Natural Folate vs. Synthetic Folic Acid in Pregnancy

NCT ID: NCT04022135

Last Updated: 2023-04-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

60 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-09-16

Study Completion Date

2021-09-08

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Pregnancy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

OTHER

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Folic acid

0.6 mg/day

Group Type ACTIVE_COMPARATOR

Folic acid

Intervention Type DIETARY_SUPPLEMENT

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

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

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

Group Type EXPERIMENTAL

(6S)-5-methyltetrahydrofolic acid

Intervention Type DIETARY_SUPPLEMENT

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

Interventions

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Folic acid

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

Intervention Type DIETARY_SUPPLEMENT

(6S)-5-methyltetrahydrofolic acid

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

Intervention Type DIETARY_SUPPLEMENT

Other Intervention Names

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Metafolin

Eligibility Criteria

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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
Minimum Eligible Age

19 Years

Maximum Eligible Age

42 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes

Sponsors

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BC Children's Hospital Research Institute

OTHER

Sponsor Role collaborator

University of British Columbia

OTHER

Sponsor Role lead

Responsible Party

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Crystal Karakochuk

Assistant Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Crystal Karakochuk, PhD

Role: PRINCIPAL_INVESTIGATOR

University of British Columbia

Locations

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University of British Columbia, Food Nutrition and Health Building

Vancouver, British Columbia, Canada

Site Status

Countries

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Canada

References

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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.

Reference Type DERIVED
PMID: 35687377 (View on PubMed)

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.

Reference Type DERIVED
PMID: 32370802 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Other Identifiers

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H18-02635

Identifier Type: -

Identifier Source: org_study_id

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