Hypertension Disorders in PregnancyBIOVASC-PreHTANCT04520048
Vascular Biomarkers Predictive of the Progression From Hypertensive Disorders in Pregnancy to Preeclampsia in Pregnant Women
A study testing Determination of the UEMP levels, Aortic central pressure and the carotid-femoral pulse wave velocity and Vascular biomarker assay in people with Hypertension Disorders in Pregnancy and Gestational Hypertension, run by Assistance Publique - Hôpitaux de Paris at 3 sites in France.
Trial summary
Hypertension during pregnancy remains a leading cause of maternal and fetal 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women only
- Conditions the study is for
- Hypertension Disorders in Pregnancy, Gestational Hypertension, Pre-Eclampsia
- What is being tested?
- Determination of the UEMP levels, Aortic central pressure and the carotid-femoral pulse wave velocity and Vascular biomarker assay
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 110 participants
- Where
- 3 sitesFrance
- Study dates
- 11 Aug 2023to Dec 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Patients with a hypertension disorder in pregnancy 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.
Who cannot join
- Presence of pathologies interfering in a major way with vascular parameters: known multicomplicated diabetes treated before pregnancy, hypercholesterolemia known (or LDL>130 mg/dl), multicomplicated connectivitis, proven cardiovascular disease (ischemic heart disease, stroke, arteriopathy of the lower limbs, heart failure), pre-existing known renal failure (serum creatinine >125 µmol/L) 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.
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
France3 sites, 3 recruiting
- Recruiting
AP-HP Avicenne Hospital, Department of internal medicine
Bobigny, Seine Saint Denis, 93000
Marilucy LOPEZ-SUBLET, MD, +33 (0)148955390, marilucy.lopez-sublet@aphp.fr
Marilucy LOPEZ-SUBLET, MD
- Recruiting
AP-HP Jean Verdier Hospital, Gynecology and Obstetrics Department
Bondy, Seine Saint Denis, 93140
Lionel CARBILLON, MD PhD, +33 (0)148026030, lionel.carbillon@aphp.fr
Lionel CARBILLON, MD PhD
- Recruiting
AP-HP Laribosière Hospital, Gynecology and Obstetrics Department
Paris, 75010
Jérémy SROUSSI, MD, +33 (0)149956217, jeremy.sroussi@aphp.fr
Jérémy SROUSSI, MD
About this study
Official title: Exploratory Study. Endothelial Function and Vascular-tropic Biomarkers: Predictive Indicators of the Progression of Hypertensive Disorders in Pregnancy to Pre-eclampsia?
Hypertension during pregnancy remains a leading cause of maternal and fetal 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 is quite complex, as it depends on a number of factors. Among the hypertensive disorders in pregnancy (HDP), the pathophysiology of pre-eclampsia (one of the most studied in terms of severity) remains poorly understood. The evolution of international guidelines in recent years has made it possible to distinguish various HDP, but schematically we distinguish two main entities by the existence of proteinuria from and after the 20th week of amenorrhea and by maternal-fetal complications, more serious in pre-eclampsia than in gestational hypertension.
Read more
Acute placental vasculature and blood flow abnormalities were observed during gestational hypertension and preeclampsia, and maybe due to generalized vascular endothelial activation and vasospasm resulting in systemic hypertension and organ hypoperfusion. Endothelial dysfunction (ED) and abnormal expression of several specific blood biomarkers are now well accepted as characteristics of preeclampsia as a leader.
However, the progression of any HDP to preeclampsia is possible, but difficult to predict. By way of example, among between 15 and 40 % of gestational hypertension cases progress to preeclampsia, suggesting that it is the same worsening disease.
ED could be pre-existing (chronic, white-coat or masked hypertension) but also at the origin of gestational hypertension (unclassified hypertension, transient pregnancy hypertension), and subsequent development of preeclampsia through an imbalance between pro- and anti-angiogenic factors.
An imbalance of pro-angiogenic and anti-angiogenic proteins can testify to ED, as can adequate levels of endothelial microparticles.
The main objective of this research is to assess the presence of urinary endothelial microparticles in stable pregnant women with hypertensive disorder of pregnancy as a marker for the occurrence of pre-eclampsia during pregnancy.
