Pregnancy Related Clinical Trial
— CAREFOL-HTOfficial title:
Clinical Antenatal Randomised Study to CharactErise Key Roles of TetrahydroFOLate in HyperTensive Pregnancies (CAREFOL-HT)
NCT number | NCT05434195 |
Other study ID # | 295830 |
Secondary ID | |
Status | Recruiting |
Phase | N/A |
First received | |
Last updated | |
Start date | June 1, 2021 |
Est. completion date | June 2024 |
Study background High blood pressure during pregnancy is a worldwide health problem that can be dangerous to mothers and commonly causes premature birth and small babies. There is also growing evidence that mothers who suffer from high blood pressure in pregnancy, and their babies, have a higher risk of high blood pressure and cardiovascular disease later in life. Previous studies have revealed detrimental changes in the structure and function of the heart and blood vessels of mothers, and their babies, who experience this common complication. These changes may explain their increased risk of later disease. The investigators have also learned through previous studies that tetrahydrobiopterin (BH4), a molecule that has a role in blood vessel health, plays an important role in stabilising blood vessel function. Lower levels of BH4 are evident in both the placenta and the umbilical cord from mothers with high blood pressure. We, therefore, want to investigate how closely BH4 levels are related to clinical features of pre-eclampsia and whether altering levels of BH4, using a nutritional supplement, improves features of the disease such as blood vessel function. To do this, the investigators need to compare the levels of BH4 between mothers with pre-eclampsia, those taking the supplement and those without pre-eclampsia. The investigators also compare how the heart and blood vessels look and function in these groups using ultrasound methods, including echocardiography and fetal sonography. Study objectives CAREFOL-HT will assess how levels of BH4 differ in pregnant women with high blood pressure and if this is reflected in functional changes in the heart and blood vessels of these women. The investigators will also determine whether changing levels of BH4, using a tetrahydrofolate supplement (5-MTHF), changes blood vessel function.
Status | Recruiting |
Enrollment | 128 |
Est. completion date | June 2024 |
Est. primary completion date | June 2023 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | Female |
Age group | 18 Years to 45 Years |
Eligibility | Inclusion Criteria (Preeclampsia individuals): - Diagnosed with preeclampsia, as defined in Section 8.1, at <34 weeks' gestation within the last 48 hours and with no delivery planned within the next week - Receiving antenatal care in the John Radcliffe Hospital - Participant is willing and able to give informed consent for participation in the study - Age >18 and =45 years Exclusion Criteria (Preeclampsia individuals): The participant may not enter the study if ANY of the following apply: Maternal - History of cardiac impairments including uncontrolled arrhythmia, unstable angina, decompensated congestive heart failure or valve disease - History of preexisting chronic renal disease - Contraindication to taking folate related supplements - Folate supplementation in excess of 400mcg in the third trimester - Low vitamin B12 levels (<148 pmol/L) - Intake of either proton pump inhibitors or anti-epileptic drugs - Organ dysfunction Fetal - Any known trisomy - Fetus with congenital heart defect - Fetus at a high risk of heart disease - Known infection of fetus - Known severe anaemia Inclusion Criteria (Normotensive individuals): - Participant is willing and able to give informed consent for participation in the study - Age >18 and =45 years - Normotensive, blood pressures <140/90 throughout antenatal period - Less than 2 moderate risk factors for hypertensive disease in pregnancy according to the NICE guideline for management of hypertension in pregnancy - SFlt/PIGF ratio <35 Exclusion Criteria (Normotensive individuals): The participant may not enter the study if ANY of the following apply: Maternal - Diagnosis of hypertensive disorder of pregnancy - Use of beta blockers such as atenolol or equivalent - History of cardiac impairments including uncontrolled arrhythmia, unstable angina, decompensated congestive heart failure or valve disease - History of preexisting chronic renal disease Fetal - Any known trisomy - Fetus with congenital heart defect - Fetus at a high risk of heart disease - Known infection of fetus - Known severe anaemia |
