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

25 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug 5-methyltetrahydrofolate, calcium salt, Folic Acid for metabolic health during pregnancy?

Research shows that folic acid supplementation during pregnancy is linked to higher birth weights and lower risks of preeclampsia (a pregnancy complication characterized by high blood pressure) and gestational hypertension (high blood pressure during pregnancy). Additionally, high-dose folic acid supplements have been associated with improved recovery rates in women with gestational diabetes. ^{1 2 3 4 5}

Is high-dose folic acid supplementation safe during pregnancy?

Research shows that folic acid and its alternative, calcium L-methylfolate, are generally safe for use in humans. Studies found no harmful effects on behavior, body weight, or organ health in animals, and folic acid is widely recommended for pregnant women to support healthy pregnancy outcomes. ^{5 6 7 8 9}

How does the drug 5-methyltetrahydrofolate, calcium salt, differ from other treatments for metabolic health during pregnancy?

5-methyltetrahydrofolate, calcium salt, is a form of folate that is already in its active form, unlike folic acid which needs to be converted in the body. This may reduce the risk of masking vitamin B12 deficiency symptoms and potentially interacts less with certain medications, making it a unique option for improving folate status during pregnancy. ^{10 11 12 13 14}

What is the purpose of this trial?

This trial compares synthetic folic acid and natural 5-MTHF to see how they affect nutrient processing in healthy people. It uses special tracking methods to observe these changes and considers genetic differences in a key enzyme. 5-MTHF is a natural form of folate that is well absorbed and more bioavailable than synthetic folic acid, even in individuals with metabolic defects.

Research Team

Yvonne Lamers, PhD

Principal Investigator

University of British Columbia

Eligibility Criteria

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

Blood donation in the last three months prior to study start

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)

Timeline

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

Treatment Details

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.

Participant Groups

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+

References

1. England pubmed.ncbi.nlm.nih.gov

Maternal folate, one-carbon metabolism and pregnancy outcomes. [2023]

2. Ireland pubmed.ncbi.nlm.nih.gov

Folic acid supplementation in early pregnancy and the risk of preeclampsia, small for gestational age offspring and preterm delivery. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Enhanced recovery in patients with gestational diabetes mellitus and MTHFR 677 TT genotype after taking high-dose folic acid supplements during mid-late pregnancy: an open-label interventional study. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Vitamin B12 Status among Pregnant Women in the UK and Its Association with Obesity and Gestational Diabetes. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Supplementation of folic acid in pregnancy and the risk of preeclampsia and gestational hypertension: a meta-analysis. [2019]

6. Ireland pubmed.ncbi.nlm.nih.gov

Safety evaluation of calcium L-methylfolate. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Folic acid supplementation: what is new? Fetal, obstetric, long-term benefits and risks. [2020]

8. England pubmed.ncbi.nlm.nih.gov

[6S]5-methyltetrahydrofolate or folic acid supplementation and absorption and initial elimination of folate in young and middle-aged adults. [2021]

9. England pubmed.ncbi.nlm.nih.gov

5-Methyl-tetrahydrofolate in prevention of recurrent preeclampsia. [2017]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Lactating Canadian Women Consuming 1000 µg Folic Acid Daily Have High Circulating Serum Folic Acid Above a Threshold Concentration of Serum Total Folate. [2023]

12. Italy pubmed.ncbi.nlm.nih.gov

Enhanced oral bioavailability of a novel folate salt: comparison with folic acid and a calcium folate salt in a pharmacokinetic study in rats. [2017]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Sodium and Calcium Salts of (6S)-5-Methyltetrahydrofolic Acid Compared to Folic Acid and Indirect Comparison of the Two Salts. [2021]

14. United States pubmed.ncbi.nlm.nih.gov

[6S]-5-Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. [2023]