Maternal Late-Pregnancy Serum Unmetabolized Folic Acid Concentrations Are Not Associated with Infant Allergic Disease: A Prospective Cohort Study

Abstract

Background The increase in childhood allergic disease in recent decades has coincided with increased folic acid intakes during pregnancy. Circulating unmetabolized folic acid (UMFA) has been proposed as a biomarker of excessive folic acid intake. Objective We aimed to determine if late-pregnancy serum UMFA and total folate concentrations were associated with allergic disease risk in the offspring at 1 y of age in a population at high risk of allergy. Methods The cohort consisted of 561 mother–infant pairs from Western Australia. To be eligible the infant had to have a first-degree relative (mother, father, or sibling) with a history of medically diagnosed allergic disease. Maternal venous blood was collected between 36 and 40 wk of gestation. Serum UMFA was measured by LC–tandem MS. Serum total folate was determined using a microbiological method with chloramphenicol-resistant Lactobacillus rhamnosus as the test organism, and was collected between 36 and 40 wk of gestation. UMFA concentrations were measured by tandem MS using stable isotope dilution; folate concentrations were determined using the microbiological method with standardized kits. Infant allergic disease outcomes of medically diagnosed eczema, steroid-treated eczema, atopic eczema, IgE-mediated food allergy, allergen sensitization, and medically diagnosed wheeze were assessed at 1 y of age. Results Median (IQR) concentrations for UMFA and serum folate were 1.6 (0.6–4.7) and 53.2 (32.6–74.5) nmol/L, respectively. Of the infants, 34.6% had medically diagnosed eczema, 26.4% allergen sensitization, and 14.9% had an IgE-mediated food allergy. In both adjusted and unadjusted models there was little evidence of association between UMFA or serum folate and any of the infant allergy outcomes. Conclusions In this cohort of children at high risk of allergic disease there was no association between maternal UMFA or serum folate concentrations measured in late pregnancy and allergic disease outcomes at 1 y of age.

High Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus

“…Accumulation of uFA itself may be detrimental, though there is limited research regarding the adverse effects of circulating uFA in pregnancy. Studies of allergic disease [ 89 ] and neurodevelopment [ 90 ], have found no adverse effects associated with uFA. However, some research indicates that higher maternal folate is associated with insulin resistance [ 36 , 37 ] and adiposity [ 37 ] in offspring.…”

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

“…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.…”

“…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) .…”

Scientific opinion on the tolerable upper intake level for folate

“…Regarding site-specific cancers (other than prostate and CRC which were discussed above), no evidence was found for an increased risk of cancer at any site in the folic acid groups compared to the control groups, in any of the reviews (O'Connor et al, 2021;Qin et al, 2013;Vollset et al, 2013;Wien et al, 2012). The number of cases for each cancer type were limited.…”