What is the pathophysiology of preeclampsia?

Pathophysiology of Preeclampsia

Overview

Preeclampsia is fundamentally a two-stage disease process: abnormal placentation (Stage 1) leads to placental ischemia, which triggers the release of anti-angiogenic factors into maternal circulation, causing widespread endothelial dysfunction and multi-organ involvement (Stage 2). 1, 2

Stage 1: Abnormal Placentation

The disease begins with failure of normal spiral artery remodeling during early pregnancy, which is the primary causative mechanism. 1

Key Placental Abnormalities

• Shallow cytotrophoblast invasion of maternal spiral arteries occurs, resulting in incomplete transformation of the uteroplacental circulation. 3

• This defective trophoblast invasion creates high-resistance uteroplacental circulation with reduced placental perfusion. 2

• The inadequate spiral artery remodeling leads to placental hypoxia and ischemia, which becomes the critical trigger for subsequent maternal syndrome. 3, 2

• Placental oxidative stress increases as a consequence of reduced placental blood flow. 3

Stage 2: Maternal Systemic Response

Angiogenic Imbalance - The Central Mediator

Excess soluble fms-like tyrosine kinase-1 (sFlt-1) produced by the stressed placenta is the central mediator of the maternal syndrome. 1

• sFlt-1 is a circulating soluble isoform of the VEGF receptor with potent anti-angiogenic properties. 3

• sFlt-1 antagonizes vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), binding these free pro-angiogenic factors and creating a deficiency. 3, 1

• Soluble endoglin (sEng) is also released in excess by the hypoxic placenta, further contributing to anti-angiogenic state. 4, 2

• This imbalance of anti-angiogenic and pro-angiogenic factors directly causes maternal endothelial dysfunction, hypertension, proteinuria, and glomerular endotheliosis. 3

Systemic Endothelial Dysfunction

The angiogenic imbalance leads to widespread endothelial dysfunction affecting multiple organ systems. 2

Vascular Effects:

• Attenuated reductions in systemic vascular resistance and impaired tolerance to plasma volume expansion characterize the hemodynamic profile. 1

• VEGF normally promotes vasodilation by increasing nitric oxide and prostacyclin production; sFlt-1 antagonism reduces these vasodilators. 3

• Increased vasoconstrictors such as endothelin-1 and thromboxane A2 contribute to elevated blood pressure. 5

• Disturbance of cerebral autoregulation may be genetically mediated, particularly in hemorrhagic complications. 3

Renal Manifestations:

• Glomerular endotheliosis develops, causing proteinuria. 3

• Decreased glomerular filtration rate occurs before and at diagnosis. 3

Hepatic Involvement:

• Liver edema and hepatic hemorrhage cause elevated liver enzymes and right upper quadrant/epigastric pain. 2

Cerebral Effects:

• Cerebral edema leads to headache, visual disturbances, and seizures (eclampsia). 2

Hematologic Changes:

• Thrombocytopenia and hemolysis occur in severe cases (HELLP syndrome). 2

Additional Pathophysiological Mechanisms

Renin-Angiotensin-Aldosterone System (RAAS) Dysregulation

• Circulating AT1 receptor autoantibodies are present in >95% of women with preeclampsia and correlate with disease severity. 3

• These antibodies bind to a specific epitope on the second extracellular loop of the AT1 receptor, inducing vasoconstriction, hypertension, and increased coagulation. 3

• AT1R autoantibodies induce placental sFlt-1 production through AT1R activation, creating a vicious cycle. 3

• Women with preeclampsia demonstrate decreased plasma renin activity (PRA) and aldosterone before and at diagnosis. 3

• Deficient natriuretic peptide signaling contributes to inadequate vascular adaptation, with lower first-trimester NT-proBNP associated with increased preeclampsia risk. 2

Oxidative Stress and Inflammation

• Placental ischemia triggers release of reactive oxygen species into maternal circulation. 5

• Inflammatory cytokines are released, contributing to systemic inflammation. 5

• Hypoxia-induced factor-1 is activated in response to placental hypoxia. 5

Immune System Activation

• Abnormal immune system activation occurs, though mechanisms remain incompletely understood. 4

• Cellular and humoral immunological factors play important roles in placental pathophysiology. 6

Genetic and Familial Factors

• A family history of preeclampsia conveys a relative risk of 2.9 for developing the condition. 3, 1

• Having 2 or more first-degree relatives with cardiovascular risk factors doubles preeclampsia risk (RR 1.9). 3

• Having 2 or more first-degree relatives with heart disease or stroke confers a 3-fold risk (RR 3.2). 3

• These data suggest genetic factors common to both preeclampsia and atherosclerotic disease. 3, 1

Clinical Heterogeneity

Preeclampsia is not a single disorder but rather different pathways converging on a common syndromic endpoint. 3

• Early-onset preeclampsia (before 34 weeks) is typically associated with abnormal placentation and more severe maternal and fetal outcomes. 3

• Term preeclampsia is the most common form, responsible for much of maternal and infant mortality, but its pathophysiology is not explained by abnormal placentation and has been largely ignored. 3

• Disease subtypes may include presentations with or without severe features, symptomatic versus asymptomatic variants. 2

Important Clinical Pitfalls

Timing Considerations:

• Pre-pregnancy or early first-trimester changes may be particularly important, as this is when therapy might be most effective. 3

• Blood pressure trends before 20 weeks may predict later development, with women showing blunted decline or increase in systolic BP at higher risk. 2

Bidirectional Relationship:

• The relationship between preeclampsia and placental insufficiency is bidirectional: placental insufficiency may precede maternal hypertensive disorders, while preeclampsia in turn exacerbates placental insufficiency. 3

RAAS Paradox:

• It remains unknown whether RAAS dysregulation is a prerequisite for preeclampsia development or a consequence of angiogenic factor dysregulation. 3

Long-term Cardiovascular Implications

• The endothelial dysfunction and vascular changes suggest parallels between preeclampsia and atherosclerosis. 3, 1

• Women with preeclampsia have approximately 75% increased risk of cardiovascular-related mortality compared with those without preeclampsia history. 1

• Changes in vascular biology associated with preeclampsia may account for increased risk for ischemic stroke after childbearing years. 3