Read the detailed 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.
Definitions of hypertensive disorders in pregnancy have evolved considerably. We know that 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 HDP as gestational hypertension, and subsequently itself contribute to the subsequent development of severe forms such 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 HDP 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.
- Being tested
- Determination of the UEMP levels, Aortic central pressure and the carotid-femoral pulse wave velocity, Vascular biomarker assay, Measurement of the uterine artery diameter
- Keywords
- Hypertension disorders in pregnancy, Gestational hypertension, Pre-eclampsia, Urinary endothelial microparticules, Endothelial dysfunction, Angiogenic biomarkers, Soluble Fms-like- tyrosine kinase 1, Placental Growth Factor, Vascular Endothelial Growth Factor, Microcirculation
- Medical subject headings
- Hypertension, Pregnancy-Induced, Pre-Eclampsia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Determination of the UEMP levelsOther
Quantification of UEMP by flow cytometry in urine (10 ml) collected at 26 ± 2 week and 34th ± 2 week of amenorrhea.
Aortic central pressure and the carotid-femoral pulse wave velocityProcedure or surgery
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) and/or Popmetre.
Vascular biomarker assayOther
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.
Measurement of the uterine artery diameterProcedure or surgery
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
| Study group | Role | What they receive |
|---|---|---|
| Women with a hypertension disorder in pregnancy and/or preeclampsia | Experimental | Pregnant patients from the 20th week of amenorrhea with the initial diagnosis of a hypertension disorder in pregnancy and/or preeclampsia. Patients in a stable state undergoing follow-up consultation (day hospital and week hospitalization) Receives: Other: Determination of the UEMP levels; Procedure: Aortic central pressure and the carotid-femoral pulse wave velocity; Other: Vascular biomarker assay; Procedure: Measurement of the uterine artery diameter |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: change between the 26th ± 2 week of amenorrhea and 34th ± 2 week of amenorrhea
Secondary outcomes (13)
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
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in circulating Endothelial Microparticle Levels between 26 weeks and 34 weeks of pregnancy
Determining of the blood levels of CEMP using flow cytometry
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in circulating Endothelial Celle Levels between 26 weeks and 34 weeks of pregnancy
Determining of the blood levels of CEC using flow cytometry
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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) and/or Popmetre.
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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)
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
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.
Measured: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Aug 2020
- Study start11 Aug 2023
- Primary completionDec 2026 (estimated)
- Study completionDec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (71)Papers the sponsor has linked to this study.
- Other trials for Hypertension Disorders in PregnancyStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 110 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Marilucy LOPEZ-SUBLET, MD, Principal investigator, AP-HP Avicenne Hospital, Department of Internal Medicine, ESH Hypertension European Excellence Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04520048
- Sponsor's protocol ID
- APHP200237
- Other IDs
- 2019-A03207-50
- Acronym
- BIOVASC-PreHTA
- Status last verified
- Sep 2025
- First submitted
- 17 Jul 2020
- Last updated
- 12 Sep 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Thomopoulos C, Hitij JB, De Backer T, Gkaliagkousi E, Kreutz R, Lopez-Sublet M, Marketou M, Mihailidou AS, Olszanecka A, Pechere-Bertschi A, Perez MP, Persu A, Piani F, Socrates T, Stolarz-Skrzypek K, Cifkova R. Management of hypertensive disorders in pregnancy: a Position Statement of the European Society of Hypertension Working Group 'Hypertension in Women'. J Hypertens. 2024 Jul 1;42(7):1109-1132. doi: 10.1097/HJH.0000000000003739. Epub 2024 Apr 11.
