Office of Dietary Supplements

Micronutrients are essential to sustain life and for optimal physiological function. Widespread global micronutrient deficiencies (MNDs) exist, with pregnant women and their children under 5 years at the highest risk. Iron, iodine, folate, vitamin A, and zinc deficiencies are the most widespread MNDs, and all these MNDs are common contributors to poor growth, intellectual impairments, perinatal complications, and increased risk of morbidity and mortality. Iron deficiency is the most common MND worldwide and leads to microcytic anemia, decreased capacity for work, as well as impaired immune and endocrine function. Iodine deficiency disorder is also widespread and results in goiter, mental retardation, or reduced cognitive function. Adequate zinc is necessary for optimal immune function, and deficiency is associated with an increased incidence of diarrhea and acute respiratory infections, major causes of death in those <5 years of age. Folic acid taken in early pregnancy can prevent neural tube defects. Folate is essential for DNA synthesis and repair, and deficiency results in macrocytic anemia. Vitamin A deficiency is the leading cause of blindness worldwide and also impairs immune function and cell differentiation. Single MNDs rarely occur alone; often, multiple MNDs coexist. The long-term consequences of MNDs are not only seen at the individual level but also have deleterious impacts on the economic development and human capital at the country level. Perhaps of greatest concern is the cycle of MNDs that persists over generations and the intergenerational consequences of MNDs that we are only beginning to understand. Prevention of MNDs is critical and traditionally has been accomplished through supplementation, fortification, and food-based approaches including diversification. It is widely accepted that intervention in the first 1,000 days is critical to break the cycle of malnutrition; however, a coordinated, sustainable commitment to scaling up nutrition at the global level is still needed. Understanding the epidemiology of MNDs is critical to understand what intervention strategies will work best under different conditions.

BACKGROUND: Dietary supplements are used by more than half of adults, although to our knowledge, the reasons motivating use have not been previously examined in US adults using nationally representative data. The purpose of this analysis was to examine motivations for dietary supplement use, characterize the types of products used for the most commonly reported motivations, and to examine the role of physicians and health care practitioners in guiding choices about dietary supplements. METHODS: Data from adults (≥20 years; n = 11 956) were examined in the 2007-2010 National Health and Nutrition Examination Survey, a nationally representative, cross-sectional, population-based survey. RESULTS: The most commonly reported reasons for using supplements were to "improve" (45%) or "maintain" (33%) overall health. Women used calcium products for "bone health" (36%), whereas men were more likely to report supplement use for "heart health or to lower cholesterol" (18%). Older adults (≥60 years) were more likely than younger individuals to report motivations related to site-specific reasons like heart, bone and joint, and eye health. Only 23% of products were used based on recommendations of a health care provider. Multivitamin-mineral products were the most frequently reported type of supplement taken, followed by calcium and ω-3 or fish oil supplements. Supplement users are more likely to report very good or excellent health, have health insurance, use alcohol moderately, eschew cigarette smoking, and exercise more frequently than nonusers. CONCLUSIONS: Supplement users reported motivations related to overall health more commonly than for supplementing nutrients from food intakes. Use of supplements was related to more favorable health and lifestyle choices. Less than a quarter of supplements used by adults were recommended by a physician or health care provider.

In early 2011, a committee convened by the Institute of Medicine issued a report on the Dietary Reference Intakes for calcium and vitamin D. The Endocrine Society Task Force in July 2011 published a guideline for the evaluation, treatment, and prevention of vitamin D deficiency. Although these reports are intended for different purposes, the disagreements concerning the nature of the available data and the resulting conclusions have caused confusion for clinicians, researchers, and the public. In this commentary, members of the Institute of Medicine committee respond to aspects of The Endocrine Society guideline that are not well supported and in need of reconsideration. These concerns focus on target serum 25-hydroxyvitamin D levels, the definition of vitamin D deficiency, and the question of who constitutes a population at risk vs. the general population.

Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them.

The human body is host to a vast number of microbes, including bacterial, fungal and protozoal microoganisms, which together constitute our microbiota. Evidence is emerging that the intestinal microbiome is intrinsically linked with overall health, including obesity risk. Obesity and obesity-related metabolic disorders are characterized by specific alterations in the composition and function of the human gut microbiome. Mechanistic studies have indicated that the gastrointestinal microbiota can influence both sides of the energy balance equation; namely, as a factor influencing energy utilization from the diet and as a factor that influences host genes that regulate energy expenditure and storage. Moreover, its composition is not fixed and can be influenced by several dietary components. This fact raises the attractive possibility that manipulating the gut microbiota could facilitate weight loss or prevent obesity in humans. Emerging as possible strategies for obesity prevention and/or treatment are targeting the microbiota, in order to restore or modulate its composition through the consumption of live bacteria (probiotics), nondigestible or limited digestible food constituents such as oligosaccharides (prebiotics), or both (synbiotics), or even fecal transplants.

