Natural Folate vs. Synthetic Folic Acid in Pregnancy

NCT04022135 | Completed

• 1 other identifier: H18-02635
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

In this two-arm, double-blind randomized pilot study, the investigators will recruit 60 generally healthy, low-risk pregnant women aged 19-42 years living in Vancouver, Canada. Participants will be randomized to supplement with either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16-weeks of their pregnancy. Randomization will occur at 8-21 weeks gestation (after neural tube closure) to reduce the risk of harm should the natural folate prove less effective. All participants will also receive a prenatal multivitamin not containing any form of folate, to ensure adequacy of other nutrients (e.g. iron) required during pregnancy. Three-hour fasting venous blood samples will be collected at baseline and endline to measure serum and red blood cell folate, unmetabolized folic acid and other related biomarkers. Women will be given the option to continue supplementing until 1-week postpartum, and provide a small (3mL) breastmilk sample and blood sample in order to measure differences in folates in breastmilk and postpartum folate. These pilot data will be used to inform a definitive trial regarding the most effective form of folate supplementation for mothers and their babies.

Conditions

Pregnancy

Keywords

folate; folic acid; nutrition; pregnancy

Outcome Measures

Primary Outcomes (3)

• Concentration of red blood cell folate levels

  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

  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)

  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 Outcomes (18)

• Concentration of total vitamin B-12

  concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)

• Concentration of pyridoxal-5'-phosphate

  concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)

• Concentration of vitamin B2

  concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)

• Concentration of betaine

  concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)

• Concentration of choline

  concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)

Study Arms (2)

Folic acid

ACTIVE COMPARATOR

0.6 mg/day

Dietary Supplement: Folic acid

(6S)-5-methyltetrahydrofolic acid (Metafolin)

EXPERIMENTAL

0.625 mg/d (an equimolar dose to folic acid)

Dietary Supplement: (6S)-5-methyltetrahydrofolic acid

Interventions

Folic acid DIETARY_SUPPLEMENT

Participants will supplement with 0.6mg/day for 16 weeks.

Folic acid

(6S)-5-methyltetrahydrofolic acid DIETARY_SUPPLEMENT

Participants will supplement with 0.625mg/day for 16 weeks.

Also known as: Metafolin

(6S)-5-methyltetrahydrofolic acid (Metafolin)

Eligibility Criteria

• Age: 19 Years - 42 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• years of age
• willing to participate

You may not qualify if:

• 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

Sponsors & Collaborators

• University of British Columbia: lead
• BC Children's Hospital Research Institute: collaborator

Study Sites (1)

University of British Columbia, Food Nutrition and Health Building

Vancouver, British Columbia, V6T 1Z4, Canada

Location

Related Publications (2)

• 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.

  PMID: 35687377 DERIVED

• 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.

  PMID: 32370802 DERIVED

MeSH Terms

Interventions

Folic Acid; levomefolate calcium

Intervention Hierarchy (Ancestors)

Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Crystal Karakochuk, PhD

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: July 14, 2019
• First Posted: July 16, 2019
• Study Start: September 16, 2019
• Primary Completion: September 8, 2021
• Study Completion: September 8, 2021
• Last Updated: April 14, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: All data will be available following publication for approximately 5 years after initial collection.
• Access Criteria: A proposal from those interested in accessing the data should be sent to study investigators for access approval.

Locations

CA (1)