Multiparametric Assessment of Maternal Vascular Function in the Prediction of Hypertensive Disorders of Pregnancy

Study Overview
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Brief Summary
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The present study is a single-centre prospective study that will enrol pregnant women during their first trimester of pregnancy (11+0 - 13+6 weeks of gestation). During pregnancy, women will undergo standard clinical evaluation and management. During the two study visits (enrollment and 24+0 - 27+6 weeks of gestation) the investigators will perform arterial tonometry (Pulsepen) and in vivo darkfield microscopy (Glycocheck) to evaluate endothelial and vascular function. A urine sample and a blood sample for specific study analyses on metabolic profile, endothelial and angiogenic markers will be collected. Pregnancy outcomes will be collected at delivery and five years after delivery all the participants will be interview to collect long-term cardiovascular outcomes. Serum endothelial and angiogenic markers will be evaluated only in participants who will develop hypertensive disorders of pregnancy and in an equal number of controls matched for age and body mass index at the time of conception.

Detailed Description
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Primary aim: To determine the role of the combination of arterial tonometry and endothelial glycocalyx measurement in predicting the risk of developing hypertensive disorders in pregnancy. Secondary aims: To determine the association between circulating markers of angiogenesis and endothelial dysfunction (ANG-1, ANG-2, ET-1, ICAM-1 and VCAM-1) and the development of hypertensive disorders of pregnancy. To define the trends of serum uric acid, lipids and xanthine oxidase activity in normotensive and hypertensive pregnancies. To determine the ability of the combination of arterial tonometry and endothelial glycocalyx measurement, performed in the two study visits during pregnancy, in predicting the risk of long-term maternal cardiovascular disease.

Official Title
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Multiparametric Assessment of Maternal Vascular Function as a New Diagnostic and Prognostic Tool for Hypertensive Disorders of Pregnancy and Preeclampsia - EDIPE Study

Conditions
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Preeclampsia, Hypertensive Disorder of Pregnancy

Intervention / Treatment
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* Device: Arterial applanation tonometry
* Device: In vivo endothelial glycocalyx measurement
* Diagnostic Test: Serum markers of angiogenesis and endothelial dysfunction
* Diagnostic Test: Blood chemistry test
* Diagnostic Test: Serum xanthine oxidase activity


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 18 years Single pregnancy No previous pregnancies lasting more than 12 weeks Participant willing and able to give informed consent for participation in the study Exclusion Criteria: Intermediate-high risk of genetic abnormalities and/or need to perform invasive tests (amniocentesis, villocentesis) History of solid organ or hematopoietic stem cell transplantation Chronic renal failure (eGFR≤45ml/min/1.73m2) Chronic treatment with antihypertensive drugs and/or xanthine oxidase (XO) inhibitors

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: The study is a single group study (Principal Arm) with a sub-group of participants undergoing additional experimental analyses. The additional analyses will be performed in participants who will develop hypertensive disorders of pregnancy and matched (age and body mass index before conception) controls with healthy pregnancies.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Principal arm<br>The entire cohort of participants will undergo all experimental procedures. Participants who will develop hypertensive disorders of pregnancy and matched participants with healthy pregnancies will also undergo serum endothelial and angiogenic markers assessment. | Device: Arterial applanation tonometry<br>* Arterial applanation tonometry will be performed at the carotid and femoral level by the PulsePen device (Software WPulsePen version 2.3.1, DiaTecne, Milan, Italy), while the subject is lying in the horizontal position and after 5 minutes of rest.<br>* Other names: Pulse wave velocity assessment;Device: In vivo endothelial glycocalyx measurement<br>* The in vivo microscopy (GlycoCheck system) is performed in the sublingual capillaries during the morning, with the participant sitting on a chair. The sublingual capillaries are visualized using an SDF video microscope (Capiscope handheld, KK Research technology Ltd).<br>* Other names: Sidestream dark field microscopy;Diagnostic Test: Serum markers of angiogenesis and endothelial dysfunction<br>* ELISA assays to measure serum circulating markers of angiogenesis and endothelial dysfunction (ANG-1, ANG-2, ET-1, ICAM-1 and VCAM-1).<br>* Other names: ANG-2;Diagnostic Test: Blood chemistry test<br>* Immunochemistry analysis of serum levels of uric acid, total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, Lipoprotein (a)<br>Diagnostic Test: Serum xanthine oxidase activity<br>* Serum xanthine oxidase (XO) activity will be assessed in blood samples measuring the ability of XO to produce uric acid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perfused Boundary Region (PBR) | Micron | Baseline visit (11/13+6 weeks of pregnancy) | 
| Perfused Boundary Region (PBR) | Micron | Follow-up visit (24/27+6 weeks of pregnancy) | 
| Carotid-femoral pulse wave velocity (cf-PWV) | m/s | Baseline visit (11/13+6 weeks of pregnancy) | 
| Carotid-femoral pulse wave velocity (cf-PWV) | m/s | Follow-up visit (24/27+6 weeks of pregnancy) | 
| Number of participants with hypertensive disorders of pregnancy | Number of participants diagnosed during pregnancy with any hypertensive disorder of pregnancy | From date of enrolment until the date of first documented diagnosis of hypertensive disorder of pregnancy, according to the International Society for the Study of Hypertension in Pregnancy Criteria, assessed up to one week after delivery | 
| Number of participants with preeclampsia | Number of participants diagnosed during pregnancy with preeclampsia according to the International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria. | From date of enrolment until the date of first documented diagnosis of preeclampsia, according to the International Society for the Study of Hypertension in Pregnancy Criteria, assessed up to one week after delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Angiopoietin 1 (ANG-1) | ng/ml | Baseline visit (11/13+6 weeks of pregnancy) | 
| Serum Angiopoietin 1 (ANG-1) | ng/ml | Follow-up visit (24/27+6 weeks of pregnancy) | 
| Serum Angiopoietin 2 (ANG-2) | ng/ml | Baseline visit (11/13+6 weeks of pregnancy) | 
| Serum Angiopoietin 2 (ANG-2) | ng/ml | Follow-up visit (24/27+6 weeks of pregnancy) | 
| Serum Endothelin-1 (ET-1) | Serum concentration assessed by ELISA (pg/ml) | Baseline visit (11/13+6 weeks of pregnancy) | 
| Serum Endothelin-1 (ET-1) | pg/ml | Follow-up visit (24/27+6 weeks of pregnancy) | 
| Serum Intercellular adhesion molecule-1 (ICAM-1) | ng/ml | Baseline visit (11/13+6 weeks of pregnancy) | 
| Serum Intercellular adhesion molecule-1 (ICAM-1) | ng/ml | Follow-up visit (24/27+6 weeks of pregnancy) | 
| Serum Vascular Cell Adhesion Molecule-1 (VCAM-1) | ng/ml | Baseline visit (11/13+6 weeks of pregnancy) | 
| Serum Vascular Cell Adhesion Molecule-1 (VCAM-1) | ng/ml | Follow-up visit (24/27+6 weeks of pregnancy) | 
| Number of participants with long-term cardiovascular outcomes | Number of participants diagnosed with stroke, myocardial infarction, heart failure or hospitalized for cardiovascular disease in the 5 years after delivery | Interview 5 years after delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preeclampsia, Hypertensive Disorders of Pregnancy, Hypertension, Obstetric Medicine, Cardio-Obstetrics, Cardiovascular outcomes, Pregnancy complications, Arterial Stiffness, Endothelial Glycocalyx, Endothelial dysfunction, Uric Acid, Oxidative stress, Xanthine oxidase, Lipids