Clinical Antenatal Randomised Study to CharactErise Key Roles of TetrahydroFOLate in HyperTensive Pregnancies
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexFemale
Age18-45
SponsorUniversity of Oxford
About this trial
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.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
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
Disqualifiers
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
Trial design
Design model
Parallel
Treatments tested in this trial
Arcofolin® 5-Methyltetrahydrofolate
Dietary supplement5-methyltetrahydrofolate (5-MTHF) is the biologically active form of reduced folate, which can increase BH4 availability. 5-MTHF is available as a nutritional vitamin (Merck \& Cie) for human use including during pregnancy. Two out of three preeclamptic study groups will receive 5-MTHF - one at a low dose and the other at a high dose.
Arcofolin® Placebo
Dietary supplementThe placebo, this consists of the same excipients as 5-MTHF, microcrystalline cellulose and silica with no active ingredient.
Treatment groups
128 Participants
are divided into 4 treatment groupsGroup A: NormotensiveNo intervention 0 interventions
Group B: Preeclampsia - PlaceboPlacebo comparator 1 intervention
Group C: Preeclampsia - low dosageActive comparator 1 intervention
Group D: Preeclampsia - high dosageActive comparator 1 intervention
Trial outcomes
Primary outcomes
1
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.
Time frame
Baseline (gestation approx. 28- 34 weeks) and prior to delivery2
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.
Time frame
Baseline (gestation approx. 28- 34 weeks) and prior to delivery3
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.
Time frame
At delivery4
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.
Time frame
At deliverySecondary outcomes
1
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
Time frame
Maternal: at baseline (gestation approx. 28- 34 weeks) and prior to delivery Umbilical cord and placenta: immediately after delivery2
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.
Time frame
At baseline (gestation approx. 28- 34 weeks) and prior to delivery3
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.
Time frame
At delivery4
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.
Time frame
At baseline (gestation approx. 34 weeks) and prior to delivery.Sponsors and contacts
Click on the lead sponsor to view all of their trials.
University of Oxford
Lead sponsor
National Institute for Health Research, United Kingdom
Collaborator
British Heart Foundation
Collaborator
Merck & Cie
Collaborator
Source ClinicalTrials.gov