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Human milk unmetabolized folic acid is increased following supplementation with synthetic folic acid as compared to (6S)-5-methyltetrahydrofolic acid.

ABSTRACT: Folic acid supplementation is recommended perinatally, but may increase unmetabolized folic acid (UMFA) in human milk; this is concerning as it is an inactive form which may be less bioavailable for the infant. "Natural" (6S)-5-methyltetrahydrofolic acid [(6S)-5-MTHF] is available as an alternative to folic acid, and may prevent the accumulation of UMFA in human milk. Pregnant women (n = 60) were enrolled at 8-21 weeks of gestation and randomized to 0.6 mg/day folic acid or (6S)-5-MTHF. At ~ 1-week postpartum, participants provided a human milk specimen. Total human milk folate (nmol/L) and concentrations of UMFA (nmol/L) were quantified via LC-MS/MS. Differences between groups were evaluated using multivariable quantile/linear regression, adjusting for dietary folate, weeks supplementing, and milk collection methods. No significant difference in total milk folate was found; however, the median milk UMFA concentration was 11 nmol/L higher in those receiving folic acid versus (6S)-5-MTHF (95% CI = 6.4-17 nmol/L), with UMFA representing 28% and 2% of total milk folate. In conclusion, the form of supplemental folate had markedly differential effects on the human milk folate profile, with folic acid increasing the mean proportion of milk UMFA by ~ 14-fold. Investigation of whether increased UMFA impacts folate-related metabolism and infant health outcomes is required.

SUBMITTER: Cochrane KM

PROVIDER: S-EPMC10338559 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Human milk unmetabolized folic acid is increased following supplementation with synthetic folic acid as compared to (6S)-5-methyltetrahydrofolic acid.

Cochrane Kelsey M KM Elango Rajavel R Devlin Angela M AM Hutcheon Jennifer A JA Karakochuk Crystal D CD

Scientific reports 20230712 1

Folic acid supplementation is recommended perinatally, but may increase unmetabolized folic acid (UMFA) in human milk; this is concerning as it is an inactive form which may be less bioavailable for the infant. "Natural" (6S)-5-methyltetrahydrofolic acid [(6S)-5-MTHF] is available as an alternative to folic acid, and may prevent the accumulation of UMFA in human milk. Pregnant women (n = 60) were enrolled at 8-21 weeks of gestation and randomized to 0.6 mg/day folic acid or (6S)-5-MTHF. At ~ 1-w ...[more]

PMID: 37438496

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Project description:(6S)-5-Methyltetrahydrofolic acid ((6S)-5-Methyl-THF) salts and folic acid may differ in their abilities to raise plasma (6S)-5-Methyl-THF levels. We compared the area under the curve (AUC), Cmax, and Tmax of plasma (6S)-5-Methyl-THF after intakes of (6S)-5-Methyl-THF-Na salt (Arcofolin®) and folic acid. Moreover, we compared the AUCs after intakes of (6S)-5-Methyl-THF-Na and the calcium salt, (6S)-5-Methyl-THF-Ca, that were tested against folic acid in two independent studies. The study was randomized, double blind, and cross over. Twenty-four adults (12 men and 12 women) received a single oral dose of 436 µg (6S)-5-Methyl-THF-Na and an equimolar dose of folic acid (400 µg) on two kinetic days with two weeks washout period in between. The plasma concentrations of (6S)-5-Methyl-THF were measured at 9 time points between 0 and 8 h. We found that the AUC0-8 h of plasma (6S)-5-Methyl-THF (mean (SD) = 126.0 (33.6) vs. 56.0 (25.3) nmol/L*h) and Cmax (36.8 (10.8) vs. 11.1 (4.1) nmol/L) were higher after administration of (6S)-5-Methyl-THF-Na than after the administration of folic acid (p < 0.001 for both). These differences were present in men and women. Only administration of folic acid resulted in a transient increase in plasma unmetabolized folic acid (2.5 (2.0) nmol/L after 0.5 h and 4.7 (2.9) nmol/L after 1 h). Intake of (6S)-5-Methyl-THF-Na was safe. The ratios of the AUC0-8 h for (6S)-5-Methyl-THF-Na and (6S)-5-Methyl-THF-Ca to the corresponding folic acid reference group and the delta of these AUC0-8 h did not differ between the studies. In conclusion, a single oral dose of (6S)-5-Methyl-THF-Na caused higher AUC0-8 h and Cmax of plasma (6S)-5-Methyl-THF compared to folic acid. The Na- and Ca- salts of (6S)-5-Methyl-THF are not likely to differ in their pharmacokinetics. Further studies may investigate whether supplementation of the compounds for a longer time will lead to differences in circulating or intracellular/tissue folate concentrations.

