Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification (PRAECIS)

The purpose of this study is to

1. Identify a cut-off for the ratio of the serum proteins soluble FMS-like Tyrosine Kinase 1 (sFLT-1) and placental growth factor (PlGF) that identifies women will who develop preeclampsia with severe features within 2 weeks of testing (clinically positive) from those who do not develop preeclampsia with severe features within 2 weeks of testing (clinically negative) among preterm pregnant women with hypertensive disorders of pregnancy.

   And

2. To validate the cut-off the ratio of sFLT-1 and PlGF and to validate the performance of the automated assays used to find the cut-off. Test performance includes positive predictive value, negative predictive value, sensitivity, and specificity.

Subjects will provide blood, urine, and saliva samples at the time of enrollment. Samples will be frozen for batch assessment of sFLT-1 and PlGF levels by automated assays. Clinicians, subjects, and researchers will be blinded to protein level assessment, therefore assay results will not affect clinical management.

Study Overview

• Status: Completed
• Conditions: Gestational Hypertension; Preeclampsia Severe; Preeclampsia and Eclampsia; Chronic Hypertension in Obstetric Context; Superimposed Pre-Eclampsia; Preeclampsia Mild

Detailed Description

Preeclampsia is a leading cause of maternal and fetal morbidity and mortality in the US, and affects about 5% of pregnancies. Despite its morbidity, preeclampsia is challenging to distinguish from worsening chronic hypertension or gestational hypertension. Furthermore, it is challenging to identify who among those with hypertensive disorders of pregnancy will develop preeclampsia with severe features, including kidney, liver, pulmonary, or cerebral injury. The only definitive treatment is delivery of the placenta, and therefore the fetus, which can lead to severe morbidity and mortality to the neonate if delivery is very premature. New methods of risk stratification are needed to identify who among women with hypertensive disorders of pregnancy are at risk of developing preeclampsia with severe features in order to allocate resources (e.g. betamethasone and magnesium for fetal neuroprotection) accordingly.

Several serum proteins (sFLT-1 and PlGF) correlate well with the development of preeclampsia, particularly with preeclampsia with severe features, and may be used to predict the development of preeclampsia with severe features within a certain timeframe. The goal of this study is to identify a cut-off of the sFLT-1/PlGF ratio using automated assays that differentiates women who will develop preeclampsia with severe features from those who will not among women with hypertensive disorders of pregnancy within 2 weeks of testing. The secondary outcomes include time to delivery, the performance of the cut-off to predict adverse maternal and adverse fetal outcomes, and a comparison of the performance of the cut-off with clinical and laboratory factors per American College of Obstetricians and Gynecologists (ACOG) guidelines. Investigators will also look at the levels of sFLT-1 and PlGF in the urine and the saliva to determine if they correlate well with serum levels and may provide a less invasive alternative to serum samples.

• Study Type: Observational
• Enrollment (Actual): 1050

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • San Diego, California, United States, 92123
      • Sharp Mary Birch Hospital for Women & Newborns
    • San Francisco, California, United States, 94158
      • UC San Francisco Medical Center
    • Torrance, California, United States, 90505
      • Torrance Memorial Medical Center
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Evanston, Illinois, United States, 60201
      • Northshore
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University Medical Center
    • Baltimore, Maryland, United States, 21237
      • MedStar Health
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts Memorial Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7516
      • University of North Carolina Medical Center- Chapel Hill
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Wexner Medical Center
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18102
      • Lehigh Valley Health Network
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

The study population includes women with singleton pregnancies at 23+0 to 34+6/7 weeks gestational age who are hospitalized with (or develop while hospitalized) a hypertensive disorder of pregnancy. Minors and patients who have received intravenous heparin within 24 hours of enrollment or who have participated in a therapeutic interventional study in the last 30 days will be excluded.

Description

Inclusion Criteria:

• Signed informed consent in a pregnant woman ≥ 18 years of age.
• Gestational age 23+0 to 34+6/7 weeks
• Singleton pregnancy
• Hospitalized with (or develop while hospitalized) a hypertensive disorder of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia or gestational hypertension) as defined by ACOG guidelines.

Exclusion Criteria:

