Accurate Diagnosis of Pre-eclampsia

sFLT-1 : PlGF ratio

Placental dysfunction, along with several other factors, is known to contribute to the development of pre-eclampsia — a complex, multisystem hypertensive disorder of pregnancy. The full aetiology of pre-eclampsia remains enigmatic; however, our understanding of the associated complications has driven the development of novel methods of predicting the onset of pre-eclampsia.

One such method is the calculation of the soluble FMS like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) ratio. By quantifying levels of these placental-related angiogenic factors and calculating a ratio, this method provides a useful measure of placental dysfunction.

Like all laboratory tests, the measurement of these analytes requires an appropriate QC procedure, and therefore, a suitable internal quality control. In this article, we’ll look at pre-eclampsia and the associated complications, the s-Flt-1:PlGF ratio and its utility, before finally presenting the Acusera Pre-eclampsia Control [https://www.randox.com/pre-eclampsia-quality-control/?highlight=pre-eclampsia].

Pre-eclampsia

Pre-eclampsia is traditionally defined as new onset hypertension and proteinuria in pregnancy (1), however, the International Federation of Gynaecology and Obstetrics’ (FIGO) clinical definition describes it as sudden onset hypertension (>20 weeks of gestation) and at least one of the following: proteinuria, maternal organ dysfunction, or uteroplacental dysfunction (2).

It is responsible for an estimated 70,000 maternal deaths, and 500,000 foetal deaths globally (3). Pre-eclampsia affects around 4% of pregnancies in the United States and is more common in low-to-middle income countries (LMICs), displaying an overall pooled incidence of 13% in a cohort from sub-Saharan Africa (4). The risk factors for pre-eclampsia are shown in Figure 1.

Pre-eclampsia is associated with increased morbidity and mortality worldwide. In the United States, pre-eclampsia is the foremost cause of maternal death, severe maternal morbidity, maternal intensive care admissions, and premature births. (5)

Traditional classification of pre-eclampsia included early-onset (<34 weeks gestation) and late-onset (>34 weeks gestation). However, this classification lacks clinical utility as they do not accurately illustrate maternal or foetal prognosis. Therefore, the International Society for the study of Hypertension in Pregnancy (ISSHP) and contemporary studies prefer to classify pre-eclampsia as preterm (delivery <37 weeks of gestation), term (delivery ≥37 weeks of gestation) and postpartum pre-eclampsia (after delivery) (Figure 2).

Complications

Acute Maternal Complications

Pre-eclampsia can lead to serious conditions including:

• Eclampsia: Characterised by seizures post 20 weeks of gestation, potentially causing permanent damage or disability (6).
• Stroke: Significantly heightened risk due to weakened blood vessels and clotting disorders (7).
• HELLP Syndrome: A severe liver and blood clotting disorder emerging after 20 weeks of gestation (6).
• Other Neurological Effects: Includes issues like visual disturbances and cerebral complications often occurring postpartum (8).
• Kidney Issues and Pulmonary Oedema: Manifests as proteinuria due to disrupted kidney function and fluid accumulation in the lungs (8).

Acute Neonatal Risks

Children born to mothers with pre-eclampsia may face:

• Growth Restrictions: Resulting in low birth weight and potential developmental delays (9).
• Premature Birth: Leads to risks like respiratory distress syndrome and intensive care needs (6).
• Increased Stillbirth Risk: Notably higher compared to non-pre-eclamptic pregnancies (10).

Long-Term Effects

The impact of pre-eclampsia extends beyond immediate delivery:

• For Mothers: Increased lifetime risk of severe conditions such as renal disease, strokes, and cardiovascular issues (5,9).
• For Offspring: Higher likelihood of developing cardiovascular problems, cognitive issues, and hormonal imbalances (9).

sFlt-1/PlGF ratio

The pathophysiology of pre-eclampsia is complex and enigmatic. However, placental dysfunction is known to be a factor in pre-eclampsia development. The placental-related angiogenic factors, sFlt-1 (anti-angiogenic), and PlGF (pro-angiogenic) have been implicated in this development. This ratio provides a useful measure of placental dysfunction as a sharp increase in sFlt-1 and decrease in PlGF has been shown approximately 5 weeks before onset of pre-eclampsia (11).

