Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Demographic, Physiologic, and Lifestyle Characteristics Observed with Serum Total Folate Differ Among Folate Forms: Cross-Sectional Data from Fasting Samples in the NHANES 2011-2016.

BACKGROUND: Serum folate forms were measured in the US population during recent NHANES to assess folate status. OBJECTIVE: We describe post-folic acid-fortification concentrations of serum folate forms in the fasting US population ≥1 y from the NHANES 2011-2016. METHODS: We measured 5 biologically active folates and 1 oxidation product (MeFox) of 5-methyltetrahydrofolate (5-methyl-THF). We calculated geometric means of 5-methyl-THF, unmetabolized folic acid (UMFA), nonmethyl folate (sum of tetrahydrofolate, 5-formyltetrahydrofolate, and 5,10-methenyltetrahydrofolate), total folate (sum of above biomarkers), and MeFox by demographic, physiologic, and lifestyle variables; estimated the magnitude of variables on biomarker concentrations after covariate adjustment; and determined the prevalence of UMFA >2 nmol/L. RESULTS: After demographic adjustment, age, sex, and race-Hispanic origin were significantly associated with most folate forms. MeFox increased with age, while 5-methyl-THF, UMFA, and nonmethyl folate displayed U-shaped age patterns. Compared with non-Hispanic whites, non-Hispanic blacks had 23% lower predicted 5-methyl-THF but comparable UMFA; non-Hispanic Asians had comparable 5-methyl-THF but 28% lower UMFA; Hispanics, non-Hispanic Asians, and non-Hispanic blacks had ∼20% lower MeFox. After additional physiologic and lifestyle adjustment, predicted UMFA and MeFox concentrations were 43% and 112% higher, respectively, in adults with chronic kidney disease and 17% and 15% lower, respectively, in adults consuming daily 1-<2 alcoholic beverages; 5-methyl-THF concentrations were 20% lower in adult smokers. The prevalence of UMFA >2 nmol/L was highest in persons aged ≥70 y (9.01%) and lowest in those aged 12-19 y (1.14%). During 2011-2014, the prevalence was 10.6% in users and 2.22% in nonusers of folic acid-containing supplements. CONCLUSIONS: In fasting persons ≥1 y, the demographic, physiologic, and lifestyle characteristics observed with serum total folate differed among folate forms, suggesting biological and/or genetic influences on folate metabolism. High UMFA was mostly observed in supplement users and older persons.

Folate status in the US population 20 y after the introduction of folic acid fortification.

BACKGROUND: Enriched cereal-grain products have been fortified in the United States for >20 y to improve folate status in women of reproductive age and reduce the risk of folic acid-responsive neural tube birth defects (NTDs). OBJECTIVES: Our objectives were to assess postfortification changes in folate status in the overall US population and in women aged 12-49 y and to characterize recent folate status by demographic group and use of folic acid-containing supplements. METHODS: We examined cross-sectional serum and RBC folate data from the NHANES 1999-2016. RESULTS: Serum folate geometric means increased from 2007-2010 to 2011-2016 in persons aged ≥1 y (38.7 compared with 40.6 nmol/L) and in women (35.3 compared with 37.0 nmol/L), whereas RBC folate showed no significant change. Younger age groups, men, and Hispanic persons showed increased serum and RBC folate concentrations, whereas non-Hispanic black persons and supplement nonusers showed increased serum folate concentrations. The folate insufficiency prevalence (RBC folate <748 nmol/L; NTD risk) in women decreased from 2007-2010 (23.2%) to 2011-2016 (18.6%) overall and in some subgroups (e.g., women aged 20-39 y, Hispanic and non-Hispanic black women, and supplement nonusers). After covariate adjustment, RBC folate was significantly lower in all age groups (by ∼10-20%) compared with persons aged ≥60 y and in Hispanic (by 8.2%), non-Hispanic Asian (by 12.1%), and non-Hispanic black (by 20.5%) compared with non-Hispanic white women (2011-2016). The 90th percentile for serum (∼70 nmol/L) and RBC (∼1800 nmol/L) folate in supplement nonusers aged ≥60 y was similar to the geometric mean in users (2011-2014). CONCLUSIONS: Blood folate concentrations in the US population overall and in women have not decreased recently, and folate insufficiency rates are ∼20%. Continued monitoring of all age groups is advisable given the high folate status particularly in older supplement users.

A report of activities related to the Dietary Reference Intakes from the Joint Canada-US Dietary Reference Intakes Working Group.