Project description:BackgroundNorth American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy.Methods/designThis double-blind, randomized trial will recruit 60 pregnant women aged 19-42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8-21 weeks' gestation (after neural tube closure) to reduce the risk of harm should (6S)-5-methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations.DiscussionThis proof-of-concept trial is needed to obtain estimates of the effect of (6S)-5-methyltetrahydrofolic acid compared to folic acid on circulating biomarkers of folate status during pregnancy. These estimates will inform the design of a definitive trial which will be powered to assess whether (6S)-5-methyltetrahydrofolic acid is as effective as folic acid in raising blood folate concentrations during pregnancy. Ultimately, these findings will inform folate supplementation policies for pregnant women.Trial registrationClinicalTrials.gov, ID: NCT04022135. Registered on 14 July 2019.

Project description:BackgroundMaternal nutrition and genetics are determinants of breast-milk nutrient composition and, as such, are determinants of the nutritional exposure of breastfed infants.ObjectivesThe aim of this study was to determine whether common maternal single nucleotide polymorphisms (SNPs) in folate-dependent enzymes are associated with breast-milk folate content in a cohort of mothers enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study.MethodsThe MIREC study is a Canadian prospective pregnancy cohort study that recruited 2001 participants between 2008 and 2011. Five folate-related SNPs-MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTHFR 1793G>A (rs2274976), MTR 2756A>G (rs1805087), and MTRR 66A>G (rs1801394)-were genotyped. Breast milk was sampled ∼1 mo postpartum, and tetrahydrofolate (THF), 5-methyl-THF, 5-formyl-THF, 5,10-methenyl-THF, and unmetabolized folic acid (UMFA) were measured using liquid chromatography-tandem mass spectrometry in a subset of participants (n = 551). Associations were assessed using Wald's test. Associations were considered significant if P ≤ 0.01 (Bonferroni correction for multiple testing).ResultsNone of the SNPs were associated with total breast-milk folate. However, the MTHFR 677C>T SNP was associated with breast-milk UMFA (R2 = 0.01; unadjusted P = 0.004), explaining a small portion of total variance; this association remained significant when adjusted for other covariates, including supplemental folic acid consumption. The MTHFR 1793G>A and MTRR 66A>G SNPs tended to be associated with 5-methyl-THF (R2 = 0.008, P = 0.04) and reduced folates (THF + 5-methyl-THF + 5-formyl-THF + 5,10-methenyl-THF; R2 = 0.01, P = 0.02), respectively.ConclusionsWe found that total breast-milk folate content was not associated with any of the folate-related SNPs examined. The association between the MTHFR 677C>T SNP and breast-milk UMFA, albeit modest, highlights the need to better understand the determinants of breast-milk folate and the impact they might have on milk folate bioavailability.

Dataset Information

Human milk unmetabolized folic acid is increased following supplementation with synthetic folic acid as compared to (6S)-5-methyltetrahydrofolic acid.

Publications

Human milk unmetabolized folic acid is increased following supplementation with synthetic folic acid as compared to (6S)-5-methyltetrahydrofolic acid.

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