High-Dose Folic Acid Supplementation for Metabolic Health During Pregnancy

Overseen By Amy McMahon, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Academic

Sponsor: University of British Columbia

Must not be taking: Antidepressants, Anticonvulsants, Anticoagulants, others

Disqualifiers: Diabetes, Asthma, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two forms of folate supplements, folic acid and 5-MTHF (5-methyltetrahydrofolate, calcium salt), affect metabolic pathways during pregnancy. Researchers aim to determine if these supplements influence health outcomes differently and how genetic differences might alter these effects. Participants will take either folic acid or 5-MTHF to assess each supplement's impact on the body's chemistry. Individuals who are generally healthy, not on a high-protein diet, and free of chronic health conditions may be suitable for this trial. As an unphased trial, this study offers a unique opportunity to contribute to scientific understanding and potentially improve health outcomes during pregnancy.

Will I have to stop taking my current medications?

Yes, you will need to stop taking long-term prescription medications like hormonal contraceptives, antidepressants, anticonvulsants, anticoagulants, or other chronic medications to participate in this trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that folic acid is generally safe to use around the time of conception and helps lower the risk of birth defects like spina bifida. Studies also indicate that folic acid can reduce the chances of pregnancy complications such as preeclampsia and preterm birth. However, excessive folic acid intake might affect the baby's brain development and cause metabolic problems.

5-methyltetrahydrofolate (5-MTHF) is another form of folate that research suggests could be a good alternative to folic acid. 5-MTHF is ready for the body to use without needing any changes, making it especially effective for people with certain genetic differences.

Both treatments are usually well-tolerated. However, as with any supplement, it's important to follow the recommended doses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore the potential benefits of high-dose folic acid and 5-methyltetrahydrofolate (5-MTHF) supplementation during pregnancy for metabolic health. Unlike standard prenatal vitamins, which typically contain lower doses of folic acid, this approach uses a higher dosage to potentially enhance one-carbon metabolism more effectively. The inclusion of 5-MTHF, a naturally occurring form of folate, offers an alternative to synthetic folic acid, which may be better utilized by the body. This study aims to determine if these enhanced supplementation strategies can improve metabolic outcomes more significantly than standard prenatal care.

What evidence suggests that this trial's treatments could be effective for metabolic health during pregnancy?

This trial will compare high-dose folic acid supplementation with 5-methyltetrahydrofolate (5-MTHF) supplementation during pregnancy. Research has shown that folic acid can prevent serious birth defects like neural tube defects (NTDs) and may also lower the risk of other issues such as heart defects and cleft lip. It might also reduce the chances of early birth and other developmental problems. Folic acid raises folate levels in the blood, supporting the healthy growth of a baby's cells.

Similarly, 5-MTHF, a natural form of folate, is another treatment option in this trial. Studies suggest that 5-MTHF might be absorbed better by the body, making it a good alternative to folic acid. Both folic acid and 5-MTHF are important for supporting healthy pregnancies by boosting folate levels, which are essential for a baby's development. ^{4 6 7 8 9}

Who Is on the Research Team?

Yvonne Lamers, PhD

Principal Investigator

University of British Columbia

Are You a Good Fit for This Trial?

This trial is for generally healthy individuals with a BMI of 19-24 kg/m2 and normal levels of folate, vitamin B12, and B6. It's not for those who've used certain supplements recently, have chronic diseases like diabetes or asthma, are pregnant or breastfeeding, smoke, use drugs, drink heavily, can't swallow pills or consent in English.

Inclusion Criteria

Body mass index of between 19-24 kg/m2

Normal folate, vitamin B12, and B6 status

Generally healthy

Exclusion Criteria

Use of vitamin supplements, amino acid or protein supplements for more than six months before study participation

Chronic consumption of a high-protein diet (e.g. Atkins Diet)

Blood donation in the last three months prior to study start

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either folic acid or 5-MTHF supplementation. Folic acid: 1 mg daily for 12 weeks, then 5 mg daily for 12 weeks. 5-MTHF: 1 mg daily for 12 weeks, then 5 mg daily for 12 weeks.

