomised trial of a selective sFlt-1-lowering intervention with paired angiogenic and lipid monitoring
    description: >-
      Randomise women with early-onset preeclampsia and a high sFlt-1/PlGF ratio
      to a selective sFlt-1-lowering intervention or to standard care, with
      time from randomisation to delivery as the primary outcome. The
      discriminating feature is the monitoring, not the endpoint: measure
      sFlt-1, free PlGF, the ratio, and the lipid fractions that the
      heparin-mediated apheresis study implicated, so that any prolongation can
      be attributed to the analyte that actually moved. A trial that reports
      only the clinical outcome would reproduce the present ambiguity.
    would_support:
    - pathophysiology#Placental Anti-Angiogenic Factor Release
    - mechanistic_hypotheses#early_onset_placenta_dominant
    supporting_outcome:
    - >-
      Pregnancy prolongation that tracks the fall in circulating sFlt-1 and in
      the sFlt-1/PlGF ratio, without a comparable change in the lipid fractions.
    refuting_outcome:
    - >-
      Prolongation without a sustained fall in sFlt-1, or prolongation that
      tracks lipid change instead, which would place the benefit of apheresis
      outside the antiangiogenic mechanism this entry models.
  evidence:
  - reference: PMID:21810665
    reference_title: "Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus."
    explanation: The positive half of the interventional argument, in which the analyte fell and the syndrome improved together.
  - reference: PMID:21810665
    reference_title: "Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting."
    explanation: >-
      The authors' own scoping of what an uncontrolled series of eight women
      establishes, which is that sFlt-1 can be lowered and not yet that lowering
      it prolongs pregnancy.
  - reference: PMID:29858106
    reference_title: "Treatment of very preterm preeclampsia via heparin-mediated extracorporeal LDL-precipitation (H.E.L.P.) apheresis: The Freiburg preeclampsia H.E.L.P.-Apheresis study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although H.E.L.P.-apheresis induced a transient peak baseline levels did not change and rather stabilized sFlt-1 levels at pre-apheresis levels throughout treatments, with sFlt-1/PLGF ratio remaining unaffected."
    explanation: >-
      Dissociates the clinical benefit of apheresis from sFlt-1 removal. This
      study prolonged pregnancy while leaving the analyte and the ratio
      unchanged, which is why it cannot be counted as interventional support for
      the antiangiogenic mechanism.
  - reference: PMID:29858106
    reference_title: "Treatment of very preterm preeclampsia via heparin-mediated extracorporeal LDL-precipitation (H.E.L.P.) apheresis: The Freiburg preeclampsia H.E.L.P.-Apheresis study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, without changing sFlt-1 levels below baseline lowering lipids or other yet undefined factors appear to be of more relevance than reducing sFlt-1."
    explanation: The authors' explicit alternative attribution, naming lipid lowering or unidentified factors ahead of sFlt-1 reduction.
  - reference: PMID:22103497
    reference_title: "Is inflammation the cause of pre-eclampsia?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, as the removal of circulating sFlt-1 (soluble Fms-like tyrosine kinase receptor-1) from pre-eclamptic patients significantly improves the clinical outcome, it fulfils the Hill's experiment principle"
    explanation: >-
      The review-level claim that the reversibility criterion is already
      satisfied. It is included because it is the position this gap qualifies:
      the criterion is asserted at review level on the strength of the pilot
      series alone.
- discussion_id: preeclampsia_complement_independence_in_hellp
  prompt: >-
    Is complement activation in HELLP syndrome an effector pathway independent
    of the antiangiogenic shift, or is it downstream of it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Hepatic Sinusoidal Obstruction and HELLP
  - pathophysiology#Maternal Endothelial Dysfunction
  - mechanistic_hypotheses#early_onset_placenta_dominant
  rationale: >-
    This entry models HELLP as a liver-specific amplification of the systemic
    endothelial injury caused by the antiangiogenic shift, and the canonical
    hypothesis claims HELLP among the subtypes it explains. Complement is the
    main candidate for a branch that would sit outside that account. The
    activation itself is not in doubt: a systematic review of 41 studies reports
    consistent consumption of C3, C4 and factor H alongside raised C4d, Bb,
    factor D, C3a, C5a and C5b-9 in preeclampsia. What is unresolved is
    dependence. The only interventional evidence is a single case in which C5
    inhibition normalised laboratory parameters and prolonged pregnancy by 17
    days, and that report measured no angiogenic factors at all, so it cannot
    show that the benefit was independent of sFlt-1. Resolving this decides
    whether complement inhibition belongs alongside or instead of antiangiogenic
    approaches in HELLP, and whether this entry needs a separate complement
    branch rather than a note.
  notes: >-
    Recorded from the 2026 assessment of the OpenScientist hypothesis report in
    kb/hypotheses/Preeclampsia/early_onset_placenta_dominant/. The report graded
