Vascular Biomarkers Predictive of the Progression From Hypertensive Disorders in Pregnancy to Preeclampsia in Pregnant Women

Официальное название

Exploratory Study. Endothelial Function and Vascular-tropic Biomarkers: Predictive Indicators of the Progression of Hypertensive Disorders in Pregnancy to Pre-eclampsia?

Обзор

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.

Подробное описание

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.

Вмешательства

• Другое 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.
• Процедура 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) and/or Popmetre.
• Другое 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.
• Процедура 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

Первичные конечные точки

• Change in the UEMP levels between 26th ± 2 week and 34th ± 2 week of pregnancy. [Срок оценки: change between the 26th ± 2 week of amenorrhea and 34th ± 2 week of amenorrhea]

Вторичные конечные точки (12)

• Change in circulating levels of soluble Fms-like tyrosine kinase (sFlt-1) between 26 weeks and 34 weeks of pregnancy [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: change between the 26th ± 2 week and 34th ± 2 week of amenorrhea]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Профилактика

Центры проведения

Франция · 3 центра

• AP-HP Avicenne Hospital, Department of internal medicine — Bobigny
• AP-HP Jean Verdier Hospital, Gynecology and Obstetrics Department — Bondy
• AP-HP Laribosière Hospital, Gynecology and Obstetrics Department — Paris

Публикации

• 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):1109-11 PMID 38690949
• Mancia 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 PMID 37345492
• Wu 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. PMID 28228456
• SFHTA, 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. PMID 14764923
• Noori 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. PMID 20644016
• Kleinrouweler 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 PMID 22433027
• Karumanchi 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. PMID 27067718

Идентификаторы

NCT: NCT04520048 · APHP200237 · 2019-A03207-50

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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