The governments of the United States and Canada have jointly undertaken the development of the Dietary Reference Intakes (DRIs) since the mid-1990s. The Federal DRI committees from each country work collaboratively to identify DRI needs, prioritize nutrient reviews, advance work to resolve methodological issues that is necessary for new reviews, and sponsor DRI-related committees through the National Academies of Sciences, Engineering and Medicine. In recent years, the Joint Canada-US DRI Working Group, consisting of members from both Federal DRI committees, developed an open and transparent nomination process for prioritizing nutrients for DRI review, by which sodium, the omega-3 (n-3) fatty acids, vitamin E, and magnesium were identified. In addition, discussions during the nutrient nomination process prompted the Federal DRI committees to address previously identified issues related to the use of chronic disease endpoints when setting DRIs. The development of guiding principles for setting DRIs based on chronic disease risk reduction will be applied for the first time during the DRI review of sodium and potassium. In summary, the US and Canadian governments have worked collaboratively to adapt our approach to prioritizing nutrients for DRI review and to broaden the scope of the DRIs to better incorporate the concept of chronic disease risk reduction in order to improve public health.

Qualified health claim for whole-grain intake and risk of type 2 diabetes: an evidence-based review by the US Food and Drug Administration.

The objective of this review is to explain how the US Food and Drug Administration (FDA) used its evidence-based review system to evaluate the scientific evidence for a qualified health claim on the role of whole-grain consumption in reducing the risk of type 2 diabetes. The labeling of health claims, including qualified health claims, on conventional foods and dietary supplements requires premarket approval by the FDA. Health claims characterize the relationship between a substance (food or food component) and a disease (eg, diabetes or cardiovascular disease) or a health-related condition (eg, hypertension). This review describes the FDA's evaluation of intervention and observational studies that characterize a relationship between whole grains and type 2 diabetes. This evidence-based review provides very limited evidence to support a health claim of a relationship between intake of whole grains and a reduced risk of type 2 diabetes.

Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2.

Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population ≥ 1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011-2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37·5 nmol/l; 100 %), UMFA (1·21 nmol/l; 99·9 %), MeFox (1·53 nmol/l; 98·8 %), and THF (1·01 nmol/l; 85·2 %) were mostly detectable. 5-FormylTHF (3·6 %) and 5,10-methenylTHF (4·4 %) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86·7 %); UMFA (4·0 %), non-methyl folate (4·7 %) and MeFox (4·5 %) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's r< 0·4) but significant (P< 0·05) correlations with physiological and lifestyle variables. Fasting, kidney function, smoking and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics.

FDA's health claim review: whey-protein partially hydrolyzed infant formula and atopic dermatitis.

In this review, we explain how the US Food and Drug Administration (FDA) used its evidence-based review system to evaluate the scientific evidence for a qualified health claim for 100% whey-protein partially hydrolyzed infant formula (W-PHF) and reduced risk of atopic dermatitis (AD). The labeling of health claims, including qualified health claims, on conventional foods and dietary supplements require premarket approval by the FDA. Health claims characterize the relationship between a substance (food or food component) and disease (eg, cancer or cardiovascular disease) or health-related condition (eg, hypertension). To determine whether sufficient evidence exists to support the qualified health claim, the FDA evaluated human intervention studies that evaluated the role of W-PHF in reducing the risk of AD. The FDA concluded there is little to very little evidence, respectively, to support a qualified health claim concerning the relationship between intake of W-PHF and a reduced risk of AD in partially breastfed and exclusively formula-fed infants throughout the first year after birth and up to 3 years of age. In addition, the FDA required a warning statement be displayed along with the health claim to indicate to consumers that partially hydrolyzed infant formulas are not hypoallergenic and should not be fed to infants who are allergic to milk or to infants with existing milk allergy symptoms.

Impact of using updated food consumption and composition data on selected MyPyramid Food Group nutrient profiles.

OBJECTIVE: To examine the changes observed in 5 nutrients of selected USDA food subgroups by partitioning the overall changes into those caused by consumption changes over time, and those caused by nutrient database revisions. DESIGN: Population-weighted estimates of food group intakes (composites) were developed using 24-hour recall data from CSFII 1994-96 and NHANES 1999-2000. Nutrient profiles of these composites were developed using Standard Reference (SR) data (SR11 and SR16-1). SUBJECTS: A total of 14,262 and 8070 individuals over the age of 2 years from CSFII and NHANES, respectively, composed the study sample. OUTCOME MEASURES: Absolute and percent change in food group nutrient content caused by food consumption changes and nutrient database updates. ANALYSIS: Changes due to consumption differences were determined by comparing nutrient profiles created with CSFII and NHANES using SR11. Changes due to nutrient database differences were determined by comparing nutrient profiles created from NHANES data using SR11 and SR16-1 nutrient values. RESULTS: Consumption differences resulted in some variations in the food group nutrient content, but a majority of the changes were associated with use of the updated nutrient database. For example, vitamin A level in the orange vegetable subgroup was increased by 2.4% owing to consumption (from CSFII to NHANES), whereas the level was decreased by 38% due to nutrient updates (from SR11 to SR16-1). CONCLUSION AND IMPLICATIONS: Consideration of the changes in nutrient databases, as well as in food consumption, is essential in monitoring both the trends in the food choices Americans make and the adequacy of their diets.

