Clinical Antenatal Randomised Study to CharactErise Key Roles of TetrahydroFOLate in HyperTensive Pregnancies

NCT05434195 | Recruiting DMC

• 1 other identifier: 295830
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 2

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.

Conditions

Pregnancy Induced Hypertension; Pregnancy Related; Pre-Eclampsia

Keywords

5-methyltetrahydrofolate; Tetrahydrobiopterin; Pre-Eclampsia; Antenatal study

Outcome Measures

Primary Outcomes (6)

• 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

• 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

• 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

• 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

• 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

• To assess the levels of nitric oxide levels in placenta.

  Levels of nitric oxide will be assessed in placental tissues.

  At delivery

Secondary Outcomes (8)

• 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

• 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

• To assess whether BH4 biomarkers levels are correlated with improved angiogenesis profile of human umbilical vein endothelial cells (HUVECs).

  At delivery

• 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.

• 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.

Study Arms (4)

Normotensive

NO INTERVENTION

A sub-cohort of 32 normotensive women will be recruited to establish normal pregnancy values for the measures performed as well as validation of outcome measures.

Preeclampsia - Placebo

PLACEBO COMPARATOR

A sub-cohort of 32 preeclampsia women will be recruited taking the placebo.

Dietary Supplement: Arcofolin® Placebo

Preeclampsia - low dosage

ACTIVE COMPARATOR

A sub-cohort of 32 preeclampsia women will be recruited taking the placebo low dose of 5-MTHF.

Dietary Supplement: Arcofolin® 5-Methyltetrahydrofolate

Preeclampsia - high dosage

ACTIVE COMPARATOR

A sub-cohort of 32 preeclampsia women will be recruited taking the placebo high dose of 5-MTHF.

Dietary Supplement: Arcofolin® 5-Methyltetrahydrofolate

Interventions

Arcofolin® 5-Methyltetrahydrofolate DIETARY_SUPPLEMENT

5-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.

Also known as: Arcofolin®

Preeclampsia - high dosage; Preeclampsia - low dosage

Arcofolin® Placebo DIETARY_SUPPLEMENT

The placebo, this consists of the same excipients as 5-MTHF, microcrystalline cellulose and silica with no active ingredient.

Preeclampsia - Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• Participant is willing and able to give informed consent for participation in the study

Sponsors & Collaborators

• University of Oxford: lead
• British Heart Foundation: collaborator
• National Institute for Health Research, United Kingdom: collaborator
• Merck & Cie: collaborator

Study Sites (2)

Oxford University Hospitals NHS Foundation Trust

Oxford, Oxfordhsire, OX3 9DU, United Kingdom

RECRUITING

Cardiovascular Clinical Research Facility

Oxford, Oxfordshire, OX3 7RD, United Kingdom

RECRUITING

Related Publications (1)

• Cutler HR, Kitt J, Sattwika PD, Finnigan LEM, Estevez-Fernandez A, Kenworthy Y, Suriano K, Frost A, Krasner S, Johnson C, McCourt A, Mills R, Tucker K, Cairns A, Roman C, Aye C, Mackillop L, Thilaganathan B, Chappell LC, Raman B, Lewandowski AJ, Lapidaire W, Leeson P. Subclinical Postpartum Renal Structure After Hypertensive Pregnancy Disorders. Hypertension. 2025 Nov;82(11):1948-1958. doi: 10.1161/HYPERTENSIONAHA.125.25130. Epub 2025 Aug 31.

  PMID: 40886083 DERIVED

Related Links

• CAREFOL-HT Study

MeSH Terms

Conditions

Pre-Eclampsia; Hypertension, Pregnancy-Induced

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Paul Leeson, FRCP

  University of Oxford, John Radcliffe Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Annabelle Frost, MD

CONTACT

01865 572833; carefol-ht@cardiov.ox.ac.uk

Cheryl Tan, MRes

CONTACT

01865 572833; cheryl-mj.tan@cardiov.ox.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 5, 2022
• First Posted: June 27, 2022
• Study Start: June 1, 2021
• Primary Completion: January 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: April 29, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)