BACKGROUND: Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. METHODS: In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. FINDINGS: We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00-1.29), 1.33 (1.16-1.51), and 1.67 (1.44-1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. INTERPRETATION: In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

Wide spread variation in measurement results of total 25-hydroxyvitamin D (25(OH)D) confounds international efforts to develop evidence-based clinical guidelines. Accordingly, NIH Office of Dietary Supplements (ODS) in collaboration with CDC National Center for Environmental Health (NCEH), National Institute of Standards and Technology (NIST) and Ghent University established the Vitamin D Standardization Program (VDSP) in November 2010. VDSP objectives include: (1) standardize 25(OH)D concentration measurements in national health surveys around the world, (2) evaluate survey differences, (3) extend standardization efforts to assay manufacturers, and to clinical, commercial, and research laboratories, (4) promote standardization of emerging metabolites of vitamin D status, and (5) enable the use of standardized data in patient care and public health. An interlaboratory comparison study is being conducted to assess measurement variability among current assays. Participants include national health surveys from Australia, Canada, Germany, Ireland, Mexico, South Korea, UK and USA, 15 assay manufacturers, and two external quality assurance programs. CDC will implement a formal laboratory certification program. Standardization activities will use single-donor, fresh-frozen serum collected using the CLSI C37 protocol. Initial assay performance criteria, based on biological variability data, are ≤ 10 % imprecision and ≤ 5 % bias in relation to the reference values. An ancillary study on commutability of NIST SRM 972a, external quality assurance testing materials is included. To increase the comparability of existing data from different national surveys, master equations will be developed to facilitate the conversion of already existing national survey data to the NIST-Ghent University reference measurement procedures.

The claim that large proportions of North American and other populations are deficient in vitamin D is based on misinterpretation and misapplication of the Institute of Medicine reference values for nutrients — misunderstandings that can adversely affect patient care.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

BACKGROUND: In 2012, the American Orthopaedic Foot & Ankle Society(®) established a national network for collecting and sharing data on treatment outcomes and improving patient care. One of the network's initiatives is to explore the use of computerized adaptive tests (CATs) for patient-level outcome reporting. QUESTIONS/PURPOSES: We determined whether the CAT from the NIH Patient Reported Outcome Measurement Information System(®) (PROMIS(®)) Physical Function (PF) item bank provides efficient, reliable, valid, precise, and adequately covered point estimates of patients' physical function. METHODS: After informed consent, 288 patients with a mean age of 51 years (range, 18-81 years) undergoing surgery for common foot and ankle problems completed a web-based questionnaire. Efficiency was determined by time for test administration. Reliability was assessed with person and item reliability estimates. Validity evaluation included content validity from expert review and construct validity measured against the PROMIS(®) Pain CAT and patient responses based on tradeoff perceptions. Precision was assessed by standard error of measurement (SEM) across patients' physical function levels. Instrument coverage was based on a person-item map. RESULTS: Average time of test administration was 47 seconds. Reliability was 0.96 for person and 0.99 for item. Construct validity against the Pain CAT had an r value of -0.657 (p < 0.001). Precision had an SEM of less than 3.3 (equivalent to a Cronbach's alpha of ≥ 0.90) across a broad range of function. Concerning coverage, the ceiling effect was 0.32% and there was no floor effect. CONCLUSIONS: The PROMIS(®) PF CAT appears to be an excellent method for measuring outcomes for patients with foot and ankle surgery. Further validation of the PROMIS(®) item banks may ultimately provide a valid and reliable tool for measuring patient-reported outcomes after injuries and treatment.

Fortification is the process of adding nutrients or non-nutrient bioactive components to edible products (e.g., food, food constituents, or supplements). Fortification can be used to correct or prevent widespread nutrient intake shortfalls and associated deficiencies, to balance the total nutrient profile of a diet, to restore nutrients lost in processing, or to appeal to consumers looking to supplement their diet. Food fortification could be considered as a public health strategy to enhance nutrient intakes of a population. Over the past century, fortification has been effective at reducing the risk of nutrient deficiency diseases such as beriberi, goiter, pellagra, and rickets. However, the world today is very different from when fortification emerged in the 1920s. Although early fortification programs were designed to eliminate deficiency diseases, current fortification programs are based on low dietary intakes rather than a diagnosable condition. Moving forward, we must be diligent in our approach to achieving effective and responsible fortification practices and policies, including responsible marketing of fortified products. Fortification must be applied prudently, its effects monitored diligently, and the public informed effectively about its benefits through consumer education efforts. Clear lines of authority for establishing fortification guidelines should be developed and should take into account changing population demographics, changes in the food supply, and advances in technology. This article is a summary of a symposium presented at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 on current issues involving fortification focusing primarily on the United States and Canada and recommendations for the development of responsible fortification practices to ensure their safety and effectiveness.

