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

Stamm, Rosemary A; March, Kaitlin; Karakochuk, Crystal D; Gray, Andrew; Brown, Rachel; Green, Timothy; Houghton, Lisa A

doi:10.1093/jn/nxy070

Cited by 9 publications

(6 citation statements)

References 26 publications

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“…(59-61) While our findings for maternal total folate and cord blood UMFA are seemingly contradictory, UMFA only represents a small percentage of circulating total folate and is uniquely derived from synthetic folic acid intake. Recent studies suggest that a strong association between UMFA and serum total folate levels only occurs when total folate levels are high (>78.5 nmol/L), (62) and thus further research regarding the determinants of each of these folate measurements is clearly needed.…”

Section: Discussionmentioning

confidence: 99%

Association Between Folate Metabolites and the Development of Food Allergy in Children

McGowan

Hong

Selhub

et al. 2020

The Journal of Allergy and Clinical Immunology: In Practice

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Background: Studies on the association between folate/folic acid exposure and the development of allergic disease have yielded inconsistent results, which may be due, in part, to lack of data distinguishing folate from folic acid exposure.Objective: To examine the association between total folate, 5-methyltetrahydrofolate (5-MTHF), and unmetabolized folic acid (UMFA) concentrations at birth and in early childhood and the development of food sensitization (FS) and food allergy (FA).Methods: A nested case control study was performed in the Boston Birth Cohort (BBC). Total folate, 5-MTHF, and UMFA were measured at birth and in early childhood. Based on foodspecific IgE (sIgE) levels, diet, and clinical history, children were classified as FS (sIgE ≥0.35 kU/L), FA, or non-FS/FA (controls). Folate concentrations were divided into quartiles, and multiple logistic regression was used to estimate ORs and 95%CIs.Results: Of a total of 1,394 children, 507 FS and 78 FA children were identified. While mean total folate concentrations at birth were lower among those who developed FA (30.2 vs. 35.3 nmol/L; p=0.02), mean concentrations of the synthetic folic acid derivative, UMFA, were higher (1.7 vs. 1.3 nmol/L, p=0.001). Higher quartiles of UMFA at birth were associated more strongly with FA (OR 8.50;; test for trend p=0.001). Neither early childhood concentrations of 5-MTHF nor UMFA were associated with the development of FS or FA. Conclusion:Among children in the BBC, higher concentrations of UMFA at birth were associated with the development of FA, which may be due to increased exposure to synthetic folic acid in utero or underlying genetic differences in synthetic folic acid metabolism.

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Section: Discussionmentioning

confidence: 99%

Association Between Folate Metabolites and the Development of Food Allergy in Children

McGowan

Hong

Selhub

et al. 2020

The Journal of Allergy and Clinical Immunology: In Practice

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“…The lower efficacy of FA for 5MTHF supply to the CSF compared to folinic acid is mainly explained by the presence of excess FA in the blood and its antagonism against 5MTHF transport at the choroid plexus expressing FR1 (Figure 1). Low DHFR activity in the human liver 14 leads to the appearance of unmetabolized FA in the blood upon high FA intake 15–17 . The dissociation between 5MTHF and total folate concentrations during FA therapy in the KSS patient was likely due to the high amount of unmetabolized FA, although we were unable to measure unmetabolized FA directly.…”

Section: Discussionmentioning

confidence: 92%

“…Low DHFR activity in the human liver 14 leads to the appearance of unmetabolized FA in the blood upon high FA intake. [15][16][17] The dissociation between 5MTHF and total folate concentrations during FA therapy in the KSS patient was likely due to the high amount of unmetabolized FA, although we were unable to measure unmetabolized FA directly. This hypothesis can be supported well by the absent or minimal dissociations after a complete switch to folinic acid therapy.…”

