The association between folic acid supplementation, maternal folate during pregnancy and intelligence development in infants: a prospective cohort study

Wang, Shaokang; Wei, Jie; Wang, Di; Li, Hua; Pan, Da; Fu, Lingmeng; Yang, Jing; Sun, Guiju

doi:10.1016/j.fshw.2021.02.009

Cited by 3 publications

(2 citation statements)

References 51 publications

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“…Excess folic acid intake has been associated with various adverse health outcomes for both the mother and child (10,13,17) . Clinical concerns related to offspring health include neurodevelopmental disorders (56)(57)(58)(59)(60)(61)(62)(63) , allergic diseases (64)(65)(66)(67)(68) , metabolic outcomes (17,(69)(70)(71)(72) and poor fetal growth (small-for-gestationalage birth) (73,74) . However, results in human studies are mixed, with some reporting a harmful association (58,(63)(64)(65)73) , null findings (56,59,(66)(67)(68)75) or a protective effect (57,(60)(61)(62)74) of maternal folic acid supplementation.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical concerns related to offspring health include neurodevelopmental disorders (56)(57)(58)(59)(60)(61)(62)(63) , allergic diseases (64)(65)(66)(67)(68) , metabolic outcomes (17,(69)(70)(71)(72) and poor fetal growth (small-for-gestationalage birth) (73,74) . However, results in human studies are mixed, with some reporting a harmful association (58,(63)(64)(65)73) , null findings (56,59,(66)(67)(68)75) or a protective effect (57,(60)(61)(62)74) of maternal folic acid supplementation. Further, the effects of folic acid may vary by dose; for example, folic acid supplementation at recommended doses (0•4 mg/d) is associated with a reduced risk of small-for-gestational-age (74) , whereas intakes > 1•0 mg have shown an increased risk (73) .…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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Ratiometric visualization of folic acid with a smartphone-assisted fluorescence paper device based on gadolinium and nitrogen co-doped CDs

et al. 2023

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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

Elango

Devlin

et al. 2023

Sci Rep

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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.

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The association between folic acid supplementation, maternal folate during pregnancy and intelligence development in infants: a prospective cohort study

Cited by 3 publications

References 51 publications

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

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

Ratiometric visualization of folic acid with a smartphone-assisted fluorescence paper device based on gadolinium and nitrogen co-doped CDs

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

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