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.

Background: For the primary prevention of neural tube defects (NTDs), public health authorities recommend women of childbearing age to take 400 μg folic acid/d 4 wk before conception and during the first trimester. The biologically active derivate [6 S]-5-methyltetrahydrofolate ([6 S]-5-MTHF) could be an alternative to folic acid. Objective: We investigated the effect of supplementation with [6 S]-5-MTHF compared with that of folic acid on red blood cell folate concentration, an indicator of folate status. Design: The study was designed as a double-blind, randomized, placebo-controlled intervention trial. Healthy women (n = 144) aged 19–33 y received 400 μg folic acid, the equimolar amount of [6 S]-5-MTHF (416 μg), 208 μg [6 S]-5-MTHF, or placebo as a daily supplement for 24 wk. Red blood cell and plasma folate concentrations were measured at baseline and at 4-wk intervals. Results: The increase in red blood cell folate over time was significantly higher in the group receiving 416 μg [6 S]-5-MTHF/d than in the groups receiving 400 μg folic acid/d or 208 μg [6 S]-5-MTHF/d (P < 0.001). No plateau was reached in red blood cell folate concentration in the 3 treatment groups during 24 wk of intervention; however, plasma folate plateaued after 12 wk. Conclusions: We showed that administration of [6 S]-5-MTHF is more effective than is folic acid supplementation at improving folate status. In addition, the study indicates that the recommended period for preconceptional folic acid supplementation should be extended to >4 wk for maximal prevention of NTDs based on folate concentrations. [6 S]-5-MTHF might be an efficient and safe alternative to folic acid.

Objectives People of South Asian ethnicity are under-represented in health research studies. The objectives of this scoping review were to examine the barriers and facilitators to recruitment of South Asians to health research studies and to describe strategies for improving recruitment. Design Scoping review Methods Using the Arksey and O’Malley framework for scoping reviews, we comprehensively searched electronic databases (MEDLINE via PubMed, Cochrane Library, CINAHL and PsycINFO). Studies that identified barriers and facilitators to recruitment, or recruitment strategies for South Asian populations were included. Recruitment barriers, facilitators and strategies were grouped thematically and summarised narratively. Synthesis Of 1846 potentially relevant articles, 15 met the inclusion criteria and were included in the thematic synthesis. Multiple facilitators and barriers to enrolment of South Asians in health research studies were identified; these most commonly related to logistical challenges, language and cultural barriers, concerns about adverse consequences of participating and mistrust of research. Several actionable strategies were discussed, the most common being engagement of South Asian communities, demonstration of cultural competency, provision of incentives and benefits, language sensitivity through the use of translators and translated materials and the development of trust and personal relationships. Conclusion There is a growing awareness of the barriers and facilitators to recruitment of South Asian participants to health research studies. Knowledge of effective recruitment strategies and implementation during the grant funding stages may reduce the risk of poor recruitment and representation of South Asians.

Breast milk is the sole source of nutrition for exclusively breastfed infants in the first 6 mo of life, yet few studies have measured micronutrient concentrations in breast milk in light of maternal diet and subsequent infant micronutrient intakes. We evaluated the adequacy of micronutrient intakes of exclusively breastfed Indonesian infants by measuring milk volume and micronutrient concentrations and assessed maternal micronutrient intakes and their relationship with milk concentrations. Mother–infant (2–5.3 mo) dyads (n = 113) were recruited for this cross-sectional study. Volume of breast-milk intake via the deuterium dose-to-mother technique over 14 d and analyzed micronutrient concentrations were used to calculate micronutrient intakes of exclusively breastfed infants. Maternal 3-d weighed food records were collected to assess median (IQR) micronutrient intakes. Multivariate regression analyses examined the association of usual maternal micronutrient intakes with milk micronutrient concentrations after adjustment for confounding variables. Mean ± SD intake of breast-milk volume was 787 ± 148 mL/d. Median daily infant intakes of iron, zinc, selenium, magnesium, sodium, and B-vitamins (thiamin, riboflavin, niacin, pantothenic acid, B-6, and B-12) were below their respective Adequate Intakes. Inadequacies in maternal intakes (as % < estimated average requirements) were >40% for calcium, niacin, and vitamins A, B-6, and B-12. Significant positive associations existed between maternal usual intakes of vitamin A, niacin and riboflavin and milk retinol, nicotinamide, and free riboflavin concentrations in both unadjusted and adjusted (for infant age, milk volume, and parity) analyses (all P < 0.05). The majority of micronutrient intakes for these exclusively breastfed infants and their mothers fell below recommendations, with associations between maternal intakes and breast-milk concentrations for 3 nutrients. Data on nutrient requirements of exclusively breastfed infants are limited, and a better understanding of the influence of maternal nutritional status on milk nutrient concentrations and its impact on the breastfed infant is needed.

Background: Increased plasma total homocysteine (tHcy) is a risk factor for vascular disease and adverse pregnancy outcomes. Health authorities recommend periconceptional supplementation with 400 μg folic acid to prevent neural tube defects. Several countries have implemented food fortification with folic acid. However, excessive intake of folic acid could mask an undiagnosed vitamin B-12 deficiency. The biologically active [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) may be an alternative to folic acid because it is unlikely to mask vitamin B-12 deficiency symptoms. Objective: We compared the tHcy-lowering potential of 2 dosages of [6S]-5-MTHF with that of 400 μg folic acid during 24 wk of supplementation. Design: In this double-blind, randomized, controlled intervention trial, 144 female participants were supplemented daily with 400 μg folic acid, 416 μg [6S]-5-MTHF, 208 μg [6S]-5-MTHF, or placebo. Concentrations of tHcy and plasma folate were measured at baseline and at 4-wk intervals. Results: After supplementation, there was a significant interaction between time and treatment with respect to changes in tHcy and plasma folate (both P < 0.001 by two-factor repeated-measures analysis of variance). The decrease in tHcy did not differ significantly between the 3 supplemented groups (P > 0.05; Tukey's post hoc test). The increase in plasma folate in the group receiving 208 μg [6S]-5-MTHF was significantly lower than that in the groups receiving 400 μg folic acid (P < 0.001) or 416 μg [6S]-5-MTHF (P < 0.05). Conclusions: [6S]-5-MTHF was shown to be an adequate alternative to folic acid in reducing tHcy concentrations. Supplementation with 416 μg [6S]-5-MTHF was no more effective than that with 208 μg [6S]-5-MTHF.

Background: Anemia is common in Cambodian women. Potential causes include micronutrient deficiencies, genetic hemoglobin disorders, inflammation, and