PubMed 38690949Mancia G, Kreutz R, Brunstrom M, Burnier M, Grassi G, Januszewicz A, Muiesan ML, Tsioufis K, Agabiti-Rosei E, Algharably EAE, Azizi M, Benetos A, Borghi C, Hitij JB, Cifkova R, Coca A, Cornelissen V, Cruickshank JK, Cunha PG, Danser AHJ, Pinho RM, Delles C, Dominiczak AF, Dorobantu M, Doumas M, Fernandez-Alfonso MS, Halimi JM, Jarai Z, Jelakovic B, Jordan J, Kuznetsova T, Laurent S, Lovic D, Lurbe E, Mahfoud F, Manolis A, Miglinas M, Narkiewicz K, Niiranen T, Palatini P, Parati G, Pathak A, Persu A, Polonia J, Redon J, Sarafidis P, Schmieder R, Spronck B, Stabouli S, Stergiou G, Taddei S, Thomopoulos C, Tomaszewski M, Van de Borne P, Wanner C, Weber T, Williams B, Zhang ZY, Kjeldsen SE. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023 Dec 1;41(12):1874-2071. doi: 10.1097/HJH.0000000000003480. Epub 2023 Sep 26.
PubMed 37345492Wu P, Haththotuwa R, Kwok CS, Babu A, Kotronias RA, Rushton C, Zaman A, Fryer AA, Kadam U, Chew-Graham CA, Mamas MA. Preeclampsia and Future Cardiovascular Health: A Systematic Review and Meta-Analysis. Circ Cardiovasc Qual Outcomes. 2017 Feb;10(2):e003497. doi: 10.1161/CIRCOUTCOMES.116.003497. Epub 2017 Feb 22.
PubMed 28228456SFHTA, M.-V.C.e.a., HTA et Grossesse. Consensus d'Experts de la Société Françaises d'Hypertension Artérielle. Consensus d'Experts avec le partenariat du Collège National des Gynécologues et Obstétriciens Français. 2015, Decembre: p. 1-5.
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.
PubMed 14764923Noori M, Donald AE, Angelakopoulou A, Hingorani AD, Williams DJ. Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension. Circulation. 2010 Aug 3;122(5):478-87. doi: 10.1161/CIRCULATIONAHA.109.895458. Epub 2010 Jul 19.
PubMed 20644016Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, Bossuyt PM, van der Post JA, von Dadelszen P, Mol BW, Pajkrt E; EBM CONNECT Collaboration. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. BJOG. 2012 Jun;119(7):778-87. doi: 10.1111/j.1471-0528.2012.03311.x. Epub 2012 Mar 20.
PubMed 22433027Karumanchi SA. Angiogenic Factors in Preeclampsia: From Diagnosis to Therapy. Hypertension. 2016 Jun;67(6):1072-9. doi: 10.1161/HYPERTENSIONAHA.116.06421. Epub 2016 Apr 11. No abstract available.
PubMed 27067718Verlohren S, Perschel FH, Thilaganathan B, Droge LA, Henrich W, Busjahn A, Khalil A. Angiogenic Markers and Cardiovascular Indices in the Prediction of Hypertensive Disorders of Pregnancy. Hypertension. 2017 Jun;69(6):1192-1197. doi: 10.1161/HYPERTENSIONAHA.117.09256. Epub 2017 May 1.
PubMed 28461601Bouloumie A, Schini-Kerth VB, Busse R. Vascular endothelial growth factor up-regulates nitric oxide synthase expression in endothelial cells. Cardiovasc Res. 1999 Mar;41(3):773-80. doi: 10.1016/s0008-6363(98)00228-4.
PubMed 10435050Dulak J, Jozkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D, Florek I, Wojtowicz A, Szuba A, Cooke JP. Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):659-66. doi: 10.1161/01.atv.20.3.659.
PubMed 10712388Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. doi: 10.1056/NEJMoa021491.
PubMed 12890841Mourad JJ, des Guetz G, Debbabi H, Levy BI. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008 May;19(5):927-34. doi: 10.1093/annonc/mdm550. Epub 2007 Dec 4.
PubMed 18056916Artunc-Ulkumen B, Guvenc Y, Goker A, Gozukara C. Relationship of neutrophil gelatinase-associated lipocalin (NGAL) and procalcitonin levels with the presence and severity of the preeclampsia. J Matern Fetal Neonatal Med. 2015 Nov;28(16):1895-900. doi: 10.3109/14767058.2014.972926. Epub 2014 Oct 29.
