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sFlt-1:PlGF Ratio in Diagnosing Superimposed Preeclampsia

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ClinicalTrials.gov Identifier: NCT03441711
Recruitment Status : Recruiting
First Posted : February 21, 2018
Last Update Posted : February 21, 2018
Sponsor:
Information provided by (Responsible Party):
University of Tennessee

Brief Summary:

Preeclampsia: associated with poor placentation, incomplete uteroplacental spiral arteries remodeling. Result: ischemia, re-perfusion injury, oxidative stress.

A low-grade systemic inflammatory response is more pronounced in preeclampsia. This results in an imbalance between maternal circulating pro-angiogenic (PlGF & VEGF) & anti-angiogenic factors (sFlt-1).

PlGF & VEGF function as vasodilators & preserve structure & function of glomerular endothelium. sFlt-1 blocks these actions, resulting in hypertension, endothelial dysfunction & nephropathy.

Various stressors, including hypoxia, villous crowding, angiotensin II, & oxidative stress are associated with preeclampsia & mediate secretion of soluble vascular growth factor 1 (sVEGFR-1 or sFlt-1) by GADD45 (Growth Arrest and DNA Damage-45). GADD45 is one of a family of stress-induced genes sFlt-1 releases into maternal circulation. Excess sFlt-1 leads to endothelial dysfunction, hypertension & proteinuria.

Exogenously administered sFlt-1 results in syndrome of nephrotic range proteinuria, hypertension, and glomerular endotheliosis in animal models.

Women with preeclampsia tend to have higher sFlt-1 & lower PlGF, resulting in an increased ratio (sFlt-1:PlGF). The difference is greater in women who develop early-onset preeclampsia (before 34 wks gestation).

Verlohren, et al., showed an increased sFlt-1/PlGF ratio in patients with preeclampsia as compared to controls & patients with chronic/gestational hypertension.

Other work has examined the longitudinal changes in the individual values of sFlt-1 & PlGF over the course of the pregnancy, as well as the ratio.

Given the low prevalence of preeclampsia in the population, the positive predictive value remained low, however the negative predictive value approached 97% late in gestation. This suggests that the utility of the sFlt-1/PlGF may be in its ability to rule out preeclampsia.

More recently the PROGNOSIS study was designed to investigate the value of the sFlt-1/PlGF ratio for the prediction of the presence or absence of preeclampsia in the short term & found that a cutoff point of 38 for the sFlt-1/PlGF ratio is useful for predicting the short-term absence of preeclampsia in women with suspected disease (Negative predictive value 99.3% for ruling out preeclampsia within 1 week).

Hypothesis: In women with chronic hypertension, the sFlt-1/PlGF ratio will better predict the development of superimposed preeclampsia than clinical criteria alone.


Condition or disease
Preeclampsia

Detailed Description:

Subjects with a diagnosis of chronic hypertension made prenatally or in the first 20 weeks of pregnancy (+/- medical therapy). The clinical diagnosis of preeclampsia will follow the current criteria outlined by ACOG (American College of Obstetricians & Gynecologists) 10.

Study/Project Procedures:

  • Blood draw at the time of initial presentation at the time of a clinically indicated blood draw (10cc maternal blood via venipuncture)
  • Blood draw at 2-7 days after initial presentation if undelivered at the time of a clinically indicated blood draw(10 cc maternal blood via venipuncture)
  • Laboratory analysis will be performed in batches after all clinical history, clinically indicated laboratory information, delivery information, and clinical outcomes recorded for sFlt-1 level, PlGF level, and the sFlt-1/PlGF ratio (not part of routine care and will be performed for research purposes only at the cost of the investigators).
  • Urine protein creatinine ratio performed as clinically indicated (will not be altered for research purposes)
  • Maternal CBC (Complete Blood Count), CMP (Complete Metabolic Profile), LDH (Lactate dehydrogenase), Uric acid as indicated clinically (will not be altered for research purposes)
  • Ultrasound performed by the investigators for research purposes only evaluating the uterine artery Doppler, middle cerebral artery Doppler, umbilical artery Doppler, estimated fetal weight, and amniotic fluid volume on a weekly basis from the time of enrollment until delivery.
  • Medical record abstraction of medical history, laboratory and clinical findings for both the mother and fetus.

Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: The Utility of the sFlt-1/PlGF Ratio in Diagnosing Superimposed Preeclampsia and Predicting Adverse Outcomes in Subjects With Chronic Hypertension
Study Start Date : February 2016
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Group/Cohort
Group 1
elevated sFlt-1/PlGF ratio
Group 2
normal sFlt-1/PlGF ratio



Primary Outcome Measures :
  1. The diagnosis rate of superimposed preeclampsia for gestations of 20 0/7 weeks through 38 6/7 as evidenced by the degree of change in the 'sFlt-1/PlGF ratio' [ Time Frame: From 20 0/7 weeks through 38 6/7 weeks. ]
    result at the point of enrollment; compared to the ratio result at 2-7 days post enrollment


