Clinical trial NCT04022135: Natural Folate vs. Synthetic Folic Acid in Pregnancy
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pregnancy
Keywords: folate
folic acid
nutrition
pregnancy
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: BC Children's Hospital Research Institute
First posted: 2019-07-16
Enrollment: 60
Sex: FEMALE
Minimum age (years): 19
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Concentration of red blood cell folate levels
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
measure: Concentration of serum folate levels
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
measure: Concentration of unmetabolized folic acid (and other folate forms: THF, 5-Methyl-THF, 5-formyl-THF, and 5,10-methenyl-THF)
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
Secondary outcomes:
measure: Concentration of total vitamin B-12
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
measure: Concentration of pyridoxal-5'-phosphate
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
measure: Concentration of vitamin B2
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
measure: Concentration of betaine
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
measure: Concentration of choline
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
measure: Concentration of dimethylglycine
timeFrame: concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
measure: Concentration of S-adenosyl-methionine
timeFrame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
measure: Concentration of S-adenosyl-homocysteine
timeFrame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
measure: Concentration of total homocysteine
timeFrame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
measure: Concentration of methionine
timeFrame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
measure: Concentration of cysteine
timeFrame: concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
measure: Collection of peripheral blood mononuclear layer cells
timeFrame: Collection at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
measure: Concentration of unmetabolized folic acid in breastmilk (and other folate forms: THF, 5-Methyl-THF, 5-formyl-THF, and 5,10-methenyl-THF)
timeFrame: Collection at 1 week postpartum
measure: Folate binding protein in breastmilk
timeFrame: Collection at 1 week postpartum
measure: Breastmilk fatty acids & choline forms (free choline, betaine, phosphocholine, glycerophosophocholine)
timeFrame: Collection at 1 week postpartum
measure: Breastmilk human milk oligosaccharides and breastmilk microbiome
timeFrame: Collection at 1 week postpartum
measure: Complete blood count
timeFrame: Baseline (8-21 weeks gestation), endline (24-37 weeks gestation), and postpartum
measure: Markers of Iron and Inflammation
timeFrame: Baseline (8-21 weeks gestation),and endline (24-37 weeks gestation)
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: University of British Columbia, Food Nutrition and Health Building
state: British Columbia
Study officials:
affiliation: University of British Columbia
name: Crystal Karakochuk, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.