• 1. Patients who have received intravenous heparin within 24 hours of enrollment. Low dose subcutaneous heparin or low molecular weight heparin (LMWH) for prophylaxis of deep venous thrombosis (DVT) is permitted.
• Patients who are currently participating in another clinical trial to evaluate a new therapeutic intervention or who have participated in another such trial in the previous 30 days.
• Multiple gestations.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Derivation and Performance of Cut-off for sFLT-1/PlGF Ratio (Serum)	Identification of the cut-off and performance (sensitivity, specificity, positive predictive value, and negative predictive value) for the sFLT-1/PlGF ratio as determined by automated assays that enable differentiation of those women with a hypertensive disorder of pregnancy who develop preeclampsia with severe features from those who do not develop preeclampsia within 2 weeks of testing.	2 weeks
Validation of Cut-off and Performance of sFLT-1/PlGF Ratio as Defined in Derivation Cohort (Serum)	Validation of the performance (sensitivity, specificity, positive predictive value, negative predictive value) of the cut-off of the sFLT-1/PlGF ratio differentiating the development of preeclampsia with severe features within 2 weeks after testing as determined by the independent Derivation cohort.	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Performance in Determining the Risk for Adverse Maternal Outcomes	Performance (sensitivity, specificity, positive predictive value, negative predictive value) of the sFLT-1/PlGF cut-off identified and validated per primary endpoint in determining the risk of adverse maternal outcomes within 2 weeks after testing.	2 weeks
Performance in Determining the Risk for Adverse Fetal/Neonatal Outcomes	Performance (sensitivity, specificity, positive predictive value, negative predictive value) of the sFLT-1/PlGF cut-off identified and validated per primary endpoint in determining the risk of adverse fetal/neonatal outcomes within 2 weeks after testing.	4 weeks
Performance As Compared to ACOG-Guidelines	Performance of the sFLT-1/PlGF ratio versus the performance of clinical and laboratory factors per ACOG guidelines in predicting maternal development of preeclampsia with severe features. ACOG guidelines in predicting the development of preeclampsia include,; systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm HG or more on at least 2 occasions at least 4 hours apart; 300 mg or more of protein per 24 hour urine collection; Protein/creatinine ration of 0.3 mg/dL or more; Urine dipstick reading of 2+; Uric acid greater than 5 mg/dL	2 years
Performance of sFLT-1/PlGF & ACOG Guidelines	Performance of the algorithm combining the sFLT-1/PlGF ratio PLUS clinical and laboratory factors per ACOG guidelines in predicting maternal development of preeclampsia with severe features. ACOG guidelines in predicting the development of preeclampsia include,; systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm HG or more on at least 2 occasions at least 4 hours apart; 300 mg or more of protein per 24 hour urine collection; Protein/creatinine ration of 0.3 mg/dL or more; Urine dipstick reading of 2+; Uric acid greater than 5 mg/dL	2 years
Time to Delivery	Time to delivery in women whose sFLT-1/PlGF ratio is above the cut-off as identified per the primary objective compared to those whose sFLT-1/PlGF ratio is below that cut-off.	2 years
sFLT-1 and PlGF Levels in Urine and Saliva	Identification of levels of sFLT-1 (pg/ml) and PlGF (pg/ml) in urine and saliva specimens.	2 years

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: ThermoFisher Scientific Brahms Biomarkers France
• Investigators: Principal Investigator: Ananth Karumanchi, MD, Cedars-Sinai Medical Center

Publications and helpful links

General Publications

• Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-1131. doi: 10.1097/01.AOG.0000437382.03963.88. No abstract available.
• Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med. 2016 Jan 7;374(1):13-22. doi: 10.1056/NEJMoa1414838.
• Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004 Feb 12;350(7):672-83. doi: 10.1056/NEJMoa031884. Epub 2004 Feb 5.
• Sunderji S, Gaziano E, Wothe D, Rogers LC, Sibai B, Karumanchi SA, Hodges-Savola C. Automated assays for sVEGF R1 and PlGF as an aid in the diagnosis of preterm preeclampsia: a prospective clinical study. Am J Obstet Gynecol. 2010 Jan;202(1):40.e1-7. doi: 10.1016/j.ajog.2009.07.025. Epub 2009 Sep 17.
• Engels T, Pape J, Schoofs K, Henrich W, Verlohren S. Automated measurement of sFlt1, PlGF and sFlt1/PlGF ratio in differential diagnosis of hypertensive pregnancy disorders. Hypertens Pregnancy. 2013 Nov;32(4):459-73. doi: 10.3109/10641955.2013.827205. Epub 2013 Aug 19.
• Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, Calda P, Holzgreve W, Galindo A, Engels T, Denk B, Stepan H. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol. 2012 Jan;206(1):58.e1-8. doi: 10.1016/j.ajog.2011.07.037. Epub 2011 Jul 30.
• Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH, Levine RJ, Lim KH, Wenger JB, Thadhani R, Karumanchi SA. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012 Feb 21;125(7):911-9. doi: 10.1161/CIRCULATIONAHA.111.054361. Epub 2012 Jan 18.

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2018
• Primary Completion (Actual): November 19, 2021
• Study Completion (Actual): October 1, 2022

Study Registration Dates

• First Submitted: January 17, 2019
• First Submitted That Met QC Criteria: January 21, 2019
• First Posted (Actual): January 24, 2019

Study Record Updates

• Last Update Posted (Actual): November 28, 2022
• Last Update Submitted That Met QC Criteria: November 23, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Pregnancy Complications; Hypertension; Eclampsia; Pre-Eclampsia; Hypertension, Pregnancy-Induced
• Other Study ID Numbers: Pro00055135

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No