Section: Discussionmentioning

confidence: 96%

Folic acid inhibits 5‐methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier: Clinical biochemical data from two cases

et al. 2022

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Objective The use of folic acid (FA) has been discouraged in cerebral folate deficiency (CFD) because, theoretically, it could inhibit the transport of 5‐methyltetrahydrofolic acid (5MTHF) across the blood–cerebrospinal fluid (CSF) barrier. We present the clinical biochemical data of two cases with CFD to support this hypothesis. Methods We measured CSF and serum 5MTHF concentrations in a patient with Kearns‐Sayre syndrome (KSS) and a patient homozygous for MTHFR C677T polymorphism before and during folate supplementation therapy. To evaluate these 5MTHF concentrations, we also analyzed CSF and serum samples in pediatric patients without folate supplementation. Results Both patients had low CSF 5MTHF before treatment and high‐dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF‐to‐serum 5MTHF ratio. Conclusions Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood–CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

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“…While a cut-off for 'high' erythrocyte folate is not established, 1360 nmol/l was reflective of the 97 th percentile as per NHANES 1999-2004 (77,78) . Overall, it is very difficult for pregnant individuals in North America to consume only 0•4 mg/d folic acid, due to folic acid food fortification and as the vast majority of prenatal vitamins contain 0•6-1•0 mg folic acid (10,11,(79)(80)(81) ; this has contributed to very high folate levels (erythrocyte folate ∼1500-2500 nmol/l) among pregnant and lactating individuals (10,(82)(83)(84) ; similarly high erythrocyte and serum folate concentrations were evident in the current study. Those consuming folic acid from fortified foods and prenatal vitamins are very likely to exceed the tolerable upper intake level of 1•0 mg/d folic acid (12,(79)(80)(81)85) .…”

Section: Discussionmentioning

confidence: 99%

Supplementation with (6S)-5-methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada

Cochrane,

Elango,

Devlin

et al. 2023

Br J Nutr

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Folic acid supplementation is recommended during pregnancy to support healthy fetal development; (6S)-5-methyltetrahydrofolic acid [(6S)-5-MTHF] is available in some commercial prenatal vitamins an alternative to folic acid, but its effect on blood folate status during pregnancy is unknown. To address this, we randomized 60 pregnant individuals at 8-21 weeks’ gestation to 0.6 mg/day folic acid or (6S)-5-MTHF x 16-weeks. Fasting blood specimens were collected at baseline and after 16-weeks (endline). Red blood cell (RBC) and serum folate were quantified via microbiological assay (as globally recommended) and plasma unmetabolized folic acid (UMFA) via LC-MS/MS. Differences in biochemical folate markers between groups were explored using multivariable linear/quantile regression, adjusting for baseline concentrations, dietary folate intake, and gestational weeks. At endline (n=54), the mean ± SD (or median, IQR) RBC folate, serum folate, and plasma UMFA (nmol/L) in those supplemented with (6S)-5-MTHF versus folic acid, respectively, was: 1826 ± 471 and 1998 ± 421; 70 ± 13 and 78 ± 17; 0.5 (0.4, 0.8) and 1.3 (0.9, 2.1). In regression analyses, RBC and serum folate did not differ by treatment group; however, concentrations of plasma UMFA in pregnancy were 0.6 nmol/L higher (95% CI: 0.2-1.1) in those supplementing with folic acid as compared to (6S)-5-MTHF. In conclusion, supplementation with (6S)-5-MTHF may reduce plasma UMFA by ∼50% as compared to supplementation with folic acid, the biological relevance of which is unclear. As folate is currently available for purchase in both forms, the impact of circulating maternal UMFA on perinatal outcomes needs to be determined.

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

Abstract: These data demonstrate the potential for high serum folic acid concentrations proportional to overall folate concentrations in lactating women with serum total folate >80 nmol/L taking high-dose supplemental folic acid. This study was registered at clinicaltrials.gov as NCT01112891.

Cited by 9 publications

References 26 publications

Association Between Folate Metabolites and the Development of Food Allergy in Children

Association Between Folate Metabolites and the Development of Food Allergy in Children

Folic acid inhibits 5‐methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier: Clinical biochemical data from two cases

Supplementation with (6S)-5-methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada

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