Natural Folate vs. Synthetic Folic Acid in Pregnancy

Pregnancy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04022135
• Other study ID #: H18-02635
• Status: Completed
• Phase: N/A
• Start date: September 16, 2019
• Est. completion date: September 8, 2021

Study information

• Verified date: April 2023
• Source: University of British Columbia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: September 8, 2021
• Est. primary completion date: September 8, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 19 Years to 42 Years

Eligibility

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

Related Conditions & MeSH terms

• Pregnancy

Intervention

Dietary Supplement:
• Folic acid
Participants will supplement with 0.6mg/day for 16 weeks.
• (6S)-5-methyltetrahydrofolic acid
Participants will supplement with 0.625mg/day for 16 weeks.

Locations

Country	Name	City	State
Canada	University of British Columbia, Food Nutrition and Health Building	Vancouver	British Columbia

Sponsors (2)

Lead Sponsor	Collaborator
University of British Columbia	BC Children's Hospital Research Institute

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Concentration of total vitamin B-12	pmol/mL; closely involved in folate metabolism and facilitating methionine cycles	concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
Secondary	Concentration of pyridoxal-5'-phosphate	nmol/L; closely involved in folate metabolism and facilitating methionine cycles	concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
Secondary	Concentration of vitamin B2	nmol/L; closely involved in folate metabolism and facilitating methionine cycles	concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
Secondary	Concentration of betaine	µmol/L; closely involved in facilitating methionine cycles	concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
Secondary	Concentration of choline	µmol/L; closely involved in facilitating methionine cycles	concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
Secondary	Concentration of dimethylglycine	µmol/L; closely involved in facilitating methionine cycles	concentrations at both baseline (8-21 weeks gestation), endline (24-37 weeks gestation)
Secondary	Concentration of S-adenosyl-methionine	µM; Metabolite produced in methionine cycles	concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
Secondary	Concentration of S-adenosyl-homocysteine	µM; Metabolite produced in methionine cycles	concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
Secondary	Concentration of total homocysteine	µmol/L; Metabolite produced in methionine cycles	concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
Secondary	Concentration of methionine	µmol/L; Metabolite produced in methionine cycles	concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
Secondary	Concentration of cysteine	µmol/L; Metabolite produced in methionine cycles	concentrations at both baseline (8-21 weeks gestation) and endline (24-37 weeks gestation)
Secondary	Collection of peripheral blood mononuclear layer cells	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)
Secondary	Concentration of unmetabolized folic acid in breastmilk (and other folate forms: THF, 5-Methyl-THF, 5-formyl-THF, and 5,10-methenyl-THF)	nmol/L; folic acid that is unmetabolized and enters breastmilk as such	Collection at 1 week postpartum
Secondary	Folate binding protein in breastmilk	nmol folate binding per liter of milk	Collection at 1 week postpartum
Secondary	Breastmilk fatty acids & choline forms (free choline, betaine, phosphocholine, glycerophosophocholine)	Quantified via LC-MS/MS	Collection at 1 week postpartum
Secondary	Breastmilk human milk oligosaccharides and breastmilk microbiome	Quantified via HPLC-FL and PCR	Collection at 1 week postpartum
Secondary	Complete blood count	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
Secondary	Markers of Iron and Inflammation	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)