Real-World Evidence for Utility of Serum sFlt-1/PlGF Test for Routine Clinical Evaluation of Hospitalized Women with Hypertensive Disorders of Pregnancy

Abstract

An imbalance of the anti-angiogenic factor, soluble fms-like tyrosine kinase-1 (sFlt-1), and pro-angiogenic factor, placental growth factor (PlGF) in the circulation is a reliable predictor for development of preeclampsia with severe features and related adverse outcomes. In 2023, the United States (US) Food and Drug Administration approved a serum sFlt-1/PlGF test at a cut-off of 40 to aid in the risk assessment of women hospitalized for hypertensive disorders of pregnancy (HDP) for the progression to preeclampsia with severe features between 23 and 35 weeks. The purpose of this study was to generate real-world evidence for clinical utility for serum sFlt-1/PlGF test when made available to clinicians in a timely fashion as an aid in risk stratification of development of preeclampsia with severe features within two weeks of testing among hospitalized patients with HDP. Hospitalized patients with HDP between 23 weeks to 34 weeks and 6 days of gestation were prospectively studied from June 2023 to Jan 2024 following implementation of serum sFlt-1/PlGF testing into routine clinical practice. Serum samples were obtained from patients via venipuncture and analyzed on an automated immunoassay platform (PlGF and sFlt-1 assays; Thermo Fisher Scientific). Before implementation, physicians were educated on appropriate use and management guidelines based on biomarkers but made pragmatic management decisions independently. Results of sFlt-1/PlGF tests were available to clinicians within 24 hours of venipuncture. The association between sFlt-1/PlGF ≥ 40 and progression to preeclampsia with severe features and adverse maternal/perinatal outcomes were assessed. Of the 65 patient encounters, 36 had a sFlt-1/PlGF < 40 (55.4%). The rate of delivery for indications related to HDP within two weeks was significantly lower among encounters with a low ratio versus high ratio (2/36 [5.6%] vs 21/29 [72.4%]) even after controlling for relevant confounders (adjusted HR 7.52, 95% CI: 3.05, 18.54; p < 0.001). A diagnosis of preeclampsia with severe features within two weeks of testing was also less likely among the encounters with sFlt-1/PlGF ratio < 40 when compared to sFlt-1/PlGF ratio ≥ 40 (2/36 [5.6%] versus 23/29 [79.3%], p<0.001; PPV 79% [95% CI: 0.65, 0.94] and NPV 0.94 [95% CI: 0.87, 1.00]). The positive and negative likelihood ratios for the development of preeclampsia with severe features within two weeks of testing were 6.13 and 0.09 respectively. Encounters with an sFlt-1/PlGF ratio <40 were less likely to experience a maternal or fetal adverse event as compared to encounters with sFlt-1/PlGF ratio ≥40 (3/36 [8.3%] vs 10/29 [34.5%], p=0.01). Among 36 encounters involving low sFlt-1/PlGF values, 22 had had equivocal clinical or laboratory criteria resembling preeclampsia at presentation but were expectantly managed based on biomarkers and none developed preeclampsia with severe features or adverse outcomes at two weeks. The median latency defined as days between biomarker measurement and delivery in patients with low biomarker ratio was 33 (IQR 23, 47) versus 7 (IQR 4, 14) days among patients with a high ratio (p<0.001). Corticosteroid use within two weeks was also significantly reduced in the low biomarker group when compared to high biomarker group (8/35 [22.9%] vs 24/29 [82.8%], p<0.001). In this study, incorporation of sFlt-1/PlGF ratio into clinical practice serves as a dependable supplement in assessing risk for progression to preeclampsia with severe features and adverse outcomes in patients with HDP in the US. Among patients with a low ratio, pregnancy may be prolonged which resulted in better neonatal outcomes without harm to the mother.