PubMed 25283849Yesil A, Kanawati A, Helvacioglu C, Kaya C, Ozgun CG, Cengiz H. Identification of patients at risk for preeclampsia with the use of uterine artery Doppler velocimetry and copeptin. J Matern Fetal Neonatal Med. 2017 Nov;30(22):2763-2768. doi: 10.1080/14767058.2016.1262841. Epub 2016 Dec 7.
PubMed 27868455
Study at a glance
From the registry record, last updated by the sponsor on 12 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exploratory Study. Endothelial Function and Vascular-tropic Biomarkers: Predictive Indicators of the Progression of Hypertensive Disorders in Pregnancy to Pre-eclampsia?
- ClinicalTrials.gov ID
- NCT04520048
- Acronym / sponsor ID
- BIOVASC-PreHTA / APHP200237
- Keywords
- Hypertension disorders in pregnancy, Gestational hypertension, Pre-eclampsia, Urinary endothelial microparticules, Endothelial dysfunction, Angiogenic biomarkers, Soluble Fms-like- tyrosine kinase 1, Placental Growth Factor
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 110 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 11 Aug 2023 (actual)
- Primary completion
- Dec 2026 (estimated)
- Study completion
- Dec 2026 (estimated)
- First posted
- 20 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Hypertension during pregnancy remains a leading cause of maternal and fetal 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 is quite complex, as it depends on a number of factors. Among the hypertensive disorders in pregnancy (HDP), the pathophysiology of pre-eclampsia (one of the most studied in terms of severity) remains poorly understood. The evolution of international guidelines in recent years has made it possible to distinguish various HDP, but schematically we distinguish two main entities by the existence of proteinuria from and after the 20th week of amenorrhea and by maternal-fetal complications, more serious in pre-eclampsia than in gestational hypertension.
Acute placental vasculature and blood flow abnormalities were observed during gestational hypertension and preeclampsia, and maybe due to generalized vascular endothelial activation and vasospasm resulting in systemic hypertension and organ hypoperfusion. Endothelial dysfunction (ED) and abnormal expression of several specific blood biomarkers are now well accepted as characteristics of preeclampsia as a leader.
However, the progression of any HDP to preeclampsia is possible, but difficult to predict. By way of example, among between 15 and 40 % of gestational hypertension cases progress to preeclampsia, suggesting that it is the same worsening disease.
ED could be pre-existing (chronic, white-coat or masked hypertension) but also at the origin of gestational hypertension (unclassified hypertension, transient pregnancy hypertension), and subsequent development of preeclampsia through an imbalance between pro- and anti-angiogenic factors.
An imbalance of pro-angiogenic and anti-angiogenic proteins can testify to ED, as can adequate levels of endothelial microparticles.
The main objective of this research is to assess the presence of urinary endothelial microparticles in stable pregnant women with hypertensive disorder of pregnancy as a marker for the occurrence of pre-eclampsia during pregnancy.
Detailed 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.
Definitions of hypertensive disorders in pregnancy have evolved considerably. We know that 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 HDP as gestational hypertension, and subsequently itself contribute to the subsequent development of severe forms such 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 HDP 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.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Women with a hypertension disorder in pregnancy and/or preeclampsia | Experimental | Other: Determination of the UEMP levels, Procedure: Aortic central pressure and the carotid-femoral pulse wave velocity, Other: Vascular biomarker assay, Procedure: Measurement of the uterine artery diameterPregnant patients from the 20th week of amenorrhea with the initial diagnosis of a hypertension disorder in pregnancy and/or preeclampsia. Patients in a stable state undergoing follow-up consultation (day hospital and week hospitalization) |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Patients with a hypertension disorder in pregnancy 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.
