sFlt-1:PlGF Ratio in Diagnosing Superimposed Preeclampsia

NCT03441711 | Completed

• 1 other identifier: 16-04377-XP
• Study Type: observational
• Target: 87
• Locations: 1 country
• Sites: 1

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.

Conditions

Preeclampsia

Outcome Measures

Primary Outcomes (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'

  result at the point of enrollment; compared to the ratio result at 2-7 days post enrollment

  From 20 0/7 weeks through 38 6/7 weeks.

Secondary Outcomes (7)

• 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'

  between 20 0/7 weeks to 38 6/7 weeks gestation

• 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'

  between 20 0/7 weeks to 38 6/7 weeks gestation

• 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'

  between 20 0/7 weeks to 38 6/7 weeks gestation

• 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'

  between 20 0/7 weeks to 38 6/7 weeks gestation

• 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'

  between 20 0/7 weeks to 38 6/7 weeks gestation

Study Arms (2)

Group 1

elevated sFlt-1/PlGF ratio

Group 2

normal sFlt-1/PlGF ratio

Eligibility Criteria

• Age: 14 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• 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.

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• University of Tennessee: lead

Study Sites (1)

Regional One Health Center for High Risk Pregnancies

Memphis, Tennessee, 38120, United States

Location

Related Publications (9)

• Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. J Soc Gynecol Investig. 2004 Sep;11(6):342-52. doi: 10.1016/j.jsgi.2004.03.003.

  PMID: 15350246 BACKGROUND

• Honigberg MC, Cantonwine DE, Thomas AM, Lim KH, Parry SI, McElrath TF. Analysis of changes in maternal circulating angiogenic factors throughout pregnancy for the prediction of preeclampsia. J Perinatol. 2016 Mar;36(3):172-7. doi: 10.1038/jp.2015.170. Epub 2015 Nov 19.

  PMID: 26583938 BACKGROUND

• Xiong Y, Liebermann DA, Holtzman EJ, Jeronis S, Hoffman B, Geifman-Holtzman O. Preeclampsia-associated stresses activate Gadd45a signaling and sFlt-1 in placental explants. J Cell Physiol. 2013 Feb;228(2):362-70. doi: 10.1002/jcp.24139.

  PMID: 22718299 BACKGROUND

• Redman CW, Sargent IL, Staff AC. IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia? Placenta. 2014 Feb;35 Suppl:S20-5. doi: 10.1016/j.placenta.2013.12.008. Epub 2014 Jan 11.

  PMID: 24477207 BACKGROUND

• Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003 Mar;111(5):649-58. doi: 10.1172/JCI17189.

  PMID: 12618519 BACKGROUND

• Leanos-Miranda A, Campos-Galicia I, Isordia-Salas I, Rivera-Leanos R, Romero-Arauz JF, Ayala-Mendez JA, Ulloa-Aguirre A. Changes in circulating concentrations of soluble fms-like tyrosine kinase-1 and placental growth factor measured by automated electrochemiluminescence immunoassays methods are predictors of preeclampsia. J Hypertens. 2012 Nov;30(11):2173-81. doi: 10.1097/HJH.0b013e328357c0c9.

  PMID: 22902831 BACKGROUND

• 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.

  PMID: 22000672 BACKGROUND

• McElrath TF, Lim KH, Pare E, Rich-Edwards J, Pucci D, Troisi R, Parry S. Longitudinal evaluation of predictive value for preeclampsia of circulating angiogenic factors through pregnancy. Am J Obstet Gynecol. 2012 Nov;207(5):407.e1-7. doi: 10.1016/j.ajog.2012.08.010. Epub 2012 Aug 10.

  PMID: 22981320 BACKGROUND

• 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.

  PMID: 26735990 BACKGROUND

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.

MeSH Terms

Conditions

Pre-Eclampsia

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Study Officials

• Giancarlo Mari, M.D.

  OB/GYN, MFM

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2018
• First Posted: February 22, 2018
• Study Start: February 1, 2016
• Primary Completion: June 30, 2020
• Study Completion: June 30, 2020
• Last Updated: November 13, 2020

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)