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Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT).
Am J Clin Nutr. 2021 05 08; 113(5):1361-1371.AJ

Abstract

BACKGROUND

Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA.

OBJECTIVES

This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia.

METHODS

For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests.

RESULTS

Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P = 0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P = 0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P = 0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ.

CONCLUSIONS

High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism.

Links

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Authors+Show Affiliations

Murphy MSQ
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Muldoon KA
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Sheyholislami H
Nutrition Research Division, Health Canada, Ottawa, Ontario, Canada. Department of Biology, Carleton University, Ottawa, Ontario, Canada.
Behan N
Nutrition Research Division, Health Canada, Ottawa, Ontario, Canada.
Lamers Y
Food, Nutrition, and Health Program, Faculty of Land and Food Systems, The University of British Columbia, Vancouver, British Columbia, Canada. British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Rybak N
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Department of Obstetrics, Gynecology, & Newborn Care, The Ottawa Hospital, Ottawa, Ontario, Canada.
White RR
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Department of Obstetrics, Gynecology, & Newborn Care, The Ottawa Hospital, Ottawa, Ontario, Canada.
Harvey ALJ
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Gaudet LM
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Department of Obstetrics and Gynecology, Kingston Health Sciences Centre, Kingston, Ontario, Canada. Department of Obstetrics and Gynecology, Queen's University, Kingston, Ontario, Canada. School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.
Smith GN
Department of Obstetrics and Gynecology, Kingston Health Sciences Centre, Kingston, Ontario, Canada. Department of Obstetrics and Gynecology, Queen's University, Kingston, Ontario, Canada. Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Walker MC
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Department of Obstetrics, Gynecology, & Newborn Care, The Ottawa Hospital, Ottawa, Ontario, Canada. School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada. Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada. BORN Ontario, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada. CHEO Research Institute, Ottawa, Ontario, Canada.
Wen SW
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada. Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada.
MacFarlane AJ
Nutrition Research Division, Health Canada, Ottawa, Ontario, Canada. Department of Biology, Carleton University, Ottawa, Ontario, Canada.

MeSH

5-Methyltetrahydrofolate-Homocysteine S-MethyltransferaseBiomarkersDietary SupplementsDose-Response Relationship, DrugDouble-Blind MethodFemaleFolic AcidGene Expression RegulationHumansMethylenetetrahydrofolate Dehydrogenase (NADP)Methylenetetrahydrofolate Reductase (NADPH2)Minor Histocompatibility AntigensPolymorphism, Single NucleotidePregnancyVitamin B Complex

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33675351

Citation

Murphy, Malia S Q., et al. "Impact of High-dose Folic Acid Supplementation in Pregnancy On Biomarkers of Folate Status and 1-carbon Metabolism: an Ancillary Study of the Folic Acid Clinical Trial (FACT)." The American Journal of Clinical Nutrition, vol. 113, no. 5, 2021, pp. 1361-1371.
Murphy MSQ, Muldoon KA, Sheyholislami H, et al. Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT). Am J Clin Nutr. 2021;113(5):1361-1371.
Murphy, M. S. Q., Muldoon, K. A., Sheyholislami, H., Behan, N., Lamers, Y., Rybak, N., White, R. R., Harvey, A. L. J., Gaudet, L. M., Smith, G. N., Walker, M. C., Wen, S. W., & MacFarlane, A. J. (2021). Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT). The American Journal of Clinical Nutrition, 113(5), 1361-1371. https://doi.org/10.1093/ajcn/nqaa407
Murphy MSQ, et al. Impact of High-dose Folic Acid Supplementation in Pregnancy On Biomarkers of Folate Status and 1-carbon Metabolism: an Ancillary Study of the Folic Acid Clinical Trial (FACT). Am J Clin Nutr. 2021 05 8;113(5):1361-1371. PubMed PMID: 33675351.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT). AU - Murphy,Malia S Q, AU - Muldoon,Katherine A, AU - Sheyholislami,Hauna, AU - Behan,Nathalie, AU - Lamers,Yvonne, AU - Rybak,Natalie, AU - White,Ruth Rennicks, AU - Harvey,Alysha L J, AU - Gaudet,Laura M, AU - Smith,Graeme N, AU - Walker,Mark C, AU - Wen,Shi Wu, AU - MacFarlane,Amanda J, PY - 2020/06/04/received PY - 2020/12/04/accepted PY - 2021/3/7/pubmed PY - 2021/6/22/medline PY - 2021/3/6/entrez KW - folate KW - folate status KW - folic acid KW - pregnancy KW - supplementation SP - 1361 EP - 1371 JF - The American journal of clinical nutrition JO - Am J Clin Nutr VL - 113 IS - 5 N2 - BACKGROUND: Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA. OBJECTIVES: This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia. METHODS: For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests. RESULTS: Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P = 0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P = 0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P = 0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ. CONCLUSIONS: High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism. SN - 1938-3207 UR - https://www.unboundmedicine.com/medline/citation/33675351/Impact_of_high_dose_folic_acid_supplementation_in_pregnancy_on_biomarkers_of_folate_status_and_1_carbon_metabolism:_An_ancillary_study_of_the_Folic_Acid_Clinical_Trial__FACT__ DB - PRIME DP - Unbound Medicine ER -