Key exclusion criteria (7 listed)
- Presence of pathologies interfering in a major way with vascular parameters: known multicomplicated diabetes treated before pregnancy, hypercholesterolemia known (or LDL>130 mg/dl), multicomplicated connectivitis, proven cardiovascular disease (ischemic heart disease, stroke, arteriopathy of the lower limbs, heart failure), pre-existing known renal failure (serum creatinine >125 µmol/L) 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Determination of the UEMP levelsQuantification of UEMP by flow cytometry in urine (10 ml) collected at 26 ± 2 week and 34th ± 2 week of amenorrhea. | Other | Women with a hypertension disorder in pregnancy and/or preeclampsia |
| Aortic central pressure and the carotid-femoral pulse wave velocityMeasurement 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) and/or Popmetre. | Procedure or surgery | Women with a hypertension disorder in pregnancy and/or preeclampsia |
| Vascular biomarker assayPlasma 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. | Other | Women with a hypertension disorder in pregnancy and/or preeclampsia |
| Measurement of the uterine artery diameterThis 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 | Procedure or surgery | Women with a hypertension disorder in pregnancy and/or preeclampsia |
Primary outcome
Change in the UEMP levels between 26th ± 2 week and 34th ± 2 week of pregnancy.
Time frame: change between the 26th ± 2 week of amenorrhea and 34th ± 2 week of amenorrhea
Quantification of UEMP by flow cytometry in urine collected at 26 ± 2 week and 34th ± 2 week of amenorrhea.
13 secondary outcomes
Change in circulating levels of soluble Fms-like tyrosine kinase (sFlt-1) between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in circulating Placental Growth factor (PIGF) between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in circulating levels of vascular endothelial growth factors (VEGF) between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in circulating levels of soluble endogline (sEng) between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in angiotensin II receptor (AT1) between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in the circulating Copetid levels between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in circulating levels of Interleukin IL-17 between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in urinary levels of Neutrophil Gelatinase-Associated Lipocalin (NGAL) between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in circulating Endothelial Microparticle Levels between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in circulating Endothelial Celle Levels between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in central aortic blood pressure between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in carotid-femoral pulse wave velocity between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Change in the uterine artery diameter between 26 weeks and 34 weeks of pregnancy
Time frame: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Sep 2025.
- Background: PubMed 38690949Thomopoulos C, Hitij JB, De Backer T, Gkaliagkousi E, Kreutz R, Lopez-Sublet M, Marketou M, Mihailidou AS, Olszanecka A, Pechere-Bertschi A, Perez MP, Persu A, Piani F, Socrates T, Stolarz-Skrzypek K, Cifkova R. Management of hypertensive disorders in pregnancy: a Position Statement of the European Society of Hypertension Working Group 'Hypertension in Women'. J Hypertens. 2024 Jul 1;42(7):1109-1132. doi: 10.1097/HJH.0000000000003739. Epub 2024 Apr 11.
- Background: PubMed 37345492Mancia G, Kreutz R, Brunstrom M, Burnier M, Grassi G, Januszewicz A, Muiesan ML, Tsioufis K, Agabiti-Rosei E, Algharably EAE, Azizi M, Benetos A, Borghi C, Hitij JB, Cifkova R, Coca A, Cornelissen V, Cruickshank JK, Cunha PG, Danser AHJ, Pinho RM, Delles C, Dominiczak AF, Dorobantu M, Doumas M, Fernandez-Alfonso MS, Halimi JM, Jarai Z, Jelakovic B, Jordan J, Kuznetsova T, Laurent S, Lovic D, Lurbe E, Mahfoud F, Manolis A, Miglinas M, Narkiewicz K, Niiranen T, Palatini P, Parati G, Pathak A, Persu A, Polonia J, Redon J, Sarafidis P, Schmieder R, Spronck B, Stabouli S, Stergiou G, Taddei S, Thomopoulos C, Tomaszewski M, Van de Borne P, Wanner C, Weber T, Williams B, Zhang ZY, Kjeldsen SE. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023 Dec 1;41(12):1874-2071. doi: 10.1097/HJH.0000000000003480. Epub 2023 Sep 26.
- Background: PubMed 28228456Wu P, Haththotuwa R, Kwok CS, Babu A, Kotronias RA, Rushton C, Zaman A, Fryer AA, Kadam U, Chew-Graham CA, Mamas MA. Preeclampsia and Future Cardiovascular Health: A Systematic Review and Meta-Analysis. Circ Cardiovasc Qual Outcomes. 2017 Feb;10(2):e003497. doi: 10.1161/CIRCOUTCOMES.116.003497. Epub 2017 Feb 22.
