Angiogenic factors for preeclampsia - is there utility in testing?

Inadequate placental development leads to preeclampsia (PE), a pregnancy-related condition associated with increased risks of maternal and neonatal morbidity and mortality (1,2). In the U.S., PE diagnosis relies on new onset of hypertension, proteinuria, or significant organ dysfunction after 20 weeks of pregnancy. Diagnosis is challenging due to symptom overlap with other hypertensive disorders of pregnancy (HDPs) and limited accuracy of current diagnostic methods.

Recent research emphasizes the potential use of the dysregulation of angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), in assessing the risk of PE development and progression (1,2). PE patients typically exhibit elevated sFlt-1 and reduced PlGF concentrations, with identified sFlt-1/PlGF ratio thresholds aiding in the exclusion of PE onset or progression to severe PE features within 1-to-2 weeks (1,2). This potential for more precise risk assessment contributed to the U.S. FDA’s 2023 approval of the adjunctive use of the sFlt-1/PlGF ratio for evaluating PE progression risk within 2 weeks in hospitalized women with singleton pregnancies and HDPs who are between 23 and 37 weeks of gestation.

The sFlt-1/PlGF ratio has primarily been proposed to rule out PE in suspected cases due to its extremely high negative predictive value (1,2). While guidelines for its clinical adoption is limited, the UK’s National Institute for Health and Care Excellence (NICE) supports its use between 20 to 36+6 weeks of gestation to aid in PE diagnosis and risk prediction, with specified thresholds (5). However, the American College of Obstetricians and Gynecologists (ACOG) views its utility more cautiously, emphasizing it as an adjunct rather than a standalone diagnostic tool for PE (4). This is partly because high ratios, while significant, are not diagnostic of severe PE, with continued comprehensive clinical and diagnostic monitoring remaining essential. Additionally, its use in the U.S. is currently restricted to specific populations, and the test currently cannot be used in asymptomatic, nonhospitalized pregnant women with suspected PE. Additional studies are needed to evaluate expanded clinical utility of Sflt-1/PlGF testing in the U.S., possibly outside the FDA’S currently approved intended use.

Employing sFlt-1/PlGF ratio testing, in conjunction with enhanced medical surveillance for patients at high risk of PE, could potentially reduce the rate of PE-related maternal deaths (3). It is anticipated that its use will aid in the early detection of PE, enabling proactive measures and helping differentiate between patients needing hospitalization versus those manageable with home care. However, these biomarkers must be used alongside conventional clinical assessments for medical decision making about PE risks and progression. Additionally, their low positive predictive values limit their utility in ruling in PE (1,4).

In conclusion, the utilization of the sFlt-1/PlGF ratio testing presents a promising advancement in the prediction, risk assessment, and management of PE. However, careful consideration of patient-specific factors and clinical judgment remains crucial in effectively using this test for PE management.

References

1. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, et al. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. New England Journal of Medicine. Massachusetts Medical Society; 2016;374:13–22.
2. Thadhani R, Lemoine E, Rana S, Costantine MM, Calsavara VF, Boggess K, et al. Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy. NEJM Evid. 2022;1:EVIDoa2200161.
3. Shennan AH, Green M, Chappell LC. Maternal deaths in the UK: pre-eclampsia deaths are avoidable. Lancet. 2017;389:582–4.
4. Biomarker prediction of preeclampsia with severe features. Clinical Practice Update. American College of Obstetricians and Gynecologists. Obstet Gynecol 2024.
5. National Institute for Health and Care Excellence (NICE). "PLGF-based testing to help diagnose suspected preterm pre-eclampsia." (2022).