By Ahizechukwu C. Eke, MD, PhD, MPH
Synopsis: The sFlt-1/PlGF ratio is a clinically valuable tool for ruling out preeclampsia and improving obstetric decision-making, although its effect depends on appropriate use, clinician confidence in negative results, and adherence to validated protocols.
Source: Lane A, Amy LU, Parange A, Dekker G. Clinical experience and major learning points following the implementation of the sFlt-1/PlGF ratio in the management of suspected preeclampsia in a South Australian tertiary hospital. Aust N Z J Obstet Gynaecol. 2025; Jul 18. doi: 10.1111/ajo.70046. [Online ahead of print].
Preeclampsia remains a leading cause of maternal and perinatal morbidity worldwide, complicating approximately 2% to 8% of all pregnancies.1-3 Despite its high prevalence, the pathogenesis of preeclampsia remains incompletely understood, although abnormal placentation and resultant angiogenic imbalance are thought to be central.1,2 One proposed pathophysiological mechanism is placental hypoxia leading to the release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1), and reduced synthesis of pro-angiogenic proteins, such as placental growth factor (PlGF).2,4-6 This dysregulation disrupts endothelial homeostasis and promotes systemic endothelial activation, a hallmark of the clinical syndrome that includes hypertension and multi-organ dysfunction.2,4-6
Traditional diagnostic approaches for preeclampsia, such as laboratory markers for renal or hepatic impairment, thrombocytopenia, or new-onset neurological symptoms, only capture the disease after end-organ involvement already is underway.1 In contrast, angiogenic biomarkers, such as the sFlt-1/PlGF ratio, offer a window into the underlying pathobiology, allowing for earlier risk stratification by identifying syncytiotrophoblast stress prior to overt clinical manifestation.2,7
The sFlt-1/PlGF ratio is a unitless value obtained by dividing serum sFlt-1 concentration by that of PlGF. An elevated ratio is indicative of an anti-angiogenic state, suggestive of placental dysfunction.2,4 The PRAECIS trial, a multicenter, prospective study of 1,014 pregnant women hospitalized with hypertensive disorders between 23 0/7 and 34 6/7 weeks of gestation, demonstrated that an sFlt-1/PlGF ratio of ≥ 40 predicted progression to preeclampsia with severe features within two weeks with a sensitivity of 94%, a specificity of 75%, a positive predictive value (PPV) of 65%, and a negative predictive value (NPV) of 96%.5 In practical terms, a ratio ≥ 40 confers a moderate likelihood of progression to severe disease in the short term, while a ratio < 40 provides strong reassurance against imminent development of preeclampsia.
The high NPV is particularly useful for identifying patients who may not require escalation of care, thereby reducing unnecessary interventions or prolonged hospital stays. Based on these results, the U.S. Food and Drug Administration (FDA) approved the sFlt-1/PlGF test in May 2023 for use as a risk-assessment tool in pregnant women with hypertensive disorders admitted between 23 weeks and 0 days and 34 weeks and six days gestation. Many obstetric units (within and outside the United States) now incorporate the sFlt-1/PlGF ratio into the assessment of pregnant women with suspected preeclampsia. As such, understanding how the assay performs in real-world practice is essential for safe implementation.
This was a retrospective clinical audit of all women who underwent sFlt-1/PlGF ratio testing at the Northern Adelaide Local Health Network (NALHN) in Adelaide, South Australia, between October 2021 and June 2023. The study included pregnant women tested for suspected preeclampsia or identified as high-risk for developing the condition, in accordance with local guidelines that recommend testing between 20+0- and 36+6- weeks of gestation. Testing outside this window was considered non-indicated because of limited clinical reliability at gestational extremes. Each sFlt-1/PlGF test was classified either as indicated or not indicated based on adherence to institutional protocols. There were no formal exclusion criteria reported beyond testing outside of validated gestational age windows.
The primary objective of the study was to assess real-world implementation of the sFlt-1/PlGF ratio in a tertiary hospital setting and identify key clinical and educational insights to improve its appropriate use in the management of suspected preeclampsia. Rather than focusing on pre-defined clinical outcomes, such as hospital discharge or escalation of care, the study evaluated adherence to testing guidelines, frequency and timing of repeat testing, and the proportion of tests conducted within or outside validated gestational windows. The audit also described maternal outcomes, including the incidence of preeclampsia; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; and other hypertensive disorders, as well as neonatal outcomes, such as admission to special care or neonatal intensive care units (NICUs). Additionally, it examined the relationship between test results and clinical outcomes, highlighting the test’s high negative predictive value and areas of misuse that could inform future quality improvement efforts.
All sFlt-1/PlGF samples were processed and analyzed as part of routine clinical care, with the ratio calculated by dividing the serum concentration of sFlt-1 by PlGF. A threshold of < 38 was considered reassuring, based on prior validation studies, and used to guide clinical management. According to local protocol, women with sFlt-1/PlGF ratios between 38 and 85 were recommended to undergo repeat testing after one week, while markedly elevated ratios (> 85) were associated with increased risk of adverse outcomes and often prompted escalated care. The analysis was descriptive, focusing on test use patterns, adherence to clinical guidelines, and correlation between test results and maternal and neonatal outcomes. No formal statistical hypothesis testing or comparative analyses were performed.
