B·R·A·H·M·S Biomarkers: Understanding Preeclampsia

What is preeclampsia?

Preeclampsia is a life-threatening hypertensive disorder occurring during pregnancy which affects 3-4% of all pregnancies in the U.S.1 The condition most often occurs after 20 weeks of gestation and can only be cured by delivery of the baby.2 Preeclampsia contributes largely to maternal and fetal mortality and may lead to complications for the mother such as stroke, eclampsia, and organ failure.

 

Preeclampsia can also have negative effects on the fetus and newborn, resulting in complications such as intrauterine growth restriction, low birth weight, and stillbirth. These complications often necessitate early induction of labor or cesarean delivery, leading to preterm birth.

Diagnosis and prognosis

The current standard diagnostic indicator for preeclampsia is the presence of hypertension and protein in the urine (proteinuria). Gestational hypertension is diagnosed when a pregnant woman's blood pressure reaches 140/90 mm Hg or higher on two separate occasions, at least 4 hours apart, after 20 weeks of gestation. This is in a woman with previously normal blood pressure. If the blood pressure readings are even higher (160/110 mm Hg and above), it is considered preeclampsia with severe features.2

 

Pregnant women may also present with other signs and symptoms (headache, shortness of breath, etc.), with or without the presence of proteinuria, that could indicate preeclampsia.2 These patients are often hospitalized to assess the risk of developing severe disease. However, the standard markers may be non-specific to preeclampsia and have limited ability to predict severe disease and adverse outcomes.1 Frequent testing, prolonged hospitalizations, and unclear diagnoses may also cause significant stress to expecting mothers. 

How can biomarkers help improve preeclampsia management?

In recent years, research has demonstrated the potential of two specific angiogenic biomarkers, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), in predicting preeclampsia and its severity.1 These biomarkers, originating from the placenta, show promise because they indicate an imbalance in angiogenesis even before the onset of overt preeclampsia. Furthermore, among individuals who have already developed preeclampsia, an elevated ratio of sFlt-1/PlGF measurement predicts a higher likelihood of progressing to severe disease.3

 

Angiogenic biomarkers offer a way to assess a patient's risk of developing preeclampsia by measuring the body's physiological response to the underlying causes. This is in contrast to current standard diagnostic measures that primarily rely on assessing symptoms, which often manifest after the patient has already developed severe disease. By utilizing these specific markers, we can bridge the gap and avoid potential issues associated with relying solely on standard laboratory tests and maternal symptoms.1,3,4 

Role of biomarkers in the pathophysiology of preeclampsia

While the exact cause of preeclampsia remains unknown, the disease is related to placental dysfunction and associated with an imbalance of angiogenic factors such as sFlt-1 and PlGF.4 

Chart showing an imbalance of pro- and anti-angiogenic factors in pre-eclampsia. In a normal pregnancy, fetal cytotrophoblast cells invade the maternal uterine wall and maternal spiral arteries are remodeled into large vessels with high capacity and low resistance. In a pre-eclamptic pregnancy, there is inadequate circulation between the placenta and uterus. Invasion of cytotrophoblasts is incomplete and maternal spiral arteries fail to be invaded and remodeled.

sFlt-1 is a truncated form of the VEGF receptor Flt-1, circulating freely in the blood. sFlt-1 is produced in the placenta and secreted into the bloodstream, where it binds VEGF and PlGF with high affinity and therefore neutralizes their effects. PlGF belongs to the VEGF family, promoting proliferation and survival of endothelial cells and inducing vascular permeability.4

Diagram illustrating signal transduction of angiogenic and anti-angiogenic factors. When signal transduction is healthy, the angiogenic factors VEGF and PlGF bind the Flt-1 receptor and signal transduction occurs. When PIGF and VEGF bind sFlt-1, this signal is inhibited.

sFlt-1 acts as potent antagonist of PlGF and VEGF by adhering to the receptor-binding domains, thus preventing interactions with endothelial receptors and inducing endothelial dysfunction.4

 

During the first and second trimesters of pregnancy, PlGF levels increase progressively and decrease towards term. In contrast, sFlt-1 levels are stable until weeks 20-24, before they rise steadily until delivery. In women with clinical preeclampsia, sFlt-1 levels are significantly increased while concentrations of circulating free PlGF are significantly decreased.4

Signs and symptoms of preeclampsia

  • Persistent and severe headache that does not subside with medication
  • Visual disturbances such as blurriness and flashing lights
  • Shortness of breath
  • Right-sided abdominal pain
  • Sudden swelling of the face, hands, or feet
  • Nausea, vomiting
  • Sudden weight gain (> 3-5 lb per week)

Note: This is not a comprehensive list or a recommendation of all symptoms of preeclampsia. If you have any of these symptoms, seek medical advice immediately.5

Risk factors for preeclampsia

  • First pregnancy
  • Multifetal gestations
  • Maternal age 35 years or older
  • Pre-pregnancy body mass index greater than 30
  • Assisted reproductive technology
  • Preeclampsia in a previous pregnancy
  • Chronic hypertension
  • Pregestational diabetes
  • Gestational diabetes
  • Systemic lupus erythematosus
  • Antiphospholipid antibody syndrome
  • Kidney disease
  • Obstructive sleep apnea

Note: This is not a comprehensive list or a recommendation of all risk factors that clinicians should use to determine a patient’s risk for preeclampsia. If you have any of these risk factors, seek medical advice.2

References

1. Burwick RM, Rodriguez MH. Angiogenic Biomarkers in Preeclampsia. Obstet Gynecol. 2024 Apr 1;143(4):515-523.

2. Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin Summary, Number 222. Obstetrics and Gynecology. 2020;135(6):1492-    1495.

3. Thadhani R, Lemoine E, Rana S, et al. Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy. NEJM Evid. 2022     Dec;1(12).

4. Levine R et al. Circulating Angiogenic Factors and the Risk of Preeclampsia. NEJM. 2004;350:672-83

5. Magee L et al. Preeclampsia. NEJM. 2022; 386(19):1817-1832

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