- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04022135
Natural Folate vs. Synthetic Folic Acid in Pregnancy
Is Natural Folate as Effective as Synthetic Folic Acid in Increasing Serum and Red Blood Cell Folate Concentrations During Pregnancy? A Proof-of-concept Pilot Study
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
A sample size of 50 women (25 in each group) are required to reliably estimate the distributions of serum and red blood cell folate. Thus, to account for drop outs or loss to follow up, a total of 60 women (30 in each group) will be recruited.
Aim 1: To establish the mean ± standard deviation change in serum folate, red blood cell folate, and unmetabolized folic acid levels in each group following supplementation with (6S)-5-methyltetrahydrofolic acid or folic acid for 16-weeks of pregnancy.
Aim 2: To determine participation recruitment and retention rate, the most effective recruitment strategies for this population, and adherence to study protocol (to inform a definitive trial).
Exploratory Aims: To explore differences in proposed clinical effects associated with folic acid supplementatation (immunity, gene methylation) and differences in biomarkers that function closely with folate in one carbon metabolism (B-vitamins, choline and its metabolites [betaine, dimethylglycine]) and which support overall blood health (ferritin, inflammation). In the postpartum phase, we will quantify proportion of total breastmilk folate as folic acid in each group, evaluate correlation of maternal postpartum plasma unmetabolized folic acid and breastmilk folic acid, and to evaluate RBC folate concentrations following delivery in each group. Differences in breastmilk biomarkers associated with folate (choline, human milk oligosaccharides, and breastmilk microbiome) will be explored.
Women may undergo informed consent process anytime <21 weeks gestation. Once participants indicate that they are interested in participating in the trial, the participant will be given a study ID, and a baseline visit will be scheduled.
The baseline visit will occur between 8-21 weeks gestation, and will involve discontinuation of current folate/prenatal vitamin supplementation, review and signing the informed consent form (a scanned copy will be shared with the participant), randomization to a folate group, provision of study supplements, completion of a baseline questionnaire, completion of a food frequency questionnaire, measurement of weight and height, and a small blood draw (12ml).
Intervention: total time: 16 weeks. Participants will supplement daily with the folate and prenatal vitamin supplements. The research coordinator will call the participants half way through the intervention period to serve as a reminder and answer any questions, which will enhance protocol adherence.
The endline visit will occur between 24-37 weeks gestation, and will involve collecting any remaining supplements (for capsule counts), a weight measurement, and a small blood draw (12ml), and completion of a short endline questionnaire.
Optional continuation of study: After the endline visit, women who are planning to breastfeed will have the option to continue supplementing with the study supplements until approximately 1 week postpartum, at which time they will provide a small (3 mL) breastmilk sample and/or blood sample.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
British Columbia
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Vancouver, British Columbia, Canada, V6T 1Z4
- University of British Columbia, Food Nutrition and Health Building
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Pregnant woman (singleton pregnancy)
- Living in the Greater Vancouver area and willing to travel to the University of British Columbia for study visits
- <21 weeks gestation
- 19-42 years of age
- willing to participate
Exclusion Criteria:
- Have a pre-existing medical condition known to impact maternal folate status (malabsorptive of irritable bowel disease, active celiac disease, gastric bypass surgery, atrophic gastritis, epilepsy, advanced liver disease, kidney dialysis, type 1 or 2 diabetes mellitus, sickle cell trait/anemia)
- Lifestyle factors known to impact maternal folate status (smoking, alcohol overuse, non-prescription drug use/abuse)
- Are medium to high risk for development of an NTD-affected pregnancy (applies to women or their male partner: personal or family history [parents or siblings] of other folate sensitive congenital anomalies, personal NTD history or a previous NTD-affected pregnancy)
- Are taking medications known to interfere with B-vitamin metabolism (Chloramphenicol, Methotrexate, Metformin, Sulfasalazine, Phenobarbital, Phenytoin, Primidone, Triamterene, Barbiturates)
- pre-pregnancy body mass index ≥30 kg/m2
- allergic to any of the supplement ingredients
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Folic acid
0.6 mg/day
|
Participants will supplement with 0.6mg/day for 16 weeks.
|
Experimental: (6S)-5-methyltetrahydrofolic acid (Metafolin)
0.625 mg/d (an equimolar dose to folic acid)
|
Participants will supplement with 0.625mg/day for 16 weeks.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Concentration of red blood cell folate levels
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
|
nmol/L; Reflects longer term status (e.g.