    the claim SPECULATIVE in its own classification table but described it in
    its evidence matrix as improvement independent of sFlt-1, which the case
    report does not establish. The systematic review also warns that complement
    measurements across this literature suffer from a lack of experimental
    uniformity and biased cohort selection, so the biomarker signal should not
    be read as a settled quantitative baseline either.
  proposed_experiments:
  - experiment_id: preeclampsia_hellp_complement_inhibition_with_angiogenic_monitoring
    name: Complement inhibition in HELLP with serial complement and angiogenic monitoring
    description: >-
      Treat HELLP syndrome with C5 inhibition against standard care, measuring
      C3a, C5a and sC5b-9 alongside sFlt-1, free PlGF and their ratio on the
      same schedule. The design point is that both pathways are tracked in the
      same patients, so a clinical response can be assigned to one of them
      rather than inferred. The existing case report failed precisely here: it
      recorded the clinical result and no angiogenic measurement.
    would_support:
    - pathophysiology#Hepatic Sinusoidal Obstruction and HELLP
    supporting_outcome:
    - >-
      Clinical and laboratory improvement following complement inhibition while
      sFlt-1 and the sFlt-1/PlGF ratio remain unchanged, which would establish
      a complement branch acting in parallel to the antiangiogenic shift.
    refuting_outcome:
    - >-
      Improvement accompanied by a fall in sFlt-1, or no improvement despite
      complement blockade, either of which would keep complement activation
      downstream of the antiangiogenic mechanism this entry already models.
  evidence:
  - reference: PMID:38983853
    reference_title: "Systematic review of the complement components as potential biomarkers of pre-eclampsia: pitfalls and opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Retrieved results consistently reported C4, C3, and factor H reduction, and increased circulating levels of C4d, Bb, factor D, C3a, C5a, and C5b-9 in PE compared to normal pregnancies, depicting an overall scenario of excessive C activation and aberrant C regulation."
    explanation: >-
      Establishes that complement activation is a consistent finding in
      preeclampsia across 41 studies, which is what makes the independence
      question worth asking rather than dismissing.
  - reference: PMID:38983853
    reference_title: "Systematic review of the complement components as potential biomarkers of pre-eclampsia: pitfalls and opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, we also discussed emerging pitfalls in C analysis, mainly due to a lack of experimental uniformity and biased cohort selection among different studies and laboratories"
    explanation: >-
      The same review's caveat on its own evidence base, which is why the
      complement signal is recorded here as an open question rather than as a
      curated mechanism node.
  - reference: PMID:23228435
    reference_title: "Eculizumab for the treatment of preeclampsia/HELLP syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient presenting with severe preeclampsia/HELLP syndrome at 26 weeks gestation that was treated with Eculizumab, a targeted inhibitor of complement protein C5, which resulted in marked clinical improvement and complete normalization of lab parameters."
    explanation: >-
      The whole of the interventional evidence, which is one patient. No
      angiogenic factors were measured, so the case cannot separate a complement
      effect from an antiangiogenic one.
  - reference: PMID:23228435
    reference_title: "Eculizumab for the treatment of preeclampsia/HELLP syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Successful use of Eculizumab in this case suggests that complement inhibition may be an effective treatment strategy for severe preeclampsia/HELLP syndrome."
    explanation: >-
      The authors' own hedged conclusion, which claims a possible treatment
      strategy and not an independent pathway.
- discussion_id: preeclampsia_gdf15_pathogenic_or_compensatory_gap
  prompt: >-
    Is circulating GDF-15 elevation in preeclampsia a pathogenic driver of the
    disease, or a compensatory response to placental stress?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Placental Anti-Angiogenic Factor Release
  - pathophysiology#Maternal Endothelial Dysfunction
  rationale: >-
    GDF-15 is highly expressed in the placenta and rises in the maternal
    circulation through gestation, and it is elevated in affected women,
    particularly in early-onset disease. Whether that elevation drives the
    placental and endothelial injury or reflects an adaptive response to it
    determines whether GDF-15 belongs in this entry as a pathophysiology node
    or only as a biomarker, and how it relates to the angiogenic pathway
    already modelled here.
  notes: >-
    Added for monarch-initiative/dismech issue 13414. The source is a review,
    so the quoted sentence is the review's own statement of an open question,
    not a primary finding. No node is added for GDF-15 until a primary study
    addresses the direction of the association.
  evidence:
  - reference: PMID:42803395
    reference_title: "Progress of GDF-15 in preeclampsia: a review."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "key unresolved questions are identified, including whether GDF-15 elevation is pathogenic or compensatory"
