sFlt-1:PlGF Ratio in Diagnosing Superimposed Preeclampsia

Preeclampsia Clinical Trial

Official title:

The Utility of the sFlt-1/PlGF Ratio in Diagnosing Superimposed Preeclampsia and Predicting Adverse Outcomes in Subjects With Chronic Hypertension

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03441711
• Other study ID #: 16-04377-XP
• Status: Completed
• Start date: February 2016
• Est. completion date: June 30, 2020

Study information

• Verified date: January 2019
• Source: University of Tennessee
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 87
• Est. completion date: June 30, 2020
• Est. primary completion date: June 30, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 14 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Pre-Eclampsia
• Preeclampsia

Locations

Country	Name	City	State
United States	Regional One Health Center for High Risk Pregnancies	Memphis	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
University of Tennessee

Country where clinical trial is conducted

United States, 

References & Publications (9)

Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. J Soc Gynecol Investig. 2004 Sep;11(6):342-52. Review. — View Citation

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. — View Citation

Leaños-Miranda A, Campos-Galicia I, Isordia-Salas I, Rivera-Leaños R, Romero-Arauz JF, Ayala-Méndez 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. — View Citation

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. — View Citation

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. — View Citation

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. — 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

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. — View Citation

Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström 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	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	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'	result at the point of enrollment; compared to the ratio result at 2-7 days post	between 20 0/7 weeks to 38 6/7 weeks gestation
Secondary	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'	result at the point of enrollment; compared to the ratio result at 2-7 days post	between 20 0/7 weeks to 38 6/7 weeks gestation
Secondary	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'	result at the point of enrollment; compared to the ratio result at 2-7 days post	between 20 0/7 weeks to 38 6/7 weeks gestation
Secondary	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'	result at the point of enrollment; compared to the ratio result at 2-7 days post	between 20 0/7 weeks to 38 6/7 weeks gestation
Secondary	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'	result at the point of enrollment; compared to the ratio result at 2-7 days post	between 20 0/7 weeks to 38 6/7 weeks gestation
Secondary	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'	result at the point of enrollment; compared to the ratio result at 2-7 days post	between 20 0/7 weeks to 38 6/7 weeks gestation
Secondary	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'	result at the point of enrollment; compared to the ratio result at 2-7 days post	between 20 0/7 weeks to 38 6/7 weeks gestation

External Links

•   [71-OR]: The revised 2013 ACOG definitions of hypertensive disorders of pregnancy significantly increase the diagnostic prevalence of preeclampsia