What are the newest research findings on the causes of preeclampsia?

Current Understanding of Preeclampsia Causes

Preeclampsia is fundamentally a two-stage disease initiated by abnormal placentation and shallow cytotrophoblast invasion of maternal spiral arteries, leading to placental ischemia that triggers release of anti-angiogenic factors (particularly excess sFlt-1) into maternal circulation, causing systemic endothelial dysfunction. 1, 2

Stage 1: Placental Pathology (The Initiating Event)

The primary causative mechanism involves failure of normal spiral artery remodeling during early pregnancy 3:

• In normal pregnancy, spiral arteries undergo extensive remodeling from small muscular vessels into significantly distended, low-resistance channels that lose their smooth muscle and inner elastic lamina layers, with modifications extending into the inner third of the myometrium 3

• In preeclampsia, this remodeling is severely impaired—vessels undergo only superficial modification that never extends beyond the decidual lining, resulting in reduced placental perfusion 3

• The placenta is definitively the key component, as evidenced by preeclampsia occurring in hydatidiform mole (almost exclusively trophoblastic tissue with minimal fetal tissue) and the fact that delivery of the placenta is the only definitive cure 3, 1

Stage 2: Maternal Syndrome (The Systemic Response)

The ischemic placenta releases pathogenic factors that induce widespread maternal vascular dysfunction 3, 1:

Anti-Angiogenic Factor Imbalance

Excess soluble Flt-1 (sFlt-1) produced by the stressed placenta is now recognized as a central mediator 3, 2:

• sFlt-1 antagonizes vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), creating a deficiency of these pro-angiogenic factors 3
• This anti-angiogenic state is responsible for the systemic endothelial dysfunction that characterizes the clinical syndrome 2, 4
• The European Society of Cardiology states these circulating factors cause endothelial dysfunction throughout maternal vasculature, including cerebral vessels 1

Endothelial Dysfunction

Systemic endothelial injury is the common pathway explaining the diverse manifestations 3:

• Glomeruloendotheliosis (endothelial cell hypertrophy in kidney glomeruli) is pathognomonic for preeclampsia and seen in no other form of hypertension 3
• Markers of endothelial activation appear in maternal circulation weeks to months before clinically evident disease 3
• Vessels from preeclamptic women show reduced endothelial-mediated relaxation 3

Genetic and Immunologic Factors

Genetic Susceptibility

Both maternal and fetal genes contribute to disease risk 3:

• Preeclampsia is more common in daughters of preeclamptic women and in pregnancies fathered by sons of preeclamptic women 3
• Genome-wide searches and candidate gene studies have identified function-perturbing polymorphisms, though findings remain inconsistent across populations 3
• The American Heart Association notes that genetic factors common to both preeclampsia and atherosclerotic disease exist, as having 2+ first-degree relatives with heart disease or stroke confers 3-fold increased risk (RR 3.2) 3

Immunologic Mechanisms

Paternal antigen exposure plays a significant role 3, 5:

• Multigravidas pregnant by a new partner have intermediate risk between first pregnancies and subsequent pregnancies with the same partner 3, 5
• Longer periods of intercourse before conception reduce risk, while barrier contraceptives that prevent semen exposure increase risk 3, 5
• Natural killer (NK) cells at the maternal-fetal interface influence placental development and vascular remodeling, with genetic studies suggesting susceptibility is influenced by polymorphic HLA-C ligands and killer cell receptors (KIR) on NK cells 6

Recent research emphasizes the inflammatory component 7:

• Various innate and adaptive immune cells (regulatory T cells, macrophages, NK cells, neutrophils, B cells) have causative roles 7
• Inflammatory cytokines and anti-angiotensin II type 1 receptor autoantibodies contribute to pathogenesis 7
• Oxidative stress activates maternal inflammatory response, leading to insufficient placental perfusion 7

Risk Factors and Epidemiology

Preeclampsia is primarily a disease of first pregnancies and extremes of maternal age 3, 5:

• First-time mothers are significantly more susceptible due to new paternal antigen exposure 5
• When controlled for first pregnancy effect, preeclampsia is actually more common in older women 3
• Black women show preponderance in many nations 3

Shared risk factors with cardiovascular disease suggest common pathophysiologic mechanisms 3:

• Hypertension, collagen vascular disease, obesity, insulin resistance, diabetes, thrombophilias, and increased circulating testosterone 3

Critical Distinction: Reduced Perfusion Alone Is Insufficient

A key insight is that placental ischemia alone does not cause preeclampsia 3:

• Many women with growth-restricted infants (also caused by reduced placental perfusion) do not develop preeclampsia 3
• The implantation defect characteristic of preeclampsia also occurs in one-third of spontaneous preterm births without preeclampsia 3
• Reduced perfusion must interact with maternal genetic, behavioral, or environmental factors to produce the maternal syndrome 3

Heterogeneity of the Syndrome

Preeclampsia represents a spectrum rather than a single disease entity 2, 8:

• Early-onset preeclampsia shares features with atherosclerosis 8
• Late-onset preeclampsia appears to result from metabolic mismatch between fetal demands and maternal supply 8
• This heterogeneity may require different biomarker thresholds or combinations for optimal prediction 2

Clinical Implications

The pathophysiology directly informs prevention and treatment strategies:

• Delivery of the placenta removes the source of circulating pathogenic factors and remains the only definitive treatment 1
• Biomarkers (sFlt-1/PlGF ratio) reflect underlying pathophysiology and can help rule out preeclampsia requiring delivery within 7-14 days in suspected cases between 20-34+6 weeks 2
• Magnesium sulfate prevents seizures by addressing cerebral autoregulation failure secondary to endothelial dysfunction 1