Women’s health | Pre-eclampsia

Pre-eclampsia develops unpredictably and progresses rapidly to eclampsia, a convulsive condition, if not recognized and the pregnancy is not delivered in time.

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Overview

Pre-eclampsia is a serious disorder that affects approximately 3 to 5 percent of pregnancies worldwide.1 Abnormal placentation plays a central role in the pathophysiology of preterm pre-eclampsia and places the pregnancy at risk for maternal (HELLP syndrome, eclampsia) and fetal (prematurity, stillbirth) complications. Impaired development of the uteroplacental vasculature leads to reduced placental blood flow, placental oxidative stress, and endothelial dysfunction.

The clinical progression of pre-eclampsia:

  • Stage 1 (Primary) – abnormal development/poor placentation
  • Stage 2 (Secondary) – Oxidative stress leading to placental injury
  • Stage 3 (Tertiary) – Fetal growth restriction and/or pre-eclampsia
  • Complications – HELLP syndrome, eclampsia, stillbirth, placental abruption and prematurity

Risk assessment of pre-eclampsia can be challenging. Pre-eclampsia usually occurs after 20 weeks of pregnancy and is defined as hypertension accompanied by either proteinuria or a severe feature (i.e., thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms).2

However, these clinical markers are not specific to pre-eclampsia, and they perform poorly in predicting pre-eclampsia and assessing the risk for deterioration. Assessment can be difficult when pre-pregnancy health is unknown or in the presence of unrelated conditions where the same clinical markers might be affected.

For example, women with medical conditions such as diabetes, hypertension, and renal impairment often present with a complicated clinical picture. Their underlying disease makes the usual assessments (blood pressure, proteinuria, and blood tests) difficult to interpret. When the pregnancy is preterm and especially when the gestational age is below 34 weeks, delivery might not be in the best interest of the fetus and prolonging the pregnancy might lead to deterioration of the maternal condition.

Placental growth factor (PlGF) is expressed in the placenta and is essential for placental angiogenesis and maintenance of the maternal endothelium.3,4 In a healthy pregnancy, PlGF concentration increases until about pregnancy week 30, reflecting placental angiogenesis and a healthy endothelium (see High PlGF bioavailability).5

However, in pregnant women destined to develop preterm pre-eclampsia, an increased expression of an anti-angiogenic factor, soluble fms-like tyrosine kinase-1 (sFlt-1), binds to free PlGF to form a complex, sFlt-1:PlGF, and lowers the concentration of free PlGF in the maternal circulation, reducing its ability to signal through the Flt-1 receptor (see Low PlGF bioavailability).6,7

Reduced bioavailability of PlGF (also known as angiogenic imbalance) leads to widespread maternal uteroplacental and endothelial dysfunction and the clinical manifestations of preterm pre-eclampsia, including vasoconstriction and end-organ injury.8, 9

Prospective longitudinal studies have demonstrated that women who develop pre-eclampsia have decreased circulating levels of bioavailable PlGF several weeks before the onset of clinical signs when compared with pregnant women with a normal outcome.7

PlGF testing helps identify the presence of pre-eclampsia and the risk for pregnancy complications. Measuring PlGF concentration on the Quidel Triage PlGF Test is helpful in anticipating and supporting a clinical diagnosis, assessing disease severity, and the risk for short-term delivery, and predicting adverse outcomes.12-15 PlGF test results fall within one of three discrete risk categories:

  • PIGF <12 pg/mL – Highly abnormal and suggestive of patients with severe placental dysfunction and at increased risk for preterm delivery with pre-eclampsia.
  • PlGF ≥ 12 pg/mL and < 100 pg/mL – Abnormal and suggestive of patients with placental dysfunction and at increased risk for preterm delivery with pre-eclampsia.
  • PlGF ≥ 100 pg/mL – Normal and suggestive of patients without placental dysfunction and unlikely to progress to delivery with pre-eclampsia within 14 days of the test.

Performance characteristics11
PlGF measured in women with a singleton pregnancy and suspected pre-eclampsia after 20 and before 35 weeks of gestation has high accuracy for predicting pre-eclampsia needing delivery within 14 days or preterm.10

PlGF ≥100 pg/mL:
A normal maternal circulating level of PlGF (≥100 pg/mL) is strongly associated with the pregnancy not requiring delivery within 14 days with pre-eclampsia:

  • Sensitivity, 96.0%
  • Negative predictive value, 97.5%
  • Long estimated time to delivery


PlGF <12 pg/mL:
A very low PlGF level (<12 pg/mL) is strongly associated with a need for preterm delivery:

  • Sensitivity, 97.1%
  • Negative predictive value, 94.2%
  • Short estimated time to delivery

  1. Redman CWG, Sargent IL. pre-eclampsia, the Placenta and the Maternal Systemic Inflammatory Response—A Review. Placenta. 2003 Apr;24 Suppl A:S21-7. 
  2. Magee LA, et al. The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens. 2022 Mar;27:148-169.
  3. Maglione D, et al. Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene. 1993;8:925-931. 
  4. Khaliq A, et al. Localisation of placenta growth factor (PIGF) in human term placenta. Growth Factors. 1996;13:243-250. 
  5. Saffer C, Olson G, Boggess KA, Beyerlein R, Eubank C, Sibai BM; NORMALS Study Group. Determination of placental growth factor (PlGF) levels in healthy pregnant women without signs or symptoms of pre-eclampsia. Pregnancy Hypertens. 2013 Apr;3(2):124-132. 
  6. Maynard S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in pre-eclampsia. J Clin Invest. 2003;111: 649-658. 
  7. Levine R, et al. Circulating angiogenic factors and the risk of pre-eclampsia. N Engl J Med. 2004;350:672-683. 
  8. Maynard SE, Karumanchi SA. Angiogenic factors and pre-eclampsia. Semin Nephrol. 2011 Jan;31(1):33-46. 
  9. McMaster MT, Zhou Y, Fisher SJ. Abnormal placentation and the syndrome of pre-eclampsia. Semin Nephrol. 2004;24:540-547. 
  10. Quidel Triage PLGF test Product Insert.
  11. Chappell LC, Shennan AH. Diagnostic accuracy of placental growth factor in women with suspected pre-eclampsia: a prospective multicenter study. Circulation. 2013 Nov 5;128(19):2121-2131. 
  12. Sibiude J, Tsatsaris V. Placental growth factor for the prediction of adverse outcomes in patients with suspected pre-eclampsia or intrauterine growth restriction. PLoS One. 2012;7(11):e50208. 
  13. Parchem JG, Sibai BM; pre-eclampsia Triage by Rapid Assay Trial (PETRA) Investigators. Placental Growth Factor and the Risk of Adverse Neonatal and Maternal Outcomes. Obstet Gynecol. 2020 Mar;135(3):665-673. 
  14. Duckworth S, Chappell LC. Diagnostic Biomarkers in Women With Suspected pre-eclampsia in a Prospective Multicenter Study. Obstet Gynecol. 2016 Aug;128(2):245-252. 
  15. Duhig KE, Chappell LC; PARROT trial group. Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial. Lancet. 2019 May 4;393(10183):1807-1818.

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