Between October 2021 and June 2023, 750 sFlt-1/PlGF assays were performed in 431 women, with 79% (596/750) of assays ordered in accordance with local protocol. Over the study period, 23% (98/431) of women developed preeclampsia, 27% (88/431) were diagnosed with gestational hypertension, 10% had essential hypertension (32/431), and 63% (207/431) remained normotensive. Only 3% (14/431) of women developed preeclampsia within four weeks of a previously reassuring result, and none required intensive care unit (ICU) admission. Five patients developed HELLP syndrome, with no cases of eclampsia or major thromboembolic events reported. Two women with markedly elevated sFlt-1/PlGF ratios (> 655) were diagnosed with preeclampsia. Among 444 births, 27% of infants were admitted to a special care nursery, 3% were admitted to the NICU, and one neonatal death occurred. Infants of mothers with sFlt-1/PlGF ratios > 85 had an average birthweight centile of 37%, compared with 23% among those with HELLP syndrome. Repeat testing occurred in 42% of women, including one high-risk case, with 10 assays who delivered at term without developing preeclampsia.
Commentary
Overall, the sFlt-1/PlGF ratio in this study demonstrated strong prognostic performance for short-term maternal and perinatal complications, with meaningful clinical distinctions between low- and high-risk pregnancies. The clinicians primarily used the test when preeclampsia was suspected, and most adhered to local testing protocols, although a notable proportion of tests were repeated unnecessarily or ordered outside validated gestational windows. Among women with reassuring results, very few progressed to preeclampsia in the short term, and severe maternal complications were rare, reinforcing the ratio’s NPV. Elevated sFlt-1/PlGF ratios were associated with adverse maternal and neonatal outcomes.
Angiogenic imbalance is a central mechanism underlying the clinical manifestations of preeclampsia. Placental hypoperfusion triggers the release of anti-angiogenic factors, such as sFlt-1, and reduces pro-angiogenic PlGF, leading to systemic endothelial dysfunction.1,2,4-8 Therefore, measuring the sFlt-1/PlGF ratio offers a window into placental health and function. The PROGNOSIS and PRAECIS studies established that a ratio below 40 accurately rules out progression to severe preeclampsia for at least two weeks (NPV ≥ 96%), whereas elevated ratios have a moderate PPV of approximately 65%.4-6 This well-established biological rationale and robust negative predictive performance support the integration of the ratio into clinical risk assessment algorithms and informed its application in this audit.
Introducing the sFlt-1/PlGF ratio into clinical practice necessitates a paradigm shift from an exclusive focus on maternal end-organ dysfunction to a broader recognition of placental disease as the underlying pathology in preeclampsia. Effective implementation requires comprehensive educational initiatives to ensure that clinicians understand the appropriate clinical indications, interpretive thresholds, and limitations of the assay. To enhance standardization and optimize care, future guidelines should provide clearer recommendations on retesting intervals, gestational age thresholds, and considerations for special populations, such as women with multifetal gestations or chronic kidney disease. Given that the sFlt-1/PlGF assay is not universally reimbursed, cost-effectiveness and resource stewardship remain critical, reinforcing the importance of judicious and protocol-driven use.
In conclusion, the sFlt-1/PlGF ratio is a valuable adjunct in the evaluation of suspected preeclampsia. According to American College of Obstetricians and Gynecologists (ACOG) and FDA guidance, its use should be limited to hospitalized patients with singleton pregnancies between 23 and 34 weeks of gestation who have hypertensive disorders, and it should be interpreted alongside clinical findings and routine laboratory tests.8 A normal result (< 40) confers a very low risk of progression to severe disease over the next two weeks, enabling clinicians to reduce unnecessary interventions. However, a positive result (≥ 40) has only moderate PPV and should not, by itself, dictate timing of delivery or discharge; continued maternal and fetal surveillance is required.
ACOG recommends restricting use of this assay to populations evaluated in the PRAECIS trial and cautions that the results should not, by themselves, dictate timing of delivery or hospital discharge.8 Clinicians should avoid testing outside the validated gestational window, and repeat testing should be reserved for intermediate results or persistent concern. Ultimately, the sFlt-1/PlGF ratio should complement, not replace, established diagnostic criteria. Its integration into clinical practice should follow evidence-based guidelines to optimize maternal and neonatal outcomes.
Ahizechukwu C. Eke, MD, PhD, MPH, is Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore.
References
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2. Hastie R, Bergman L, Walker SP, et al. Associations between soluble fms-like tyrosine kinase-1 and placental growth factor and disease severity among women with preterm eclampsia and preeclampsia. J Am Heart Assoc. 2022;11(16):e024395.
3. Abalos E, Cuesta C, Grosso AL, et al. Global and regional estimates of preeclampsia and eclampsia: A systematic review. Eur J Gynecol Reprod Biol. 2013;170(1):1-7.
4. Zeisler H, Llurba E, Chantraine F, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med. 2016;374(1):13-22.
5. Thadhani R, Lemoine E, Rana S, et al. Circulating angiogenic factor levels in hypertensive disorders of pregnancy. NEJM Evid. 2022;1(12):EVIDoa2200161.
6. Zeisler H, Llurba E, Chantraine FJ, et al. Soluble fms-like tyrosine kinase-1 to placental growth factor ratio: Ruling out pre-eclampsia for up to 4 weeks and value of retesting. Ultrasound Obstet Gynecol. 2019;53(3):367-375.
7. 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.
8. [No authors listed]. Biomarker prediction of preeclampsia with severe features. Obstet Gynecol. 2024; Apr 3. doi: 10.1097/aog.0000000000005576. [Online ahead of print].
The sFlt-1/PlGF ratio is a clinically valuable tool for ruling out preeclampsia and improving obstetric decision-making, although its effect depends on appropriate use, clinician confidence in negative results, and adherence to validated protocols.
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