Clinical Antenatal Randomised Study to CharactErise Key Roles of TetrahydroFOLate in HyperTensive Pregnancies
- Conditions
- Pre-EclampsiaPregnancy Induced HypertensionPregnancy Related
- Interventions
- Dietary Supplement: Arcofolin® 5-MethyltetrahydrofolateDietary Supplement: Arcofolin® Placebo
- Registration Number
- NCT05434195
- Lead Sponsor
- University of Oxford
- Brief Summary
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.
- Detailed Description
High blood pressure during pregnancy is a world-wide 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 both have a higher risk of high blood pressure and cardiovascular disease in later 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 which may be important in understanding the subsequent increased risk of later disease. The investigators have also learned through previous work carried out by our research group that certain biological processes may be disturbed in women with high blood pressure in pregnancy. One of these processes involves a molecule called tetrahydrobiopterin (also known as BH4) which is required for the correct functioning of blood vessels. Supplementation with biologically-active forms of reduced folate are able to increase the levels of this molecule and can reverse the changes caused by high blood pressure in pregnant mice, and in cultured human endothelial cells. These particular folate supplements are safe and approved for use in pregnancy, but are not widely used as they are more specialised and currently less available than folic acid, the oxidized form of folate that is widely used for supplementation in pregnancy. However, folic acid does not have the same effects as the specific biologically-active form of reduced folate (tetrahydrofolate), because folic acid requires enzymatic conversion within the body in order to generate the biologically-active form of reduced folate. Whilst the use of folic acid appears to be sufficient in most cases to increase folate levels in the prevention of fetal abnormalities such as neural tube defects, the conversion of folic acid to its biologically-active reduced form may be itself deficient or detrimental in women with preeclampsia, and does not increase tetrahydrobiopterin levels. Indeed, folic acid treatment has been found to be ineffective in a large clinical trial to improve high blood pressure in pregnancy women.
This clinical trial will investigate the levels of biologically-active forms of reduced folates. As a way to increase the levels of tetrahydrobiopterin, in pregnant women with high blood pressure, women participating in the trial will take either a low dose or a high dose of a biologically-active form of reduced folate (tetrahydrofolate supplement) until delivery of their baby. A further group of women with high blood pressure will be recruited and will take a placebo. Blood tests will be taken and measurements performed to evaluate the heart and blood vessels of the participating women and their babies upon entry into the study and again at the time of birth. The investigators will also collect the umbilical cord and placenta tissue samples once the baby has been born, so that the investigators can assess blood vessel cell function following tetrahydrofolate supplementation in laboratory studies. In addition to the groups of women with high blood pressure, the investigators will also invite a group of women with an uncomplicated pregnancy to take part, as a comparison group, these women will not receive any supplementation. The investigators aim to investigate how levels of factors in the folate pathway 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 also aim to study whether this tetrahydrofolate supplement can increase the levels of tetrahydrobiopterin and if this improves blood vessel function. If successful, the investigators hope that the results of this study will enable us to design and conduct a larger study in future in order to test whether taking this tetrahydrofolate supplement will stop or reverse the changes caused by high blood pressure in pregnancy.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- Female
- Target Recruitment
- 128
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Preeclampsia - low dosage Arcofolin® 5-Methyltetrahydrofolate A sub-cohort of 32 preeclampsia women will be recruited taking the placebo low dose of 5-MTHF. Preeclampsia - high dosage Arcofolin® 5-Methyltetrahydrofolate A sub-cohort of 32 preeclampsia women will be recruited taking the placebo high dose of 5-MTHF. Preeclampsia - Placebo Arcofolin® Placebo A sub-cohort of 32 preeclampsia women will be recruited taking the placebo.
- Primary Outcome Measures
Name Time Method To assess the change of maternal nitric oxide levels at baseline to prior to delivery. Baseline (gestation approx. 28- 34 weeks) and prior to delivery Levels of nitric oxide will be assessed in maternal serum samples.
To assess the levels of BH4 biomarkers in umbilical cord blood. At delivery Levels of BH4, Dihydrobiopterin (BH2), tetrahydrofolate, dihydrofolate reductase (DHFR), GTP cyclohydrolase I (GTPCH) will be assessed in cord blood serum.
To assess the change of maternal circulating BH4 biomarkers levels at baseline to prior to delivery. Baseline (gestation approx. 28- 34 weeks) and prior to delivery Levels of BH4, Dihydrobiopterin (BH2), tetrahydrofolate, dihydrofolate reductase (DHFR), GTP cyclohydrolase I (GTPCH) will be assessed.
To assess the levels of BH4 biomarkers in placenta. At delivery Levels of BH4, Dihydrobiopterin (BH2), tetrahydrofolate, dihydrofolate reductase (DHFR), GTP cyclohydrolase I (GTPCH) will be assessed in placental tissues.
To assess the levels of nitric oxide levels in umbilical cord blood. At delivery Levels of nitric oxide will be assessed in cord blood serum.
To assess the levels of nitric oxide levels in placenta. At delivery Levels of nitric oxide will be assessed in placental tissues.
- Secondary Outcome Measures
Name Time Method To assess whether BH4 biomarkers levels are correlated with circulating angiogenic molecules (soluble fms-like tyrosine kinase-1 and placental growth factor). At baseline (gestation approx. 34 weeks) and prior to delivery. Measurement of sFlt-1 and PlGF will be measure in serum samples in the clinical biochemistry laboratory.
To assess whether BH4 biomarkers levels are correlated with in-vivo flow-mediated dilatation (FMD) changes. At baseline (gestation approx. 34 weeks) and prior to delivery. Brachial artery FMD induced by reactive hyperemia to assess vascular endothelial function.
To assess whether maternal BH4 biomarkers levels are correlated with changes in the offspring. Maternal: at baseline (gestation approx. 28- 34 weeks) and prior to delivery Umbilical cord and placenta: immediately after delivery Levels of folates, BH4 BH2, tetrahydrofolate, DHFR, and GTPCH will be assessed
To assess whether BH4 biomarkers levels are correlated with improved angiogenesis profile of human umbilical vein endothelial cells (HUVECs). At delivery Angiogenesis profile of HUVECs (tube length, diameter, total area and duration for regression) will be determined via in vitro tube formation assay.
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. At baseline (gestation approx. 28- 34 weeks) and prior to delivery Angiogenesis profile of ECFCs (tube length, diameter, total area and duration for regression) will be determined via in vitro tube formation assay.
To assess whether BH4 biomarkers levels are correlated with peripheral blood pressure changes. At baseline (gestation approx. 34 weeks) and prior to delivery. Flow mediated dilatation, peripheral blood pressure, left and right ventricular mass and volumes and cardiac diastolic function.
To assess whether tetrahydrofolate levels are associated with cardiac remodelling. At baseline (gestation approx. 34 weeks) and prior to delivery. Echocardiography will be performed and left and right ventricular mass and volumes and cardiac diastolic function will be investigated.
To investigate the acceptability and feasibility of taking the supplementation during pregnancy via questionnaire. After delivery 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.
Trial Locations
- Locations (2)
Oxford University Hospitals NHS Foundation Trust
🇬🇧Oxford, Oxfordhsire, United Kingdom
Cardiovascular Clinical Research Facility
🇬🇧Oxford, Oxfordshire, United Kingdom