The prevalence of obesity has increased in the past 30 years, and at the same time a steep increase in consumption of soft drinks has been seen. This paper reviews the literature for studies on associations between intake of calorically sweetened beverages and obesity, relative to adjustment for energy intake. Conclusions from previous reviews have been inconsistent, but some included many cross-sectional studies or studies supported by sugar industry. A literature search was performed for prospective and experimental studies using Medline and Scirus. Fourteen prospective and five experimental studies were identified. The majority of the prospective studies found positive associations between intake of calorically sweetened beverages and obesity. Three experimental studies found positive effects of calorically sweetened beverages and subsequent changes in body fat. Two experimental studies did not find effects. Eight prospective studies adjusted for energy intake. Seven of these studies reported associations that were essentially similar before and after energy adjustment. In conclusion, a high intake of calorically sweetened beverages can be regarded as a determinant for obesity. However, there seems to be no support that the association between intake of calorically sweetened beverages and obesity is mediated via increased energy intake, and alternative biological explanations should be explored.

For a number of years it has been widely assumed that measurement of serum 25-hydroxyvitamin D [25(OH)D] concentration is the best approach to assessing an individual's vitamin D status. However, it has also been recognized that there is substantial within-assay variation in 25(OH)D measurement and even greater between-assay variability. Such assay variation clearly confounds attempts to define what constitutes the diagnosis of hypovitaminosis D. Importantly, assay variability makes pooling of 25(OH)D results from different studies in systematic reviews for the specific purpose of determining dose-response and/or clinical cut points at best problematic. Therefore, to develop and implement evidence-based clinical guidelines, it is essential that 25(OH)D measurement be standardized in both clinical and research laboratories. In this Perspective we outline a way forward toward achieving this goal-the Vitamin D Standardization Program (VDSP).

The discovery of multiple selenoproteins has raised tantalizing questions about their role in maintaining normal cellular function. Unfortunately, many of these remain inadequately investigated. While they have a role in maintaining redox balance, other functions are becoming increasingly recognized. As the roles of these selenoproteins are further characterized, a better understanding of the true physiological significance of this trace element will arise. This knowledge will be essential in defining optimum intakes to achieve cellular homeostasis in order to optimize health, including a reduction in cancer, for diverse populations. Human variation in the response to selenium likely reflects significant interactions between the type and amounts of selenium consumed with the genome and a host of environmental factors including the totality of the diet, as discussed in this review.

Concerns exist about the adequacy of vitamin D in pregnant and lactating women. This review assesses the evidence that maternal vitamin D status influences maternal, fetal, and breast-fed infant bone health; maternal adverse outcomes (preeclampsia, gestational diabetes, obstructed labor, and infectious disease); fetal adverse outcomes (growth, gestational age, and developmental programming); and infant adverse outcomes. The evidence for all of these outcomes is contradictory (except for maternal infectious disease) and lacking causality; thus, it is inconclusive. The 2011 Dietary Reference Intakes for vitamin D and their implications for assessing vitamin D status are discussed. An estimated 5% to 29% of American pregnant women may have inadequate vitamin D status, with the higher prevalence in African Americans. Little is known about the prevalence of inadequacy in American lactating women. Research needs are also identified, especially the need for rigorous and well-designed randomized clinical trials to determine the role of vitamin D in nonbone health outcomes in pregnancy and lactation.

Low vitamin D status is common in Europe. The major source of vitamin D in humans is ultraviolet B (UVB)-induced dermal synthesis of cholecalciferol, whereas food sources are believed to play a lesser role. Our objectives were to assess UVB availability (Jm(-2)) across several European locations ranging from 35° N to 69° N, and compare these UVB data with representative population serum 25-hydroxyvitamin D (25(OH)D) data from Ireland (51-54° N), Iceland (64° N) and Norway (69° N), as exemplars. Vitamin D-effective UVB availability was modelled for nine European countries/regions using a validated UV irradiance model. Standardized serum 25(OH)D data was accessed from the EC-funded ODIN project. The results showed that UVB availability decreased with increasing latitude (from 35° N to 69° N), while all locations exhibited significant seasonal variation in UVB. The UVB data suggested that the duration of vitamin D winters ranged from none (at 35° N) to eight months (at 69° N). The large seasonal fluctuations in serum 25(OH)D in Irish adults was much dampened in Norwegian and Icelandic adults, despite considerably lower UVB availability at these northern latitudes but with much higher vitamin D intakes. In conclusion, increasing the vitamin D intake can ameliorate the impact of low UVB availability on serum 25(OH)D status in Europe.

