Vascular Biomarkers Predictive of the Progression From Gestational Hypertension to Preeclampsia in Pregnant Women

Pre-eclampsia Clinical Trial

— BIOVASC-PreHTA  

Official title:

Exploratory Study. Endothelial Function and Vascular Biomarkers: Predictive Indicators of the Progression From Gestational Hypertension to Preeclampsia?

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04520048
• Other study ID #: APHP200237
• Secondary ID: 2019-A03207-50
• Status: Recruiting
• Phase: N/A
• Start date: August 11, 2023
• Est. completion date: December 2026

Study information

• Verified date: January 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Marilucy LOPEZ-SUBLET, MD
• Phone: +33 (0)148955390
• Email: marilucy.lopez-sublet[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Hypertension during pregnancy remains a leading cause of maternal and foetal morbidity and mortality. The frequency (5 to 10% of pregnancies) and potential severity of these diseases, both for the mother and the child, are reasons for standardizing and optimizing medical practices. The cause of hypertension during pregnancy and in particular the pathophysiology of preeclampsia remains poorly understood. Guidelines distinguish these two entities by the existence of proteinuria from and after the 20th week of amenorrhea and by maternal-foetal complications, more serious in pre-eclampsia than in gestational hypertension. During gestational hypertension and preeclampsia acute placental vasculature and blood flow abnormalities were observed, maybe due to generalized vascular endothelial activation and vasospasm resulting in systemic hypertension and organ hypoperfusion. Endothelial dysfunction and abnormal expression of several specific blood biomarkers are now well accepted as characteristics of preeclampsia. However, the progression of gestational hypertension to preeclampsia is difficult to predict; between 15 and 40 % of gestational hypertension cases progress to preeclampsia, suggesting that it is the same worsening disease. Endothelial dysfunction could be at the origin of gestational hypertension, and subsequent development of preeclampsia through an imbalance between pro- and anti-angiogenic factors. The main objective of this research is to assess whether the alteration of endothelium-dependent vasodilatation in pregnant women with stable hypertension is correlated with the occurrence of preeclampsia later during pregnancy.

Description:

