What is the physiopathology of preeclampsia?

Pathophysiology of Preeclampsia

Preeclampsia is a multisystem disorder resulting from abnormal placentation that triggers a cascade of maternal endothelial dysfunction through angiogenic imbalance, immune dysregulation, and oxidative stress. 1

Two-Stage Pathophysiological Model

The pathophysiology of preeclampsia is best understood as a two-stage process: placental abnormalities (Stage 1) followed by maternal systemic response (Stage 2). 1

Stage 1: Abnormal Placentation

The initiating event involves defective trophoblast invasion and inadequate spiral artery remodeling, leading to placental ischemia and hypoxia. 1, 2

• Cytotrophoblast cells fail to properly invade and remodel the maternal spiral arteries during early pregnancy 3
• This incomplete transformation results in high-resistance uteroplacental circulation and reduced placental perfusion 1, 4
• Placental hypoxia and ischemia develop as a consequence of inadequate blood flow 2
• These changes occur early in pregnancy, well before clinical manifestations appear after 20 weeks gestation 3

Stage 2: Maternal Systemic Response

The ischemic placenta releases factors that provoke generalized maternal endothelial dysfunction, manifesting as the clinical syndrome of preeclampsia. 3

Key Pathophysiological Mechanisms

Angiogenic Imbalance

An imbalance between pro-angiogenic and anti-angiogenic factors has emerged as one of the most important pathophysiological mechanisms. 5

• The placenta releases excessive soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) into maternal circulation 1, 2
• These anti-angiogenic factors antagonize vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) 1
• The resulting angiogenic imbalance causes widespread endothelial dysfunction affecting multiple organ systems 2, 5
• This leads to poor organ perfusion characteristic of preeclampsia 1, 4

Immune System Dysregulation

Abnormal immune system activation contributes significantly to the pathophysiology through multiple pathways. 1

• Autoimmune activation of the renin-angiotensin system occurs 1
• Complement system activation is present 1
• Autoantibodies to type-1 angiotensin II receptor have been implicated 5
• Intravascular inflammation develops as part of the systemic response 5

Oxidative Stress and Mitochondrial Dysfunction

Oxidative stress and mitochondrial abnormalities further exacerbate endothelial dysfunction. 1, 2

• Placental hypoxia generates excessive reactive oxygen species 2
• Mitochondrial dysfunction in placental and maternal tissues contributes to cellular stress 2, 6
• Endoplasmic reticulum stress occurs in affected tissues 5
• These processes amplify the inflammatory cascade and endothelial damage 6

Metabolic Dysfunction

Metabolic abnormalities represent an additional pathophysiological pathway that is not mutually exclusive with other mechanisms. 1

Disease Heterogeneity

Preeclampsia is a clinical syndrome resulting from multiple different biological pathways, not a single disease entity. 1

• Clinical heterogeneity is apparent (early versus late onset, with or without severe features, symptomatic versus asymptomatic) 1
• Pathophysiological subtypes exist but are not clearly defined or routinely used in clinical practice 1
• The link between underlying biological mechanisms and clinical manifestations remains complex and poorly understood 1
• Different pathways may predominate in different patients, explaining variable presentations 1

Genetic and Epigenetic Factors

Genetic variations and epigenetic modifications play critical roles in disease susceptibility. 2

• Genome-wide association studies have identified variations in maternal and fetal genomes associated with increased preeclampsia risk 1
• Polymorphisms in the FLT1 gene (encoding sFlt-1) are implicated 2
• Altered microRNA expression affects gene regulation 2
• These factors help explain why some women are more susceptible than others 1

Clinical Implications of Pathophysiology

Understanding the pathophysiology explains the multisystem nature of clinical manifestations. 1

• Endothelial dysfunction causes hypertension through increased vascular resistance 3
• Glomerular endothelial damage (glomeruloendotheliosis) produces proteinuria 5
• Hepatic involvement causes elevated liver enzymes and epigastric pain 1
• Cerebral edema leads to headache, visual disturbances, and seizures 1
• Platelet activation and consumption result in thrombocytopenia 5
• Hemolysis occurs in severe cases (HELLP syndrome) 1

Important Caveats

The severity and timing of angiogenic imbalance, combined with maternal susceptibility, determine clinical presentation. 5

• Angiogenic imbalance is not specific to preeclampsia—it also occurs in intrauterine growth restriction, fetal death, and spontaneous preterm labor 5
• Blood pressure trends before 20 weeks may predict later development of preeclampsia, with women showing blunted decline or increase in systolic BP at higher risk 1
• Deficient natriuretic peptide signaling has been identified as a potential causal risk factor, with lower first-trimester NT-proBNP associated with increased preeclampsia risk 1
• The mechanisms underlying preeclampsia are not fully understood despite significant research advances 1