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

Gestational Hypertension Clinical Trial

— PRAECIS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03815110
• Other study ID #: Pro00055135
• Status: Completed
• Start date: December 20, 2018
• Est. completion date: October 1, 2022

Study information

• Verified date: November 2022
• Source: Cedars-Sinai Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1050
• Est. completion date: October 1, 2022
• Est. primary completion date: November 19, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Hypertension in Obstetric Context
• Eclampsia
• Gestational Hypertension
• Hypertension
• Hypertension, Pregnancy-Induced
• Pre-Eclampsia
• Preeclampsia and Eclampsia
• Preeclampsia Mild
• Preeclampsia Severe
• Superimposed Pre-Eclampsia

Locations

Country	Name	City	State
United States	Lehigh Valley Health Network	Allentown	Pennsylvania
United States	Johns Hopkins University Medical Center	Baltimore	Maryland
United States	MedStar Health	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	University of North Carolina Medical Center- Chapel Hill	Chapel Hill	North Carolina
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Northshore	Evanston	Illinois
United States	Baylor College of Medicine	Houston	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of Utah	Salt Lake City	Utah
United States	Sharp Mary Birch Hospital for Women & Newborns	San Diego	California
United States	UC San Francisco Medical Center	San Francisco	California
United States	University of South Florida	Tampa	Florida
United States	Torrance Memorial Medical Center	Torrance	California
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Cedars-Sinai Medical Center	ThermoFisher Scientific Brahms Biomarkers France

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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