- BackgroundSFHTA, M.-V.C.e.a., HTA et Grossesse. Consensus d'Experts de la Société Françaises d'Hypertension Artérielle. Consensus d'Experts avec le partenariat du Collège National des Gynécologues et Obstétriciens Français. 2015, Decembre: p. 1-5.
- Background: PubMed 14764923Levine 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.
- Background: PubMed 20644016Noori M, Donald AE, Angelakopoulou A, Hingorani AD, Williams DJ. Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension. Circulation. 2010 Aug 3;122(5):478-87. doi: 10.1161/CIRCULATIONAHA.109.895458. Epub 2010 Jul 19.
- Background: PubMed 22433027Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, Bossuyt PM, van der Post JA, von Dadelszen P, Mol BW, Pajkrt E; EBM CONNECT Collaboration. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. BJOG. 2012 Jun;119(7):778-87. doi: 10.1111/j.1471-0528.2012.03311.x. Epub 2012 Mar 20.
- Background: PubMed 27067718Karumanchi SA. Angiogenic Factors in Preeclampsia: From Diagnosis to Therapy. Hypertension. 2016 Jun;67(6):1072-9. doi: 10.1161/HYPERTENSIONAHA.116.06421. Epub 2016 Apr 11. No abstract available.
- Background: PubMed 28461601Verlohren S, Perschel FH, Thilaganathan B, Droge LA, Henrich W, Busjahn A, Khalil A. Angiogenic Markers and Cardiovascular Indices in the Prediction of Hypertensive Disorders of Pregnancy. Hypertension. 2017 Jun;69(6):1192-1197. doi: 10.1161/HYPERTENSIONAHA.117.09256. Epub 2017 May 1.
- Background: PubMed 10435050Bouloumie A, Schini-Kerth VB, Busse R. Vascular endothelial growth factor up-regulates nitric oxide synthase expression in endothelial cells. Cardiovasc Res. 1999 Mar;41(3):773-80. doi: 10.1016/s0008-6363(98)00228-4.
- Background: PubMed 10712388Dulak J, Jozkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D, Florek I, Wojtowicz A, Szuba A, Cooke JP. Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):659-66. doi: 10.1161/01.atv.20.3.659.
- Background: PubMed 12890841Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. doi: 10.1056/NEJMoa021491.
- Individual participant dataSharing planned: No
Related trials for Hypertension Disorders in Pregnancy
Recruiting
Investigating Vascular Properties of HEMI and SPG Signals in Individuals With or at Risk for Chronic Kidney Disease
Chronic Kidney Disease, Hypertension (HTN)
RecruitingPhase 3
A Phase III Renal Outcomes and Cardiovascular Mortality Study to Investigate the Efficacy and Safety of Baxdrostat in Combination With Dapagliflozin in Participants With Chronic Kidney Disease and High Blood Pressure
Chronic Kidney Disease and Hypertension
Recruiting
Guiding Optimal Blood Pressure Management in Peritoneal Dialysis Pilot Trial
End Stage Kidney Disease (ESKD), Hypertension (HTN)
Active, not recruitingObservational study
A Longitudinal Cohort Study to Evaluate Cardiovascular Risk Factors and Disease in Haiti
Hypertension, Diabetes
RecruitingObservational study
Molecular Study of the Maternal-fetal Interface in Preeclampsia.
Preeclampsia
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Marilucy LOPEZ-SUBLET, MD principal investigator
AP-HP Avicenne Hospital, Department of Internal Medicine, ESH Hypertension European Excellence Centre
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Determination of the UEMP levels, Aortic central pressure and the carotid-femoral pulse wave velocity and Vascular biomarker assay in people with Hypertension Disorders in Pregnancy and Gestational Hypertension, run by Assistance Publique - Hôpitaux de Paris at 3 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 12 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Marilucy LOPEZ-SUBLET, MD (+33 (0)148955391, marilucy.lopez-sublet@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in the UEMP levels between 26th ± 2 week and 34th ± 2 week of pregnancy. (time frame: change between the 26th ± 2 week of amenorrhea and 34th ± 2 week of amenorrhea). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04520048, which also lists 71 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Sep 2025.