Hypertension in pregnancy is defined by PAS ≥140 mmHg and/or PAD ≥ 90 mmHg, mild to moderate hypertension by PAS = 140-159 mmHg and/or PAD = 90-109 mmHg and severe hypertension by PAS ≥ 160 mmHg and/or PAD ≥ 110 mmHg. During gestational hypertension (GE) there is no pathologic elevation of proteinuria (after 20 weeks of amenorrhea). Preeclampsia (PE) is defined as high blood pressure (controlled or uncontrolled) associated with proteinuria discovered after the 20th week of amenorrhea. The cause of hypertension and pathophysiology during pregnancy and in particular of preeclampsia remains poorly understood. Endothelial dysfunction and abnormal blood levels of several biomarkers are associated with PE, such as: soluble Fms-like- tyrosine kinase 1 (sFlt-1), Placental Growth Factor (PIGF) and Vascular Endothelial Growth Factor (VEGF). VEGF is of particular importance due to its direct vasodilating effect at systemic level through its interaction with nitric oxide (NO). There is a bi-directional regulation between VEGF and NO, which has direct implications for endothelium, capillary permeability and angiogenesis. sFlt-1 (circulating form of VEGF receptor) has the property of neutraliting the growth factors VEGF and PIGF. Inhibition of VEGF has a known biological effect on endothelial function in adults and is believed to be a key factor in explaining elevated blood pressure. This has been demonstrated in patients undergoing anti-angiogenic therapy in combination with chemotherapy. Other biomarkers of preeclampsia are less known and could be involved in pathophysiological mechanisms; mainly hypervolemia, renal dysfunction and activation of inflammation. The progression of gestational hypertension to preeclampsia is difficult to predict; between 15 and 40 % of gestational hypertension cases progress to preeclampsia, suggesting that it is a single worsening disease. Preeclampsia is known to be one of the few diseases in which acute placental abnormalities manifest at the mother's vascular and renal system levels. These abnormalities are attributable to generalized vascular endothelial activation and vasospasm, resulting in hypertension and hypoperfusion of organs. Endothelial dysfunction could be at the origin of gestational hypertension, and subsequently itself contribute to the subsequent development of preeclampsia through an imbalance between pro- and anti-angiogenic factors likely in relation with increased oxidative stress. It is now accepted that angiogenic biomarkers (such as soluble fms-like tyrosine kinase 1, Placenta growth factor and soluble endoglin) contribute to endothelial dysfunction through VEGF antagonizing among others. The dosage of these angiogenic biomarkers in the maternal bloodstream is highly predictive and significantly abnormal from the 23th week of amenorrhea on average, and with a maximum peak between the 32th and 36th week of amenorrhea. Endothelial microparticles (EMPs) are involved in intracellular communication and produced in normal pregnancy and in PE. The renal damage associated with PE and the potential role of extracellular vesicles are in the main adverse mechanisms that distinguish the different types of hypertension in pregnancy. Adequate levels of circulating endothelial microparticles (CEMP), circulating endothelial cells (CECs), and endothelial progenitor cells most likely play an important role in the development and regulation of the vasculature during pregnancy, but the exact role in the pathogenesis of PE is unknown. These endothelial microparticles (EMPs) reflects systemic endothelial damage and can also be measured in urine by flow cytometry. In general, in hypertensive patients, there is peritubular capillary loss (PCL) and it can be measured by these EMPs. Urinary (not blood) MP levels correlate directly with renal hypoxia and fibrosis and inversely with cortical perfusion. Therefore, the level of EMPs could be useful as "new biomarkers" of intrarenal capillary loss. However, only a few in-depth studies in the field of hypertension in pregnancy have focused on this issue. The main objective is to assess whether the presence of urinary endothelial microparticles (UEMP) in the pregnant woman in a stable condition with discovery of gestational hypertension is a marker of the occurrence of preeclampsia later during pregnancy. The investigators further explore a possible correlation of alteration of UEMP to other biomarkers of pre-eclampsia endothelial dysfunction and vascular involvement in pregnancy hypertension.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: December 2026
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Patients with gestational hypertension and/or preeclampsia from the 20th amenorrhea week until the 26th ± 2 amenorrhea week.
• Age between 18 and 40 years old.
• Having given written consent
• Patients affiliated to a social security scheme

Exclusion Criteria:

• Presence of pathologies interfering in a major way with vascular parameters: known multicomplicated diabetes treated before pregnancy, hypercholesterolemia known (or LDL>130 mg/dl), connectivitis, proven cardiovascular disease (ischemic heart disease, stroke, arteriopathy of the lower limbs, heart failure), pre-existing known renal failure (MDRD <60 ml/min) and/or pre-existing proteinuria = 300 mg/24h).
• Cardiac arrhythmia.
• Hepatitis C, HIV infection (assay performed within 6 months prior to diagnosis of pre- eclampsia)
• Recent history of venous (pulmonary embolism, phlebitis) or arterial (myocardial infarction, unstable angina, stroke, transient ischemic attack), thrombotic event = 3 months.
• Patient already engaged in a therapeutic protocol
• Patients under legal protective measures
• Patients receiving State Medical Assistance

Related Conditions & MeSH terms

• Eclampsia
• Gestational Hypertension
• Hypertension
• Hypertension, Pregnancy-Induced
• Pre-eclampsia

Intervention

Other:
• Determination of the UEMP levels
Quantification of UEMP by flow cytometry in urine (10 ml) collected at 26 ± 2 week and 34th ± 2 week of amenorrhea.

Procedure:
• Aortic central pressure and the carotid-femoral pulse wave velocity
Measurement of the aortic central arterial pressure (systolic and diastolic arterial pressure) by applanation tonometry, and the index of aortic increase by applanation tonometry, the carotid-femoral pulse wave velocity using the SphygmoCor® system (PWV Medical)

Other:
• Vascular biomarker assay
Plasma angiogenic biomarker levels determination using an immunoassay, including circulating sFlt-1, circulating PIGF, sFlt-1 / PIGF ratio, circulating VEGF, circulating soluble endoglin (sEng), other biomarkers assessment, including anti-angiotensin II receptor (AT1), circulating copeptin, circulating interleukin 17 (IL-17), Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL), as well as CEMP and CEC quantification using flow cytometry.

