Preeclampsia: Causes, Biomarkers, and Why Delivery Cures It

The Leading Cause of Maternal and Fetal Death Worldwide

Preeclampsia complicates 5–8 percent of pregnancies globally and is directly responsible for approximately 76,000 maternal deaths and 500,000 infant deaths each year, according to the Preeclampsia Foundation. In the United States, it is the second leading cause of direct maternal death after hemorrhage, and its incidence has increased by 25 percent since 1987 — driven partly by rising rates of obesity, diabetes, and advanced maternal age. Despite decades of research, delivery of the placenta remains the only definitive cure.

The Placental Ischemia Model

Preeclampsia originates in the placenta — specifically, in the failure of normal trophoblast invasion during the first and second trimesters. In a normal pregnancy, trophoblast cells from the developing placenta invade the spiral arteries of the uterine wall and remodel them from small, high-resistance vessels into large, low-resistance conduits that can sustain the blood flow demands of the growing fetus. In preeclampsia, this remodeling is incomplete. The spiral arteries remain narrow, creating placental ischemia (insufficient blood and oxygen delivery).

The ischemic placenta responds by releasing a cascade of anti-angiogenic factors into maternal circulation — most critically, soluble FMS-like tyrosine kinase-1 (sFlt-1). sFlt-1 is a decoy receptor that binds and inactivates two pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). With VEGF and PlGF neutralized, maternal blood vessels across multiple organ systems — kidney glomeruli, hepatic sinusoids, brain arterioles, placenta — undergo endothelial dysfunction. The result is the syndrome of hypertension, proteinuria, and multi-organ involvement that defines preeclampsia.

sFlt-1/PlGF Ratio: Emerging Biomarker Diagnosis

The sFlt-1/PlGF ratio has emerged as the most specific biomarker for preeclampsia prediction and diagnosis. In normal pregnancy, PlGF levels are high (supporting angiogenesis) and sFlt-1 is low. As preeclampsia develops, PlGF is consumed by excess sFlt-1, and the ratio inverts sharply weeks before clinical symptoms appear.

The PROGNOSIS study (Verlohren et al., NEJM 2016) demonstrated that a ratio below 38 had a negative predictive value of 99.3 percent for ruling out preeclampsia in the following week. This test has been approved in Europe since 2010 and is increasingly available in the U.S. to replace the less specific 24-hour urine protein collection in diagnostic workups.

Diagnostic Criteria

The American College of Obstetricians and Gynecologists (ACOG) 2013 criteria (reaffirmed 2019) define preeclampsia as new-onset hypertension (blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic on two occasions at least four hours apart) after 20 weeks of gestation, plus one or more of the following:

• Proteinuria (≥300 mg in 24-hour urine, protein:creatinine ratio ≥0.3, or urine dipstick ≥2+)
• Thrombocytopenia (platelet count <100,000/µL)
• Renal insufficiency (serum creatinine >1.1 mg/dL or doubling of baseline)
• Impaired liver function (liver enzymes at twice normal; severe right upper quadrant pain)
• Pulmonary edema
• New-onset headache unresponsive to medication, or visual disturbances

HELLP Syndrome

HELLP syndrome — Hemolysis, Elevated Liver enzymes, Low Platelets — occurs in 10–20 percent of preeclampsia cases with severe features and carries maternal mortality of 1–3 percent in high-resource settings. It can present without significant hypertension or proteinuria in 15–20 percent of cases, making it a clinical trap. Diagnosis requires all three components: microangiopathic hemolysis (elevated LDH >600 IU/L, abnormal peripheral smear), elevated AST ≥70 IU/L, and platelets <100,000/µL. Rapid delivery is the definitive treatment; maternal corticosteroids (betamethasone) are given to accelerate fetal lung maturity before 34 weeks.

Aspirin Prevention: 81 mg After 12 Weeks

Low-dose aspirin at 81 mg/day initiated at 12–16 weeks of gestation reduces preeclampsia risk by 24 percent overall and by approximately 62 percent in high-risk women, according to a 2017 NEJM trial (ASPRE, Rolnik et al.) using first-trimester combined screening to identify high-risk women. Aspirin inhibits thromboxane A2 synthesis in platelets — reducing vasoconstriction and platelet aggregation — while largely sparing prostacyclin production in the vascular endothelium, improving the vasoconstriction/vasodilation balance in placental circulation.

Management and the Delivery Imperative

Blood pressure control with labetalol, nifedipine, or hydralazine prevents maternal stroke but does not treat the underlying pathology. Magnesium sulfate, given intrapartum and for 24 hours postpartum, reduces the risk of eclampsia (seizures) by 58 percent and is standard of care for severe preeclampsia. Betamethasone accelerates fetal lung maturity before 34 weeks to reduce neonatal respiratory distress.

Preeclampsia resolves after delivery of the placenta — the source of sFlt-1. Blood pressure and laboratory abnormalities typically normalize within days to weeks postpartum, though some women require antihypertensive treatment for up to 12 weeks. Women with a history of preeclampsia have double the lifetime cardiovascular disease risk, making ongoing cardiovascular monitoring essential.

This article is for informational purposes only. Consult a qualified healthcare professional.