Natural Folate vs. Synthetic Folic Acid in Pregnancy
Condition: Pregnancy
Study type: Interventional

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.
    

Intervention name(s): Folic acid; (6S)-5-methyltetrahydrofolic acid
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Participants will supplement with 0.6mg/day for 16 weeks.; Participants will supplement with 0.625mg/day for 16 weeks.
Other intervention name(s): Metafolin
Intervention MeSH terms: Folic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Other
Keywords: folate; folic acid; nutrition; pregnancy