Procedure:
• Measurement of the uterine artery diameter
This measurement is added to the routine examination of the uterine artery. Bi-dimensional ultrasound imaging with angio-Doppler allows the study of the artery as the blood flow velocity and vessel diameter. Uterine artery Doppler pulsatility index (UtA-PI), mean flow velocity and diameter measurement could be calculated with Doppler instrument with software could determine instantaneous true mean blood flow velocity. Measurement is made by placing the cursor from outer edge to outer edge of the artery adventitia, on a cross-section and taking the largest diameter

Locations

Country	Name	City	State
France	AP-HP Avicenne Hospital, Department of internal medicine	Bobigny	Seine Saint Denis
France	AP-HP Jean Verdier Hospital, Gynecology and obstetrics Department	Bondy	Seine Saint Denis

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

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* Note: There are 69 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the UEMP levels between 26th ± 2 week and 34th ± 2 week of pregnancy.	Quantification of UEMP by flow cytometry in urine collected at 26 ± 2 week and 34th ± 2 week of amenorrhea.	change between the 26th ± 2 week of amenorrhea and 34th ± 2 week of amenorrhea
Secondary	Change in circulating levels of soluble Fms-like tyrosine kinase (sFlt-1) between 26 weeks and 34 weeks of pregnancy	Determining of circulating levels of sFlt-1 in the serum of patients using un immunoassay	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in circulating Placental Growth factor (PIGF) between 26 weeks and 34 weeks of pregnancy	Determining of circulating levels of PlGF in the serum of patients using un immunoassay	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in circulating levels of vascular endothelial growth factors (VEGF) between 26 weeks and 34 weeks of pregnancy	Determining of circulating levels of VEGF in the serum of patients using un immunoassay	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in circulating levels of soluble endogline (sEng) between 26 weeks and 34 weeks of pregnancy	Determining of circulating levels of sEng-1 in the serum of patients using un immunoassay	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in angiotensin II receptor (AT1) between 26 weeks and 34 weeks of pregnancy	Measurement of the angiotensin II receptor (AT1) levels in the serum of patients using un immunoassay	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in the circulating Copetid levels between 26 weeks and 34 weeks of pregnancy	Measurement of circulating Copetid levels in the serum of patients using un immunoassay	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in circulating levels of Interleukin IL-17 between 26 weeks and 34 weeks of pregnancy	Determining of circulating levels of Interleukin IL-17 in the serum of patients using un immunoassay	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in urinary levels of Neutrophil Gelatinase-Associated Lipocalin (NGAL) between 26 weeks and 34 weeks of pregnancy	Determining of urinary levels of NGAL using un immunoassay	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in circulating Endothelial Microparticle Levels between 26 weeks and 34 weeks of pregnancy	Determining of the blood levels of CEMP using flow cytometry	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in circulating Endothelial Celle Levels between 26 weeks and 34 weeks of pregnancy	Determining of the blood levels of CEC using flow cytometry	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in central aortic blood pressure between 26 weeks and 34 weeks of pregnancy	Measurement of the aortic central arterial pressure (systolic and diastolic arterial pressure) by applanation tonometry, and the index of aortic increase by applanation tonometry, using the SphygmoCor® system (PWV Medical)	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in carotid-femoral pulse wave velocity between 26 weeks and 34 weeks of pregnancy	Measurement of the carotid-femoral pulse wave velocity using the SphygmoCor® system (PWV Medical)	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Secondary	Change in the uterine artery diameter between 26 weeks and 34 weeks of pregnancy	Determining of the uterine artery diameter by bi-dimensional ultrasound imaging with angio-Doppler allows the study of the artery as the blood flow velocity and vessel diameter.	change between the 26th ± 2 week and 34th ± 2 week of amenorrhea