Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing - 28/06/24

Doi : 10.1016/j.ajog.2024.05.050

Jimmy Espinoza, MD, MSc ^a,^⁎ , Vinicius F. Calsavara, PhD ^b, Sarah Kilpatrick, MD, PhD ^c, Sarosh Rana, MD, MPH ^d, Maged M. Costantine, MD ^e, Kim Boggess, MD ^f, Blair J. Wylie, MD, MPH ^g, Tiffany A. Moore Simas, MD, MPH, MEd ^h,ⁱ, Judette M. Louis, MD, MPH ^j, Stephanie L. Gaw, MD, PhD ^k, Amy Murtha, MD ^l, Samantha Wiegand, MD ^m, Yvonne Gollin, MD ⁿ, Deepjot Singh, MD, MMM ^o, Robert M. Silver, MD ^p, Danielle E. Durie, MD, MPH ^q, Britta Panda, MD ^r, Errol R. Norwitz, MD, PhD ^r,^s, Irina Burd, MD, PhD ^t, Beth Plunkett, MD, MPH ^u, Rachel K. Scott, MD, MPH ^v, Elizabeth Lemoine, MD ^w, Ravi Thadhani, MD, MPH ^x, S. Ananth Karumanchi, MD ^c,^y
^a Division of Fetal Intervention, Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern Medical School, University of Texas Health Science Center, Houston, TX
^b Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA
^c Department of Obstetrics and Gynecology at Cedars-Sinai Medical Center, Santa Monica, CA
^d Section of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago Medical Center, Chicago, IL
^e Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH
^f Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
^g Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University, New York, NY
^h Departments of Obstetrics and Gynecology, Pediatrics, Psychiatry, and Population and Quantitative Health Sciences, UMass Chan Medical School, Worcester, MA
ⁱ Department of Obstetrics and Gynecology, UMass Memorial Health - UMass Memorial Medical Center, Worcester, MA
^j Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL
^k Division of Maternal-Fetal Medicine and Reproductive Genetics, Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, CA
^l Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, CA
^m Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Miami Valley Hospital, Dayton, OH
ⁿ Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sharp Mary Birch Hospital for Women and Newborns, San Diego, CA
^o Department of Obstetrics and Gynecology, Torrance Memorial Medical Center, Torrance, CA
^p Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Medical Center, Salt Lake City, UT
^q Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Lehigh Valley Health Network, Allentown, PA
^r Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA
^s Department of Obstetrics and Gynecology, Newton-Wellesley Hospital, Newton, MA
^t Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Johns Hopkins Medical Center, Baltimore, MD
^u Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, NorthShore University Health System (Endeavor Health), Evanston, IL
^v Department of Obstetrics and Gynecology, MedStar Health Research Institute, Washington, DC
^w Department of Obstetrics and Gynecology at University of North Carolina School of Medicine, Chapel Hill, NC
^x Emory University, Atlanta, GA
^y Department of Medicine, Cedars-Sinai Medical Center, Santa Monica, CA

^∗Corresponding author: Jimmy Espinoza, MD, MSc.

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Friday 28 June 2024

Abstract

Background

Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform.

Objective

This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features.

Study Design

We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks’ gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks’ gestation], and fetal or neonatal death).

Results

Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve–derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11–14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36–14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95–5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89–0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values.

Conclusion

A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week’s gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.

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Key words : 11.5, adverse outcomes, likelihood ratio, MoM, multiples of the median, plasma, prediction, preeclampsia, severe features, sFlt-1/PlGF ratio

Plan

Introduction

Materials and methods

Subanalysis of participants with preeclampsia or superimposed preeclampsia

Subanalysis of participants with chronic hypertension or gestational hypertension

Comment

Principal findings

Results in the context of what is known

Clinical implications

Research implications

Strengths and limitations

Conclusion

	R.T. and S.A.K. report having multiple biomarker patents related to preeclampsia held by Harvard hospitals and having financial interest in Aggamin Pharmaceuticals and Comanche Biopharma. R.T. and S.A.K. are also named as co-inventors on a provisional patent held by Cedars-Sinai Medical Center, Los Angeles, CA on a novel, lateral-flow assay for use in preeclampsia and related conditions. In addition, S.A.K. reports receiving research funding from and serving as a consultant for ThermoFisher Scientific, Siemens, and Roche. S.R. reports serving as a consultant for Roche Diagnostics, ThermoFisher, Beckman Coulter, and Siemens and receiving research funding from Roche Diagnostics and Siemens for work related to angiogenic biomarkers unrelated to the submitted work. R.S. reports receiving investigator-sponsored research funding from Gilead Science and ViiV Healthcare managed by MedStar Health.
	The findings of this study were presented at the 44th annual pregnancy meeting of the Society for Maternal-Fetal Medicine, National Harbor, MD, February 10–14, 2024.
	This study was supported by Cedars-Sinai Medical Center, and assays were provided by ThermoFisher Scientific
	Cite this article as: Espinoza J, Calsavara VF, Kilpatrick S, et al. Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing. Am J Obstet Gynecol 2024;XX:x.ex–x.ex.