Serum soluble fms-like tyrosine kinase kinase 1-to-placental growth factor ratio on Elecsys immunoassay platform predicts preeclampsia with severe features in hospitalized women with hypertensive disorders of pregnancy

Anders H Berg; Vinicius F Calsavara; Martin Hund; Ge Guo; Sarosh Rana; Maged M Costantine; Jimmy Espinoza; Kim Boggess; Blair J Wylie; Tiffany A Moore Simas; Judette M Louis; Stephanie L Gaw; Amy Murtha; Samantha Wiegand; Yvonne Gollin; Deepjot Singh; Robert M Silver; Danielle E Durie; Britta Panda; Errol R Norwitz; Irina Burd; Beth Plunkett; Rachel K Scott; Martha Bautista; Elizabeth Lemoine; Sarah Kilpatrick; Ravi Thadhani; S Ananth Karumanchi

doi:10.1016/j.ajog.2025.11.006

Serum soluble fms-like tyrosine kinase kinase 1-to-placental growth factor ratio on Elecsys immunoassay platform predicts preeclampsia with severe features in hospitalized women with hypertensive disorders of pregnancy

Am J Obstet Gynecol. 2025 Nov 11:S0002-9378(25)00828-2. doi: 10.1016/j.ajog.2025.11.006. Online ahead of print.

Authors

Anders H Berg¹, Vinicius F Calsavara¹, Martin Hund², Ge Guo³, Sarosh Rana⁴, Maged M Costantine⁵, Jimmy Espinoza⁶, Kim Boggess⁷, Blair J Wylie⁸, Tiffany A Moore Simas⁹, Judette M Louis¹⁰, Stephanie L Gaw¹¹, Amy Murtha¹², Samantha Wiegand¹³, Yvonne Gollin¹⁴, Deepjot Singh¹⁵, Robert M Silver¹⁶, Danielle E Durie¹⁷, Britta Panda¹⁸, Errol R Norwitz¹⁹, Irina Burd²⁰, Beth Plunkett²¹, Rachel K Scott²², Martha Bautista¹, Elizabeth Lemoine²³, Sarah Kilpatrick¹, Ravi Thadhani²⁴, S Ananth Karumanchi²⁵

Affiliations

¹ Cedars-Sinai Medical Center, Los Angeles, CA.
² Roche Diagnostics, Risch-Rotkreuz, Switzerland.
³ Roche Diagnostics, Indianapolis, IN.
⁴ University of Chicago Medical Center, Chicago, IL.
⁵ The Ohio State University Wexner Medical Center, Columbus, OH.
⁶ University of Texas Health Houston Fetal Center, University of Texas Health Science Center, Houston, TX.
⁷ University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC.
⁸ Beth Israel Deaconess Medical Center, Boston, MA.
⁹ University of Massachusetts Memorial Medical Center, University of Massachusetts Chan Medical School, Worcester, MA.
¹⁰ University of South Florida, Tampa, FL.
¹¹ University of California, San Francisco, San Francisco, CA.
¹² University of California, San Francisco, San Francisco, CA; Rutgers Health, Robert Wood Johnson Medical School, New Brunswick, NJ.
¹³ Miami Valley Hospital, Dayton, OH.
¹⁴ Sharp Mary Birch Hospital for Women & Newborns, San Diego, CA.
¹⁵ Torrance Memorial Medical Center, Torrance, CA.
¹⁶ University of Utah Medical Center, Salt Lake City, UT.
¹⁷ Lehigh Valley Health Network, Allentown, PA.
¹⁸ Tufts Medical Center, Boston, MA.
¹⁹ Newton-Wellesley Hospital, Newton, MA.
²⁰ University of Maryland, Baltimore, MD.
²¹ NorthShore University Health System (Endeavor Health), Evanston, IL.
²² MedStar Health Research Institute, Washington, DC.
²³ Wake Forest University School of Medicine, Winston-Salem, NC.
²⁴ Emory University, Atlanta, GA. Electronic address: PRAECIS@cshs.org.
²⁵ Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address: PRAECIS@cshs.org.

PMID: 41232788
DOI: 10.1016/j.ajog.2025.11.006

Abstract

Background: Previous single-center studies conducted in the United States in women with suspected preeclampsia indicated that serum soluble fms-like tyrosine kinase 1-to-placental growth factor ratio values of >38 measured on a widely available Elecsys immunoassay platform during the third trimester of pregnancy predicted the development of preeclampsia with severe features and adverse outcomes within 2 weeks of testing.

Objective: This study aimed to validate the Elecsys soluble fms-like tyrosine kinase 1-to-placental growth factor ratio test for the prediction of preeclampsia with severe features in a United States population using the prospective Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification cohort that recruited women with a hypertensive disorder of pregnancy (gestational hypertension, chronic hypertension, de novo and superimposed preeclampsia) across 18 tertiary and community hospitals throughout the United States.

Study design: We measured soluble fms-like tyrosine kinase 1-to-placental growth factor ratios using the Elecsys platform in archived serum samples from the Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification study that recruited hospitalized women with a hypertensive disorder of pregnancy between 23 0/7 and 34 6/7 weeks of gestation. The primary study outcome was prediction of preeclampsia with severe features within 2 weeks after testing. The secondary outcomes included a composite of adverse maternal and fetal/neonatal outcomes and prediction of delivery within 2 weeks.

Results: In the validation cohort of the Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification study (556 enrollments), the serum soluble fms-like tyrosine kinase 1-to-placental growth factor ratio at a cutoff value of >38 demonstrated a 67% positive predictive value (95% confidence interval, 61-73) and a 95% negative predictive value (95% confidence interval, 92-97) for the progression to preeclampsia with severe features within 2 weeks. Among women at <30 weeks of gestation (n=188), serum soluble fms-like tyrosine kinase 1-to-placental growth factor ratio at a cutoff value of >38 demonstrated a 78% positive predictive value (95% confidence interval, 68-86) and a 100% negative predictive value (95% confidence interval, 96-100) for the progression to preeclampsia with severe features within 2 weeks. The Elecsys soluble fms-like tyrosine kinase 1-to-placental growth factor ratio test performed better than standard-of-care clinical measures, with an area under the receiver operating characteristic curve of 0.92 (95% confidence interval, 0.89-0.90) for soluble fms-like tyrosine kinase 1-to-placental growth factor ratio vs <0.70 for standard-of-care tests, such as liver enzymes, platelet count, and serum creatinine (P<.001). Compared with women with a ratio of ≤38, those with a ratio of >38 had a higher risk of developing adverse maternal (relative risk, 4.9 [95% confidence interval, 2.6-9.9]; P<.001) and fetal/neonatal (relative risk, 3.2 [95% confidence interval, 2.6-4.0]; P<.001) outcomes and were more likely to deliver within 2 weeks (adjusted hazard ratio, 3.3 [95% confidence interval, 2.7-4.0]; P<.001).

Conclusion: The soluble fms-like tyrosine kinase 1-to-placental growth factor ratio of >38 measured on the Elecsys platform predicted the development of preeclampsia with severe features, delivery, and adverse maternal and fetal/neonatal outcomes within 2 weeks of testing among preterm pregnant women hospitalized with a hypertensive disorder of pregnancy.

Keywords: adverse outcome; anti-angiogenesis; biomarker; immunoassay; placental growth factor; preeclampsia; soluble fms-like tyrosine kinase 1–to–placental growth factor ratio.