previous 3-4 months)
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
|
Concentration of serum folate levels
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
|
nmol/L; Reflects recent status or dietary intake
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
|
Concentration of unmetabolized folic acid (and other folate forms: THF, 5-Methyl-THF, 5-formyl-THF, and 5,10-methenyl-THF)
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
|
nmol/L; unmetabolized folic acid is not incorporated into RBCs, rather it circulates in plasma
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Concentration of total vitamin B-12
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
pmol/mL; closely involved in folate metabolism and facilitating methionine cycles
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
Concentration of pyridoxal-5'-phosphate
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
nmol/L; closely involved in folate metabolism and facilitating methionine cycles
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
Concentration of vitamin B2
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
nmol/L; closely involved in folate metabolism and facilitating methionine cycles
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
Concentration of betaine
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
µmol/L; closely involved in facilitating methionine cycles
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
Concentration of choline
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
µmol/L; closely involved in facilitating methionine cycles
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
Concentration of dimethylglycine
Time Frame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
µmol/L; closely involved in facilitating methionine cycles
|
concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
Concentration of S-adenosyl-methionine
Time Frame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
µM; Metabolite produced in methionine cycles
|
concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
Concentration of S-adenosyl-homocysteine
Time Frame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
µM; Metabolite produced in methionine cycles
|
concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
Concentration of total homocysteine
Time Frame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
µmol/L; Metabolite produced in methionine cycles
|
concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
Concentration of methionine
Time Frame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
µmol/L; Metabolite produced in methionine cycles
|
concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
Concentration of cysteine
Time Frame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
µmol/L; Metabolite produced in methionine cycles
|
concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
|
Collection of peripheral blood mononuclear layer cells
Time Frame: Collection at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
Gene variant assessment of MTHFR (677 C>T, rs1801133, and 1298 A>C, rs1801131) and DHFR (rs1643649 and rs70991108) and differences in DNA methylation, and frequency and cytotoxicity of immune cells in PBMCs.
|
Collection at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
|
Concentration of unmetabolized folic acid in breastmilk (and other folate forms: THF, 5-Methyl-THF, 5-formyl-THF, and 5,10-methenyl-THF)
Time Frame: Collection at 1 week postpartum
|
nmol/L; folic acid that is unmetabolized and enters breastmilk as such
|
Collection at 1 week postpartum
|
Folate binding protein in breastmilk
Time Frame: Collection at 1 week postpartum
|
nmol folate binding per liter of milk
|
Collection at 1 week postpartum
|
Breastmilk fatty acids & choline forms (free choline, betaine, phosphocholine, glycerophosophocholine)
Time Frame: Collection at 1 week postpartum
|
Quantified via LC-MS/MS
|
Collection at 1 week postpartum
|
Breastmilk human milk oligosaccharides and breastmilk microbiome
Time Frame: Collection at 1 week postpartum
|
Quantified via HPLC-FL and PCR
|
Collection at 1 week postpartum
|
Complete blood count
Time Frame: Baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
|
Analysis will be performed using an automated hematology analyzer (Sysmex XNL550, Kobe, Japan)
|
Baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
|
Markers of Iron and Inflammation
Time Frame: Baseline (8-21 weeks gestation),and endline (24-37 weeks gestation)
|
This will include measurement of serum ferritin (µg/L), soluble transferrin receptor (mg/L), body iron stores (mg/kg), retinol binding protein (µmol/L), CRP (mg/L), and AGP (g/L) in serum using a sandwich ELISA, and hormones that influence iron regulation in pregnancy, including serum hecipdin (ng/mL; measured with an ELISA) and serum erythropoietin (mIU/mL; measured with an immunoassay)
|
Baseline (8-21 weeks gestation),and endline (24-37 weeks gestation)
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Crystal Karakochuk, PhD, University of British Columbia
Publications and helpful links
General Publications
- Cochrane KM, Hutcheon JA, Karakochuk CD. Iron-Deficiency Prevalence and Supplementation Practices Among Pregnant Women: A Secondary Data Analysis From a Clinical Trial in Vancouver, Canada. J Nutr. 2022 Oct 6;152(10):2238-2244. doi: 10.1093/jn/nxac135.
- Cochrane KM, Mayer C, Devlin AM, Elango R, Hutcheon JA, Karakochuk CD. Is natural (6S)-5-methyltetrahydrofolic acid as effective as synthetic folic acid in increasing serum and red blood cell folate concentrations during pregnancy? A proof-of-concept pilot study. Trials. 2020 May 5;21(1):380. doi: 10.1186/s13063-020-04320-3.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- H18-02635
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
- ANALYTIC_CODE
- CSR
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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