Development of food intake patterns for the MyPyramid Food Guidance System.

OBJECTIVE: The purpose of this research was to design food intake patterns based on typical American food selections that would meet Dietary Guidelines and Dietary Reference Intake recommendations. DESIGN: Analytic process to identify appropriate amounts from each food group that together will meet nutritional goals for various age/gender groups. VARIABLES MEASURED: Projected intake of energy, 9 vitamins, 8 minerals, 8 macronutrients, and dietary fiber in each food intake pattern. ANALYSIS: Iterative comparison of nutrients in each food intake pattern to Dietary Reference Intakes and Dietary Guidelines recommendations set as goals for that pattern. RESULTS: Food intake patterns were established that met almost all nutrient goals within estimated energy needs. Intakes of vitamin E at all energy levels, potassium at lower energy levels, and sodium at higher energy levels did not meet goals. CONCLUSIONS AND IMPLICATIONS: The food intake patterns provide a foundation of food choices that will meet nutritional recommendations. They form the scientific basis for the MyPyramid Food Guidance System and can also be used as a starting point for developing other educational programs or materials.

Development of food group composites and nutrient profiles for the MyPyramid Food Guidance System.

OBJECTIVE: To identify food selections in each MyPyramid food group or subgroup reflective of typical consumption patterns by Americans, and the nutrient intake that can be expected from consuming a specified amount of these foods from each group, in a low-fat and no-added-sugars form. DESIGN: An analytical process to identify food consumption choices within each food group and subgroup using national food consumption surveys, and to identify the expected nutrient content of each group using food composition databases. VARIABLES MEASURED: Relative consumption of foods within each food group; nutrient content for each food group and subgroup (energy plus 27 nutrients). ANALYSIS: Disaggregated foods from consumption surveys into component ingredients. Combined similar ingredients into "item clusters" and determined relative consumption of each. Calculated a consumption-weighted nutrient profile for each food group. RESULTS: Consumption-weighted food intake selections and nutrient profiles were developed for all MyPyramid food groups and subgroups. CONCLUSIONS AND IMPLICATIONS: This analytical process derived food group and subgroup composites which estimate typical food choices within each MyPyramid food group. These were used to assess the adequacy of the MyPyramid food intake patterns as they were being iteratively developed.

Carotenoid composition of human milk during the first month postpartum and the response to beta-carotene supplementation.

BACKGROUND: Information is lacking regarding normal changes in milk carotenoid concentrations in healthy, well-nourished women during the first month of lactation. OBJECTIVES: This study investigated milk carotenoid concentrations during days 4-32 postpartum and assessed the effects of maternal beta-carotene supplementation. DESIGN: Subjects (n = 21; aged 19-39 y) were randomly assigned to receive beta-carotene (30 mg/d) or placebo from days 4 to 32 postpartum. Each subject provided 8 diet records and 8 milk samples during the study. Diet records were analyzed for energy, macronutrients, vitamins A and E, and carotenoids. Milk samples were analyzed with HPLC for concentrations of carotenoids, retinol, and alpha-tocopherol. Data were analyzed by using repeated-measures analysis and orthogonal contrasts. RESULTS: No significant differences in average dietary intakes, body mass index, age, or parity were found between groups at baseline or after supplementation. Milk carotenoid concentrations decreased over time (P < 0.01), as did retinol and alpha-tocopherol concentrations (P < 0.003). Concentrations of most carotenoids decreased to those reported for mature milk by day 32 postpartum. Milk lutein concentrations remained elevated throughout the study compared with values reported for mature milk, whereas plasma lutein concentrations decreased significantly over time. beta-carotene supplementation did not significantly change the milk concentrations of beta-carotene, the other carotenoids, retinol, or alpha-tocopherol. CONCLUSIONS: The lack of increase in milk beta-carotene despite supplementation suggests that transitional milk may be already nearly saturated with beta-carotene. The elevated milk lutein concentration and simultaneous decrease in plasma lutein suggest that lutein metabolism may be altered during early lactation.