Until recently, diagnosis of pre-eclampsia was one of clinical manifestation. However, studies such as PROGNOSIS (12) and PROGNOSIS Asia (13), along with others (14,15), have shown strong utility of this ratio. The PROGNOSIS study showed that a ratio cut-off of ≥38 was useful for ruling out pre-eclampsia within one week with a negative predictive value (NPV) of 99.3% or four weeks with a positive predictive value (PPV) of 36.7% (12). The definitions of pre-eclampsia used by the International Society for the Study of Hypertension in Pregnancy (ICCHP) and the American College of Obstetricians and Gynaecologists (ACOG) have a PPV of around 20%, but when used in combination with the sFlt-1/PlGF ratio, the PPV is enhanced to 65.5% for ruling in pre-eclampsia within four weeks (16).

Similar results have been shown in an Asian cohort in the PROGNOSIS Asia Study. Using the same cut-off value, this study reported an NPV of 98.9% (13). Furthermore, in a sub-analysis of this cohort that looked at Japanese participants, a cut-off of ≥38 displayed an NPV of 100% for ruling out pre-eclampsia within one week and a PPV of 32.4% for ruling in within four weeks (17).

Acusera Pre-eclampsia Control

The complexities of pre-eclampsia present significant risks, making reliable diagnostic methods critical. Randox has responded to this need with the Acusera Pre-eclampsia Control, a pivotal tool for laboratories aiming to enhance their diagnostic accuracy and reliability in detecting this condition.

Enhanced Diagnostic Precision

The Acusera Pre-eclampsia Control is designed for use with assays measuring the sFlt-1/PlGF ratio, a key indicator of placental dysfunction and a predictor of pre-eclampsia. This control ensures that your laboratory can confidently rely on the precision of these assays, which are crucial for early detection and management of pre-eclampsia. Given the significant maternal and foetal risks associated with delayed or inaccurate diagnosis—ranging from eclampsia to increased neonatal morbidity—maintaining assay accuracy is not just a matter of scientific integrity, but of patient safety.

Supporting Early Detection

Early detection through the sFlt-1/PlGF ratio can dramatically alter patient outcomes. Studies, including the PROGNOSIS and PROGNOSIS Asia, have demonstrated the utility of this biomarker ratio in predicting the onset of pre-eclampsia weeks before clinical symptoms manifest. The Acusera Pre-eclampsia Control ensures that these predictive measurements are accurate and reliable, supporting clinical decisions that can prevent severe complications.

Quality You Can Trust

The Acusera Pre-eclampsia Control, like all Randox controls, is manufactured to the highest quality standards. It offers excellent batch consistency and stable values that align with real patient samples, providing a robust basis for quality control in your laboratory. This reliability is crucial when dealing with a condition where the diagnostic window is narrow, and the stakes are high.

A Cost-Effective Solution

Investing in high-quality controls is not only about improving health outcomes but also about economic efficiency. The use of effective quality controls, such as the Acusera Pre-eclampsia Control, can significantly reduce the long-term costs associated with repeat testing, misdiagnosis and late detection, such as extended hospital stays, intensive neonatal care, and long-term treatment of chronic conditions.

Key Features

• Analytes: sFlt-1 & PlGF
• Liquid frozen for user convenience
• Human based serum ensuring a commutable sample matrix
• 30 days open vial stability when stored at 2oC to 8oC keeping waste and costs to a minimum
• True third-party control providing an unbiased assessment of performance
• Assayed target values provided

Incorporating the Acusera Pre-eclampsia Control into your laboratory’s testing regime is an investment in accuracy, reliability, and patient care. Given the critical role of the sFlt-1/PlGF ratio in the early detection and management of pre-eclampsia, and the associated risks detailed in our discussions, ensuring the precision of your diagnostic tools with Randox’s trusted quality control products is not just beneficial—it’s essential.

