What is the etiology of preeclampsia?

Etiology of Preeclampsia

Primary Pathophysiologic Mechanism

Preeclampsia is fundamentally a two-stage disease initiated by abnormal placentation with shallow cytotrophoblast invasion of maternal spiral arteries, leading to placental ischemia that triggers release of anti-angiogenic factors into maternal circulation, causing systemic endothelial dysfunction. 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:

• In normal pregnancy, cytotrophoblasts deeply invade the maternal spiral arteries, transforming them into significantly distended, low-resistance vessels that extend into the inner third of the myometrium 2
• In preeclampsia, this remodeling is severely impaired, with trophoblastic invasion remaining shallow and confined to the decidual layer 2
• This failed remodeling results in reduced placental perfusion and placental ischemia, creating a persistent high-resistance, high-impedance circulation 2
• The placenta is the key component, as evidenced by the disease occurring even in hydatidiform mole (where no fetus is present) and the fact that delivery of the placenta is the only definitive cure 1

Stage 2: Maternal Syndrome

The ischemic placenta releases pathogenic factors that induce widespread maternal vascular dysfunction 1:

Angiogenic Imbalance

Excess soluble Flt-1 (sFlt-1) produced by the stressed placenta is the central mediator 3, 1:

• sFlt-1 antagonizes vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), creating a deficiency of these pro-angiogenic factors 3, 1
• VEGF normally promotes vasodilation by increasing nitric oxide and prostacyclin production 3
• The resulting angiogenic imbalance is characterized by elevated sFlt-1, reduced PlGF, and elevated soluble endoglin (sEng) 4
• These circulating anti-angiogenic factors cause endothelial dysfunction throughout maternal vasculature 1

Systemic Endothelial Dysfunction

The maternal syndrome manifests as multi-organ endothelial dysfunction 5:

• Systemic inflammation and widespread endothelial damage affect multiple organ systems 5
• Attenuated reductions in systemic vascular resistance and impaired tolerance to plasma volume expansion characterize the hemodynamic profile 2
• Deficient natriuretic peptide signaling contributes to inadequate vascular adaptation 2

Genetic and Immunologic Factors

Genetic Contributions

Both maternal and fetal genes contribute to disease risk, with genetic factors common to both preeclampsia and atherosclerotic disease 1:

• A family history of preeclampsia conveys a relative risk of 2.9 for developing the condition 3
• Having 2 or more first-degree relatives with cardiovascular risk factors doubles the risk (RR 1.9), while having 2 or more first-degree relatives with heart disease or stroke triples the risk (RR 3.2) 3
• The familial nature suggests extensive genetic research is warranted, including candidate gene studies and linkage analysis 6

Immunologic Mechanisms

Paternal antigen exposure plays a significant role in disease pathogenesis 1:

• Preeclampsia is primarily a disease of first pregnancies, with first-time mothers being significantly more susceptible due to new paternal antigen exposure 1
• Multigravidas pregnant by a new partner have intermediate risk between first pregnancies and subsequent pregnancies with the same partner 1
• Various innate and adaptive immune cells have been implicated, including regulatory T cells, macrophages, natural killer cells, neutrophils, and B cells 7
• Abnormal immune system activation, including autoimmune activation of the renin-angiotensin system and complement activation, contributes to pathophysiology 3
• Anti-angiotensin II type 1 receptor autoantibodies have causative roles in the pathology 7

Additional Pathophysiologic Mechanisms

Beyond the primary placental-angiogenic pathway, preeclampsia involves 3:

• Metabolic dysfunction as a contributing mechanism 3
• Oxidative stress associated with activation of maternal inflammatory response 7
• Thrombophilia as an important contributing factor 3

Disease Heterogeneity

Evidence suggests that preeclampsia is a clinical syndrome resulting from multiple different biological pathways 3:

• The disease manifests with clinical heterogeneity (early vs late onset, with vs without severe features, symptomatic vs asymptomatic, progressive vs stable) 3
• Pathophysiological subtypes exist but are not clearly defined or used routinely in clinical practice 3
• The link between underlying biologic mechanism and clinical manifestation is complex and poorly understood 3

Risk Factors Supporting Etiologic Understanding

Key risk factors that illuminate the etiology include 3, 1:

• Extremes of maternal age, particularly age >35 years 3
• Black ethnicity, with Black women showing preponderance in many nations and experiencing disproportionate morbidity and mortality 3, 1
• Nulliparity due to new paternal antigen exposure 1
• Chronic conditions including hypertension, chronic kidney disease, diabetes, obesity, and lupus 3, 8
• Multiple gestation increasing placental demand 3
• Thrombophilia contributing to inadequate placental perfusion 3

Parallels with Atherosclerotic Disease

The pathophysiology involves endothelial dysfunction, suggesting parallels between preeclampsia and atherosclerosis 3:

• Shared risk factors with cardiovascular disease suggest common pathophysiologic mechanisms 1
• Women with preeclampsia have approximately 75% increased risk of cardiovascular-related mortality compared with no history of preeclampsia 3
• This supports the hypothesis that preeclampsia-associated ischemic stroke is a complex disorder mediated in part by genetically determined endotheliopathy and thrombophilia 3

Critical Knowledge Gaps

Despite decades of research, the aetiology of preeclampsia, particularly of term and postpartum pre-eclampsia, remains poorly defined 5:

• The mechanisms underlying term and postpartum preeclampsia are less well understood than preterm preeclampsia 5
• Future research must investigate the pathways that lead to various subtypes of preeclampsia 3
• Inclusion of diverse patient populations is essential, as recent work shows a one-size-fits-all approach is inadequate 3