Secondary Outcome Measures :
  1. The diagnosis rate of Maternal morbidity HELLP syndrome for gestations of 20 0/7 weeks through 38 6/7 as evidenced by the degree of change in the 'sFlt-1/PlGF ratio' [ Time Frame: between 20 0/7 weeks to 38 6/7 weeks gestation ]
    result at the point of enrollment; compared to the ratio result at 2-7 days post

  2. The diagnosis rate of Eclampsia for gestations of 20 0/7 weeks through 38 6/7 as evidenced by the degree of change in the 'sFlt-1/PlGF ratio' [ Time Frame: between 20 0/7 weeks to 38 6/7 weeks gestation ]
    result at the point of enrollment; compared to the ratio result at 2-7 days post

  3. The diagnosis rate of Pulmonary edema for gestations of 20 0/7 weeks through 38 6/7 as evidenced by the degree of change in the 'sFlt-1/PlGF ratio' [ Time Frame: between 20 0/7 weeks to 38 6/7 weeks gestation ]
    result at the point of enrollment; compared to the ratio result at 2-7 days post

  4. The diagnosis rate of DIC (Disseminated Intravascular Coagulation) for gestations of 20 0/7 weeks through 38 6/7 as evidenced by the degree of change in the 'sFlt-1/PlGF ratio' [ Time Frame: between 20 0/7 weeks to 38 6/7 weeks gestation ]
    result at the point of enrollment; compared to the ratio result at 2-7 days post

  5. The diagnosis rate of Liver hematoma/rupture for gestations of 20 0/7 weeks through 38 6/7 as evidenced by the degree of change in the 'sFlt-1/PlGF ratio' [ Time Frame: between 20 0/7 weeks to 38 6/7 weeks gestation ]
    result at the point of enrollment; compared to the ratio result at 2-7 days post

  6. The diagnosis rate of Stroke for gestations of 20 0/7 weeks through 38 6/7 as evidenced by the degree of change in the 'sFlt-1/PlGF ratio' [ Time Frame: between 20 0/7 weeks to 38 6/7 weeks gestation ]
    result at the point of enrollment; compared to the ratio result at 2-7 days post

  7. The diagnosis rate of Death for gestations of 20 0/7 weeks through 38 6/7 as evidenced by the degree of change in the 'sFlt-1/PlGF ratio' [ Time Frame: between 20 0/7 weeks to 38 6/7 weeks gestation ]
    result at the point of enrollment; compared to the ratio result at 2-7 days post


Biospecimen Retention:   Samples Without DNA

When blood sampling is clinically indicated, 10cc of maternal blood collected: at initial presentation, and at 2-7 d after initial, if undelivered.

Lab analysis performed in batches: sFlt-1 level, PlGF level, & sFlt-1/PlGF ratio (for research purpose only at cost of investigators), post-collection of history, lab data, delivery data & outcomes.

As clinically indicated (not altered for research purposes): Results for maternal urine-protein/creatinine ratio, CBC, CMP, LDH, & Uric acid will be collected.

Ultrasound, performed by investigators for research purpose only, on weekly basis from the time of enrollment until delivery, to evaluate uterine artery Doppler, middle cerebral artery Doppler, umbilical artery Doppler, estimated fetal weight, & amniotic fluid volume.



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Ages Eligible for Study:   14 Years to 45 Years   (Child, Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

150 pregnant subjects and their respective fetuses (total 300 subjects)

Prospective cohort:

  • Group 1: elevated sFlt-1/PlGF ratio;
  • Group 2: normal sFlt-1/PlGF ratio.
Criteria

Inclusion Criteria:

  • Gestational age at enrollment: 20 0/7 weeks to 38 6/7 weeks gestation Pregnant women aged 14 to 45 years
  • Presenting for admission for suspected superimposed preeclampsia
  • Diagnosis of chronic hypertension made prenatally or in the first 20 weeks of pregnancy (+/- medical therapy)
  • The clinical diagnosis of preeclampsia will follow the current criteria outlined by ACOG 10.

Exclusion Criteria:

  • Age 45 years;
  • Gestational age 19 6/7 weeks or less or 39 weeks or more ;
  • Multiple gestations.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03441711


Contacts
Contact: Giancarlo Mari, M.D. 901-448-2531 gmari@uthsc.edu
Contact: Michael M Aziz, MD 901-448-1829 maziz5@uthsc.edu

Locations
United States, Tennessee
Regional One Health Center for High Risk Pregnancies Recruiting
Memphis, Tennessee, United States, 38120
Contact: Giancarlo Mari, M.D.    901-448-2531    gmari@uthsc.edu   
Contact: , M.D.         
Sponsors and Collaborators
University of Tennessee
Investigators
Principal Investigator: Giancarlo Mari, M.D. OB/GYN, MFM

Additional Information:
Publications:

Responsible Party: University of Tennessee
ClinicalTrials.gov Identifier: NCT03441711     History of Changes
Other Study ID Numbers: 16-04377-XP
First Posted: February 21, 2018    Key Record Dates
Last Update Posted: February 21, 2018
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Pre-Eclampsia
Hypertension, Pregnancy-Induced
Pregnancy Complications