For more information on how the Acusera Pre-eclampsia Control can support your laboratory's needs and contribute to better health outcomes, visit our product page or reach out to us at [email protected].

References

1. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in Pregnancy. Obstetrics & Gynecology. 2013;122(5):1122-1131. doi:10.1097/01.AOG.0000437382.03963.88
2. Poon LC, Shennan A, Hyett JA, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre‐eclampsia: A pragmatic guide for first‐trimester screening and prevention. International Journal of Gynecology & Obstetrics. 2019;145(S1):1-33. doi:10.1002/ijgo.12802
3. Karrar SA, Hong PL. Preeclampsia. StatPearls Publishing; 2023.
4. Jikamo B, Adefris M, Azale T, Alemu K. Incidence, trends and risk factors of preeclampsia in sub-Saharan Africa: a systematic review and meta-analysis. PAMJ - One Health. 2023;11. doi:10.11604/pamj-oh.2023.11.1.39297
5. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia. Circ Res. 2019;124(7):1094-1112. doi:10.1161/CIRCRESAHA.118.313276
6. NHS. Pre-eclampsia. Health A to Z. Published September 28, 2021. Accessed January 3, 2024. https://www.nhs.uk/conditions/pre-eclampsia/complications/
7. Crovetto F, Somigliana E, Peguero A, Figueras F. Stroke during pregnancy and pre-eclampsia. Curr Opin Obstet Gynecol. 2013;25(6):425-432. doi:10.1097/GCO.0000000000000024
8. Dimitriadis E, Rolnik DL, Zhou W, et al. Pre-eclampsia. Nat Rev Dis Primers. 2023;9(1):8. doi:10.1038/s41572-023-00417-6
9. Turbeville HR, Sasser JM. Preeclampsia beyond pregnancy: long-term consequences for mother and child. American Journal of Physiology-Renal Physiology. 2020;318(6):F1315-F1326. doi:10.1152/ajprenal.00071.2020
10. Harmon QE, Huang L, Umbach DM, et al. Risk of Fetal Death With Preeclampsia. Obstetrics & Gynecology. 2015;125(3):628-635. doi:10.1097/AOG.0000000000000696
11. Verlohren S, Galindo A, Schlembach D, et al. An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia. Am J Obstet Gynecol. 2010;202(2):161.e1-161.e11. doi:10.1016/j.ajog.2009.09.016
12. Zeisler H, Llurba E, Chantraine F, et al. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. New England Journal of Medicine. 2016;374(1):13-22. doi:10.1056/NEJMoa1414838
13. Bian X, Biswas A, Huang X, et al. Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Asian Women With Suspected Preeclampsia. Hypertension. 2019;74(1):164-172. doi:10.1161/HYPERTENSIONAHA.119.12760
14. Hughes RCE, Phillips I, Florkowski CM, Gullam J. The predictive value of the sFlt‐1/PlGF ratio in suspected preeclampsia in a New Zealand population: A prospective cohort study. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2023;63(1):34-41. doi:10.1111/ajo.13549
15. Nikuei P, Rajaei M, Roozbeh N, et al. Diagnostic accuracy of sFlt1/PlGF ratio as a marker for preeclampsia. BMC Pregnancy Childbirth. 2020;20(1):80. doi:10.1186/s12884-020-2744-2
16. Verlohren S, Brennecke SP, Galindo A, et al. Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia. Pregnancy Hypertens. 2022;27:42-50. doi:10.1016/j.preghy.2021.12.003
17. Ohkuchi A, Saito S, Yamamoto T, et al. Short-term prediction of preeclampsia using the sFlt-1/PlGF ratio: a subanalysis of pregnant Japanese women from the PROGNOSIS Asia study. Hypertension Research. 2021;44(7):813-821. doi:10.1038/s41440-021-00629-x