Folate dose and form during pregnancy may program maternal and fetal health and disease risk

Abstract

The role of folate, in its synthetic and bioactive form, as an in utero modifier of metabolic outcomes in mothers and offspring is examined in this review. During pregnancy, a continuum of adaptive changes occurs to support maternal and fetal requirements. However, an unfavorable in utero environment may lead to permanent changes in cellular and physiological functions, adversely affecting the development of the child and postpartum health of the mother. In North American countries, synthetic folic acid (FA) is overconsumed by pregnant women, and uncertainty exists about its potential unintended health effects. Because the metabolism of FA is different than that of other folate forms, it may modulate disease risk differently. The bioactive form of folate, 5-methyltetrahydrofolic acid, has emerged as a popular alternative to FA, but clinical studies comparing their effects during pregnancy are limited. Current evidence points to the need for caution when maternal intake of either folate form exceed recommended amounts. Research directed toward defining an optimal folate dose and form for healthy pregnancy and long-term metabolic outcomes in mothers and children is urgently needed.

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

“…Thus, the biological relevance of this difference is uncertain. 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) .…”

“…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.…”

“…Other considerations regarding the use of (6S)-5-MTHF v. folic acid include the lack of an established conversion factor of (6S)-5-MTHF to DFE, stability differences and cost. North American supplement manufacturers are permitted to use the folic acid factor of 1•7 to convert μg (6S)-5-MTHF to DFE (11,17) . Appropriateness of this is unclear, given potential differences in bioavailability as observed in non-pregnant populations (86) ; however, findings of the current trial suggest that bioavailability of folate forms during pregnancy may differ from non-pregnant individuals, in that a greater effect of (6S)-5-MTHF on folate status was not observed at a 0•6 mg dose.…”

“…However, unmetabolised folic acid (UMFA) is detected in biological fluids upon folic acid intake, suggesting that the capacity of intestinal dihydrofolate reductase to reduce folic acid in humans may be limited (15,16) . The biological and clinical relevance of UMFA on human health remains unclear (17) .…”

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

“…UMFA is widely detected among adults 24 and pregnant women in the United States and Canada 25 ; UMFA is an inactive form of folate, but its impact on folate-related metabolism and infant health remains unclear. The developmental origins of health and disease hypothesis suggests that susceptibility to future health and disease risk may be partially mediated by exposures in utero and early life 26 ; such exposures may include elevated concentrations of folate or UMFA, leading to perturbations in 1C metabolism and impacting fetal programming via epigenetic mechanisms, altered gene expression, and changes in cellular function 21 , 27 , 28 .…”