    explanation: >-
      The review's own statement that the direction of the GDF-15 association
      is unresolved, which is the gap this discussion records.
datasets:
- accession: geo:GSE324111
  title: Vascular endothelial growth factor receptors 1 and 3 mediate placental trophoblast leptin production in preeclampsia, inducing vascular dysfunction
  description: Heightened soluble FMS-like tyrosine kinase-1 (sFlt-1) level is a hallmark of preeclampsia patients and induces a state of angiogenic imbalance by sequestering free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). The receptors for VEGF and PlGF, membrane-bound VEGFR, are expressed in placental trophoblast cells, but their functions in this cell type are largely unknown. Placenta production of leptin significantly increases in preeclampsia, and we recently showed leptin induces placental and vascular endothelial dysfunction in pregnancy. We hypothesized that inappropriately high sFlt-1 in preeclampsia leads to an increase in trophoblast leptin production.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:42422950
  notes: Identified by GEO DataSets index search for Preeclampsia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE309563
  title: Differences in miRNAs profile in pregnant women with preeclampsia compared with healthy pregnant women
  description: Individualized outcome prediction classifiers were successfully constructed through expression profiling of a total of 800 human miRNAs in serum samples of 12 pregnant women (4 samples from severe preeclampsia pregnancies, 4 samples from mild preeclampsia pregnancies and 4 samples from healthy pregnancies)
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 12
  publication: PMID:42135755
  notes: Identified by GEO DataSets index search for Preeclampsia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE303840
  title: Racial discrepancies in placental gene expressions between Black and White healthy and preeclampsia patients of equivalent BMI and blood pressure in a Southeastern USA cohort
  description: Preeclampsia is a devastating hypertensive disorder of pregnancy that afflicts between 5-10% of pregnancies in the US, with a higher prevalence in the southern regions of the United States. Black pregnant women are disproportionally at higher risk for preeclampsia onset and severity of disease than other racial groups, including White women. Although this has been recognized in the maternal fetal medicine literature for many years, the underlying mechanism(s) for this racial disparity are unclear. One confounding issue with many studies of racial discrepancies in pregnant women is differences in comorbidities between racial groups.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 24
  notes: Identified by GEO DataSets index search for Preeclampsia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001000416
  title: 'Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Uzbeks (DNA samples from the Institute of Immunology, Uzbek Academy of Sciences, Tashkent, Uzbekistan; Republic Specialized Scientific Practical Medical Centre of Obstetrics and Gynecology, Tashkent, Uzbekistan)'
  description: Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:33239696
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Preeclampsia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001000417
  title: 'Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Kazakhs (DNA samples from the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan; Gulnara Svyatova, Principal Investigator'
  description: Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:33239696
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Preeclampsia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001001048
  title: 'Preeclampsia InterPregGen Consortium: GWAS meta-analysis summary statistics for European fetal preeclampsia cases versus controls and GWAS genotype data for European fetal preeclampsia cases'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:28628106
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Preeclampsia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST001360
  title: Maternal blood lipidomics associated with severe preeclampsia
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Preeclampsia"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST002151
  title: Integrative Exposomic, Transcriptomic, Epigenomic Analyses of Human Placental Samples Links Understudied Chemicals to Preeclampsia
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Preeclampsia"). Retrieved 2026-08-02.
- accession: massive:MSV000085361
  title: Molecular Signatures of Preeclampsia and Gestational Diabetes Mellitus Utilizing Multi-Omics Analyses, Part 2
  description: The application of multi-omic evaluations, multi-dimensional analysis methods, and new cheminformatics-based visualization tools to provide an in depth understanding of the molecular changes taking place in preeclampsia (PRE) and gestational diabetes mellitus (GDM) patients. Since PRE and GDM are two prevalent pregnancy complications that result in adverse health effects for both the mother and fetus during pregnancy and later in life, a better understanding of each is essential.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Preeclampsia"). Retrieved 2026-08-02.