24 weeks

3 visits (in-person) at baseline, Week 12, and Week 24

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 5-methyltetrahydrofolate, calcium salt
• Folic Acid

Trial Overview The study compares the effects of high-dose folic acid versus a natural form called 5-MTHF on DNA-related cellular mechanisms in humans. Researchers will track how these substances influence metabolic pathways using stable isotope tracer protocols.

How Is the Trial Designed?

Group I: Folic acid supplementation Experimental Treatment 1 Intervention

Folic acid will be given orally in form of tablets. A supplement of 1 mg will be taken daily for 12 weeks. Thereafter, a supplement of 5 mg will be taken daily for 12 weeks (i.e., until Week 24). At baseline, Week 12, and Week 24, subjects will receive a 9-hour primed constant infusion of amino acids in saline solution for quantification of kinetics of one-carbon metabolism.

Group II: 5-MTHF supplementation Experimental Treatment 1 Intervention

The calcium salt of 5-methyltetrahydrofolate (5-MTHF; Brand name "Metafolin") will be given orally in form of tablets. A supplement of 1 mg will be taken daily for 12 weeks. Thereafter, a supplement of 5 mg will be taken daily for 12 weeks (i.e., until Week 24). At baseline, Week 12, and Week 24, subjects will receive a 9-hour primed constant infusion of amino acids in saline solution for quantification of kinetics of one-carbon metabolism.

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11435031/

Supplementation with Folic Acid or 5-Methyltetrahydrofolate ... The results indicate that women supplemented with 400 µg of FA or equimolar doses of 5-MTHF achieved significantly higher levels of erythrocyte ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06935630

Comparison of The Effect of 5-MTHF and Folic Acid ... This randomized controlled trial aims to compare the efficacy of 5-methyltetrahydrofolate (5-MTHF) and folic acid supplementation in increasing red blood ...

3. gmr.scholasticahq.com gmr.scholasticahq.com/article/124570-the-critical-role-of-folate-in-prenatal-health-and-a-proposed-shift-from-folic-acid-to-5-methyltetrahydrofolate-supplementation

The Critical Role of Folate in Prenatal Health and a Proposed ... Research supports the use of 5-methyltetrahydrofolate in place of traditional folic acid prenatal supplements based on the increased bioavailability.

4. jogc.com jogc.com/article/S1701-2163(24)00389-X/fulltext

Current Evidence and Controversies Related to Folate ... While this may provide some assurance that 5-MTHF appears similarly effective as compared to folic acid in raising blood folate levels during ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0301211520303754

Review article Folic acid versus 5- methyl tetrahydrofolate ... This paper reviews the advantages and disadvantages of folate supplementation with folic acid versus 5-MTHF, with a focus on maternal and fetal health.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9380836/

Active Folate Versus Folic Acid: The Role of 5-MTHF ... 5-Methyltetrahydrofolate [methylfolate, 5-MTHF, or (6S)-5-MTHF], has been evaluated as a better alternative to folic-acid supplementation.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7558284/

Safety and efficacy of supplements in pregnancy - PMC An analysis of almost 23 000 pregnant women in the New England Journal of Medicine identified a highly conservative safe threshold of 3000 µg RE/d of preformed ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06935630

Comparison of The Effect of 5-MTHF and Folic Acid ... By comparing 5-MTHF and folic acid directly, this research will provide evidence-based recommendations for healthcare providers to ensure adequate folate levels ...

9. cdc.gov cdc.gov/folic-acid/data-research/mthfr/index.html

MTHFR Gene Variant and Folic Acid Facts If you could become pregnant, you should get 400 mcg of folic acid daily, even if you have an MTHFR variant. The two most important factors that ...