Country | Name | City | State |
---|---|---|---|
United Kingdom | Cardiovascular Clinical Research Facility | Oxford | Oxfordshire |
United Kingdom | Oxford University Hospitals NHS Foundation Trust | Oxford | Oxfordhsire |
Lead Sponsor | Collaborator |
---|---|
University of Oxford | British Heart Foundation, Merck & Cie, National Institute for Health Research, United Kingdom |
United Kingdom,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | To assess the change of maternal circulating BH4 biomarkers levels at baseline to prior to delivery. | Levels of BH4, Dihydrobiopterin (BH2), tetrahydrofolate, dihydrofolate reductase (DHFR), GTP cyclohydrolase I (GTPCH) will be assessed. | Baseline (gestation approx. 28- 34 weeks) and prior to delivery | |
Primary | To assess the change of maternal nitric oxide levels at baseline to prior to delivery. | Levels of nitric oxide will be assessed in maternal serum samples. | Baseline (gestation approx. 28- 34 weeks) and prior to delivery | |
Primary | To assess the levels of BH4 biomarkers in umbilical cord blood. | Levels of BH4, Dihydrobiopterin (BH2), tetrahydrofolate, dihydrofolate reductase (DHFR), GTP cyclohydrolase I (GTPCH) will be assessed in cord blood serum. | At delivery | |
Primary | To assess the levels of BH4 biomarkers in placenta. | Levels of BH4, Dihydrobiopterin (BH2), tetrahydrofolate, dihydrofolate reductase (DHFR), GTP cyclohydrolase I (GTPCH) will be assessed in placental tissues. | At delivery | |
Primary | To assess the levels of nitric oxide levels in umbilical cord blood. | Levels of nitric oxide will be assessed in cord blood serum. | At delivery | |
Primary | To assess the levels of nitric oxide levels in placenta. | Levels of nitric oxide will be assessed in placental tissues. | At delivery | |
Secondary | To assess whether maternal BH4 biomarkers levels are correlated with changes in the offspring. | Levels of folates, BH4 BH2, tetrahydrofolate, DHFR, and GTPCH will be assessed | Maternal: at baseline (gestation approx. 28- 34 weeks) and prior to delivery Umbilical cord and placenta: immediately after delivery | |
Secondary | To assess whether BH4 biomarkers levels are correlated with improved angiogenesis profile of maternal blood-derived endothelial cell forming colonies (ECFCs). changes in in-vitro maternal and fetal vascular function. | Angiogenesis profile of ECFCs (tube length, diameter, total area and duration for regression) will be determined via in vitro tube formation assay. | At baseline (gestation approx. 28- 34 weeks) and prior to delivery | |
Secondary | To assess whether BH4 biomarkers levels are correlated with improved angiogenesis profile of human umbilical vein endothelial cells (HUVECs). | Angiogenesis profile of HUVECs (tube length, diameter, total area and duration for regression) will be determined via in vitro tube formation assay. | At delivery | |
Secondary | To assess whether BH4 biomarkers levels are correlated with circulating angiogenic molecules (soluble fms-like tyrosine kinase-1 and placental growth factor). | Measurement of sFlt-1 and PlGF will be measure in serum samples in the clinical biochemistry laboratory. | At baseline (gestation approx. 34 weeks) and prior to delivery. | |
Secondary | To assess whether BH4 biomarkers levels are correlated with in-vivo flow-mediated dilatation (FMD) changes. | Brachial artery FMD induced by reactive hyperemia to assess vascular endothelial function. | At baseline (gestation approx. 34 weeks) and prior to delivery. | |
Secondary | To assess whether BH4 biomarkers levels are correlated with peripheral blood pressure changes. | Flow mediated dilatation, peripheral blood pressure, left and right ventricular mass and volumes and cardiac diastolic function. | At baseline (gestation approx. 34 weeks) and prior to delivery. | |
Secondary | To assess whether tetrahydrofolate levels are associated with cardiac remodelling. | Echocardiography will be performed and left and right ventricular mass and volumes and cardiac diastolic function will be investigated. | At baseline (gestation approx. 34 weeks) and prior to delivery. | |
Secondary | To investigate the acceptability and feasibility of taking the supplementation during pregnancy via questionnaire. | All participants will also be asked to complete a questionnaire assessing the acceptability of 5-MTHF supplementation. This questionnaire can be completed at any point before discharge. | After delivery |
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