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References & Deep Research

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Research Summary: Preeclampsia (MONDO:0005081) ▸

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)

Phenotype	HP term	Notes
Hypertension	`HP:0000822`	Core diagnostic criterion
Proteinuria	`HP:0000093`	Common but not required
Edema	`HP:0000969` (peripheral)	Classic but removed from criteria
Thrombocytopenia	`HP:0001873`	HELLP; <100K/µL is threshold
Elevated hepatic transaminases	`HP:0002910`	HELLP component
Seizures	`HP:0001250`	Defines eclampsia
Headache	`HP:0002315`	New-onset, unresponsive to medication
Intrauterine growth retardation	`HP:0001511`	Fetal consequence
Renal insufficiency	`HP:0000083`	Cr >1.1 mg/dL
Visual impairment	`HP:0000505`	Scotomata, blurred vision
Hemolysis	`HP:0001878`	HELLP — microangiopathic
Pulmonary edema	`HP:0100598`	Severe feature
Abnormal platelet morphology	—	see thrombocytopenia
Placental abruption	`HP:0011410` — verify	Obstetric complication

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

Treatment	Term	Notes
Low-dose aspirin (prevention)	MAXO:0000058 + CHEBI:29177 (aspirin)	USPSTF Grade B; 81 mg/day from 12–28 wks
Magnesium sulfate (seizure prophylaxis)	MAXO:0000058 + CHEBI:32006 (verify)	Reduces eclampsia 58%; IV loading dose
Labetalol (BP control)	MAXO:0000058 + CHEBI:6522 (labetalol — verify)	First-line IV acute
Nifedipine (BP control)	MAXO:0000058 + CHEBI:7565 (nifedipine — verify)	Oral; first-line
Hydralazine	MAXO:0000058 + CHEBI:5757 (hydralazine — verify)	IV acute management
Delivery	MAXO:0000004 (surgical procedure) or MAXO:0001187	Definitive treatment
Calcium supplementation (prevention)	MAXO:0000088 (dietary intervention)	Effective in low-calcium populations
Corticosteroids (fetal lung maturation)	MAXO:0000647 + CHEBI:16723 (betamethasone — verify)	If < 34 wks gestation

Key Evidence References (Verified PMIDs)

The following PMIDs were confirmed by direct abstract retrieval:

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

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References & Deep Research

Deep Research

Research Summary: Preeclampsia (MONDO:0005081)

Disease Overview

Pathophysiology: The Two-Stage Model

Pathophysiology Nodes (Suggested Structure)

Node 1: Defective Trophoblast Invasion and Spiral Artery Remodeling

Node 2: Placental Oxidative Stress and sFlt-1 Overproduction

Node 3: Maternal Endothelial Dysfunction and Multi-Organ Injury

Clinical Phenotypes (Suggested HPO Terms)

Subtypes

Treatments

Key Evidence References (Verified PMIDs)

Orphanet / Structured Sources

Suggested Module Conformance

Long-term Consequences (for progression or outcomes section)

Long-term Consequences (for `progression` or `outcomes` section)