What is the pathophysiology of preeclampsia in a pregnant woman, particularly one with a history of hypertension or previous pregnancies complicated by preeclampsia?

Pathophysiology of Preeclampsia

Overview

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

Stage 1: Abnormal Placentation

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

• Shallow cytotrophoblast invasion of maternal spiral arteries occurs, preventing the normal transformation of these vessels from high-resistance to low-resistance conduits. 2
• This incomplete vascular remodeling results in high-resistance uteroplacental circulation and reduced placental perfusion. 2
• The inadequate blood flow creates placental hypoxia and ischemia, which becomes the critical trigger for the subsequent maternal syndrome. 2
• Importantly, this implantation defect is not unique to preeclampsia—it also occurs in intrauterine growth restriction and one-third of spontaneous preterm births, suggesting that placental hypoxia alone is insufficient to cause the maternal syndrome. 3

Stage 2: Maternal Systemic Response

Angiogenic Imbalance

The stressed, hypoxic placenta releases pathogenic factors into maternal circulation:

• Excess soluble Flt-1 (sFlt-1) is the central mediator of angiogenic imbalance. 1
• sFlt-1 acts as a decoy receptor, antagonizing vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), creating a deficiency of these pro-angiogenic factors. 1
• The placenta also releases soluble endoglin (sEng), which further contributes to endothelial dysfunction. 2
• VEGF normally promotes vasodilation by increasing nitric oxide and prostacyclin production; sFlt-1 antagonism reduces these vasodilators, leading to vasoconstriction. 2

Widespread Endothelial Dysfunction

The angiogenic imbalance causes generalized endothelial dysfunction affecting multiple organ systems—this is the unifying pathophysiological mechanism. 3

• Glomeruloendotheliosis is the pathognomonic renal lesion, consisting of glomerular enlargement caused by hypertrophy of endothelial cells—a change seen in no other form of hypertension. 3
• Markers of endothelial activation appear in circulation weeks to months before clinically evident disease, indicating that hypertension does not cause the endothelial injury but rather results from it. 3
• Vessels from preeclamptic women manifest reduced endothelial-mediated relaxation, and plasma from these women can adversely alter endothelial function in vitro. 3

Hemodynamic and Coagulation Changes

Multiple systemic alterations compound the endothelial dysfunction:

• Increased sensitivity to virtually all circulating pressor agents causes vasoconstriction, though endogenous pressor levels are not elevated. 3
• Activation of the coagulation cascade occurs in most preeclamptic women, with larger platelet size indicating increased platelet turnover. 3
• Reduced plasma volume develops due to accelerated loss of protein from the vascular compartment. 3
• Longitudinal studies reveal that abnormal coagulation activation and reduced plasma volume antedate clinically evident preeclampsia. 3
• Attenuated reductions in systemic vascular resistance and impaired tolerance to plasma volume expansion characterize the hemodynamic profile. 1

Multi-Organ Manifestations

The systemic endothelial dysfunction and reduced perfusion affect multiple organs:

• Hepatic involvement: Reduced perfusion causes necrosis and hemorrhage, manifesting as elevated liver enzymes and right upper quadrant/epigastric pain. 3
• Cardiac involvement: Subendocardial necrosis can occur, similar to hypovolemic shock. 3
• Cerebral involvement: Cerebral edema leads to headache, visual disturbances, hyperreflexia, and potential seizures. 2
• Renal involvement: Glomerular endotheliosis causes proteinuria and decreased glomerular filtration rate. 2

Oxidative Stress Hypothesis

Oxidative stress has been proposed as the linkage between the two stages of preeclampsia. 3

• The hypothesis proposes that hypoxia at the fetal-maternal interface generates free radicals that lead to oxidative stress, depending on maternal constitution. 3
• Abundant evidence of oxidative stress exists in blood and tissues of preeclamptic women. 3
• A small study showed that prophylactic antioxidants reduced markers of endothelial activation and decreased preeclampsia frequency in high-risk women, though this requires confirmation in larger trials. 3

Maternal-Fetal Interaction and Risk Factors

Reduced placental perfusion must interact with maternal factors to produce the maternal syndrome. 3

Maternal risk factors that predispose to preeclampsia (notably similar to cardiovascular disease risk factors) include: 3

• Hypertension
• Collagen vascular disease
• Obesity
• Black race
• Insulin resistance
• Diabetes
• Increased circulating testosterone
• Thrombophilias

Additional risk factors include:

• Family history of preeclampsia conveys a relative risk of 2.9. 1
• Extremes of maternal age, particularly age >35 years. 1
• Black ethnicity is associated with higher risk and disproportionate morbidity and mortality. 1

Genetic and Immunologic Factors

• Both maternal and fetal genes contribute to disease risk, with genetic factors common to both preeclampsia and atherosclerotic disease. 1
• Having 2 or more first-degree relatives with cardiovascular risk factors doubles preeclampsia risk; having relatives with heart disease or stroke confers a 3-fold risk. 2
• Autoimmune activation of the renin-angiotensin system occurs, with circulating AT1 receptor autoantibodies present in >95% of women with preeclampsia, correlating with disease severity. 2

Clinical Implications

Timing of Pathophysiological Changes

The pathophysiological changes of preeclampsia are present long before clinical presentation, which explains why all management of overt preeclampsia other than delivery is only palliative. 3

• Deficient natriuretic peptide signaling contributes to inadequate vascular adaptation, with lower first-trimester NT-proBNP associated with increased preeclampsia risk. 1, 2
• Blood pressure trends before 20 weeks may predict later development, with women showing blunted decline or increase in systolic BP at higher risk. 2

Heterogeneity

Preeclampsia is not a single disorder but rather different pathways converging on a common syndromic endpoint. 2

• Clinical heterogeneity includes early versus late onset, with or without severe features, symptomatic versus asymptomatic presentations. 2
• Early-onset preeclampsia (before 34 weeks) is typically associated with abnormal placentation and more severe maternal and fetal outcomes. 2

Relation to Long-Term Cardiovascular Disease

The endothelial dysfunction and vascular changes suggest parallels between preeclampsia and atherosclerosis. 1, 2

• Women with preeclampsia have approximately 75% increased risk of cardiovascular-related mortality compared with those without preeclampsia history. 1, 2
• The shared risk factors and pathophysiological mechanisms suggest that preeclampsia may be a stress test revealing underlying cardiovascular vulnerability. 3

Key Pitfalls and Caveats

• Reduced placental perfusion alone does not explain preeclampsia: Many women with growth-restricted infants do not develop preeclampsia, and some preeclamptic women have large fetuses. 3
• The sequence of causation remains incompletely understood: While the two-stage model is well-supported, the exact mechanisms linking placental ischemia to specific maternal factors remain under investigation. 3
• Multiple competing hypotheses exist: Other postulates include abnormalities in maternal circulatory adaptations, cytokine-mediated endothelial dysfunction, altered autocoid systems, vitamin/mineral deficiencies, infectious agents, and impaired barriers against fetal material importation. 3
• Future successful therapies will require institution before clinically evident disease, given that pathophysiological changes precede clinical manifestations by weeks to months. 3