The objective of this study was to estimate the prevalence of use and types of dietary supplements (DS) used by U.S. adults (≥19 years) by sociodemographic characteristics: family income-to-poverty ratio (PIR), food security status, and Supplemental Nutrition Assistance Program (SNAP) participation using NHANES 2011–2014 data (n = 11,024). DS use was ascertained via a home inventory and a retrospective 30-day questionnaire. Demographic and socioeconomic differences related to DS use were evaluated using a univariate t statistic. Half of U.S. adults (52%) took at least one DS during a 30-day period; multivitamin-mineral (MVM) products were the most commonly used (31%). DS and MVM use was significantly higher among those with a household income of ≥ 350% of the poverty level, those who were food secure, and SNAP income-ineligible nonparticipants across all sex, age, and race/ethnic groups. Among women, prevalence of use significantly differed between SNAP participants (39%) and SNAP income-eligible nonparticipants (54%). Older adults (71+ years) remained the highest consumers of DS, specifically among the highest income group (82%), while younger adults (19–30 years), predominantly in the lowest income group (28%), were the lowest consumers. Among U.S. adults, DS use and the types of products consumed varied with income, food security, and SNAP participation.

The use of botanicals and dietary supplements derived from natural substances as an adjunct to an improved quality of life or for their purported medical benefits has become increasingly common in the United States. This review addresses the safety assessment and regulation of food products containing these substances by the U.S. Food and Drug Administration (FDA). The issue of safety is particularly critical given how little information is available on the toxicity of some of these products. The first section uses case studies for stevia and green tea extracts as examples of how FDA evaluates the safety of botanical and herbal products submitted for consideration as Generally Recognized as Safe under the Federal Food, Drug, and Cosmetics Act. The 1994 Dietary Supplement Health Education Act (DSHEA) created a regulatory framework for dietary supplements. The article also discusses the regulation of this class of dietary supplements under DSHEA and addresses the FDA experience in analyzing the safety of natural ingredients described in pre-market safety submissions. Lastly, we discuss an ongoing interagency collaboration to conduct safety testing of nominated dietary supplements.

Iron is particularly important in pregnancy and infancy to meet the high demands for hematopoiesis, growth and development. Much attention has been given to conditions of iron deficiency (ID) and iron deficient anemia (IDA) because of the high global prevalence estimated in these vulnerable life stages. Emerging and preliminary evidence demonstrates, however, a U-shaped risk at both low and high iron status for birth and infant adverse health outcomes including growth, preterm birth, gestational diabetes, gastrointestinal health, and neurodegenerative diseases during aging. Such evidence raises questions about the effects of high iron intakes through supplementation or food fortification during pregnancy and infancy in iron-replete individuals. This review examines the emerging as well as the current understanding of iron needs and homeostasis during pregnancy and infancy, uncertainties in ascertaining iron status in these populations, and issues surrounding U-shaped risk curves in iron-replete pregnant women and infants. Implications for research and policy are discussed relative to screening and supplementation in these vulnerable populations, especially in developed countries in which the majority of these populations are likely iron-replete.

OBJECTIVE: To describe dietary supplement use among US children. DESIGN: Analysis of nationally representative data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES). SETTING: Home interviews and a mobile examination center. PARTICIPANTS: Children from birth through 18 years who participated in NHANES (N=10,136). MAIN EXPOSURE: Frequency of use of any dietary supplement product. OUTCOME MEASURE: Prevalence of use and intake of key nutrients from supplements among children. RESULTS: In 1999-2002, 31.8% of children used dietary supplements, with the lowest use reported among infants younger than 1 year (11.9%) and teenagers 14 to 18 years old (25.7%) and highest use among 4- to 8-year-old children (48.5%). Use was highest among non-Hispanic white (38.1%) and Mexican American (22.4%) participants, lowest among non-Hispanic black participants (18.8%), and was not found to differ by sex. The type of supplement most commonly used was multivitamins and multiminerals (18.3%). Ascorbic acid (28.6%), retinol (25.8%), vitamin D (25.6%), calcium (21.1%), and iron (19.3%) were the primary supplemental nutrients consumed. Supplement use was associated with families with higher incomes; a smoke-free environment; not being certified by the US Department of Agriculture Special Supplemental Nutrition Program for Women, Infants and Children in the last 12 months; lower child body mass index; and less daily recreational screen time (television, video games, computers, etc) (P<.005). The highest prevalence of supplement use (P<.005) was in children who were underweight or at risk for underweight (P<.005). CONCLUSIONS: More than 30% of children in the United States take dietary supplements regularly, most often multivitamins and multiminerals. Given such extensive use, nutrient intakes from dietary supplements must be included to obtain accurate estimates of overall nutrient intake in children.