Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. OBJECTIVE: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. RESULTS: The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. CONCLUSION: The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.

A Systematic Review Supporting the Endocrine Society Clinical Practice Guidelines on Vitamin D.

CONTEXT: Low vitamin D status is common and is associated with various common medical conditions. OBJECTIVE: To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease. METHODS: We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence. RESULTS: Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with variable certainty of evidence. There was a very small reduction in mortality among adults older than 75 years with high certainty of evidence. In pregnant women, low-certainty evidence suggested possible benefit on various maternal, fetal, and neonatal outcomes. In adults with prediabetes, moderate certainty of evidence suggested reduction in the rate of progression to diabetes. Administration of high-dose intermittent vitamin D may increase falls, compared to lower-dose daily dosing. We did not identify trials on the benefits and harms of screening with serum 25(OH)D. CONCLUSION: The evidence summarized in this systematic review addresses the benefits and harms of vitamin D for the prevention of disease. The guideline panel considered additional information about individuals' and providers' values and preferences and other important decisional and contextual factors to develop clinical recommendations.

Access to nutrition advice and knowledge, attitudes and practices of pregnant women in Ireland: A cross-sectional study.

BACKGROUND: Healthy nutritional status, appropriate gestational weight gain and a balanced diet are important predictors of perinatal health outcomes. However, gaps exist in the translation of nutrition recommendations into dietary practices of women before and during pregnancy. The present study explored the relationship between access to nutrition advice, nutrition knowledge, attitudes and practices among pregnant women. METHODS: Pregnant women aged > 18 years in Ireland were eligible to complete a self-administered survey consisting of four subsections (demographics, nutrition knowledge, attitudes and practices) delivered online through Qualtrics. RESULTS: In this convenience sample (n = 334, median [interquartile range] gestation, 25.0 [16.0, 34.0] weeks), 85% had at least an honours bachelor degree and 88.9% planned their pregnancy. Two out of five women received nutrition advice during their pregnancy, mostly from a midwife. Based on the percentage of correct answers (of 15 questions), women with previous nutrition education (e.g., school home economics) had better median [interquartile range] nutrition knowledge than those with none (80.0% [66.7, 86.7%] vs. 73.3% [60.0, 80.0%], p < 0.001). Those who received nutrition advice during pregnancy did not score higher than those who did not (73.3% [66.7, 80.0%] vs. 73.3% [66.7, 80.0%], p = 0.6). Over three-quarters of participants considered nutritional supplement use to be very or extremely important. Although 73.6% and 92.4% took supplements prior to and during pregnancy, only 25.7% reported compliance with periconceptional folic acid supplementation guidelines. Half of respondents considered healthy eating during pregnancy as very or extremely important. CONCLUSIONS: Access to nutrition advice during pregnancy was inadequate with poor nutrition knowledge, attitudes and practices observed. Accessible, evidence-based nutrition education for women prior to and during pregnancy is required.

Impact of consuming an environmentally protective diet on micronutrients: a systematic literature review.

BACKGROUND: A global move toward consumption of diets from sustainable sources is required to protect planetary health. As this dietary transition will result in greater reliance on plant-based protein sources, the impact on micronutrient (MN) intakes and status is unknown. OBJECTIVE: Evaluate the evidence of effects on intakes and status of selected MNs resulting from changes in dietary intakes to reduce environmental impact. Selected MNs of public health concern were vitamins A, D, and B12, folate, calcium, iron, iodine, and zinc. METHODS: We systematically searched 7 databases from January 2011 to October 2022 and followed the PRISMA guidelines. Eligible studies had to report individual MN intake and/or status data collected in free-living individuals from the year 2000 onward and environmental outcomes. RESULTS: From the 10,965 studies identified, 56 studies were included, mostly from high-income countries (n = 49). Iron (all 56) and iodine (n = 20) were the most and least reported MNs, respectively. There was one randomized controlled trial (RCT) that also provided the only biomarker data, 10 dietary intake studies, and 45 dietary modeling studies, including 29 diet optimization studies. Most studies sought to reduce greenhouse gas emissions or intake of animal-sourced foods. Most results suggested that intakes of zinc, calcium, iodine, and vitamins B12, A, and D would decrease, and total iron and folate would increase in a dietary transition to reduce environmental impacts. Risk of inadequate intakes of zinc, calcium, vitamins A, B12 and D were more likely to increase in the 10 studies that reported nutrient adequacy. Diet optimization (n = 29) demonstrated that meeting nutritional and environmental targets is technically feasible, although acceptability is not guaranteed. CONCLUSIONS: Lower intakes and status of MNs of public health concern are a potential outcome of dietary changes to reduce environmental impacts. Adequate consideration of context and nutritional requirements is required to develop evidence-based recommendations. This study was registered prospectively with PROSPERO (CRD42021239713).

Development and validation of a food frequency questionnaire to assess habitual iodine intake among women of childbearing age.

BACKGROUND: Adequate iodine status is critical for thyroid hormone synthesis, which is essential for foetal brain development. Suboptimal iodine status has been reported in young women across Europe. Although urinary iodine concentration (UIC) is a good indicator of recent exposure, it does not reflect habitual iodine intake. This study aimed to develop and validate an iodine-specific food frequency questionnaire (I-FFQ) to assess habitual intake in Irish women aged 18-50 years. METHODS: A 47-item interviewer-administered I-FFQ, informed by national food consumption data on Irish women aged 18-35 years, was developed and validated in a study of 100 nonpregnant women using a 4-day weighed food diary (FD) and UIC as the reference methods. Correlation, cross-classification and Bland-Altman analyses were used to assess agreement and bias between the I-FFQ and FD. Validity coefficients were calculated using the method of triads. RESULTS: Median (interquartile range [IQR]) UIC was 82 (49, 139) µg/L. Median (IQR) intakes were 161 (106, 217) and 133 (98, 182) µg/day for the I-FFQ and FD, respectively (p = 0.001). Estimates were moderately correlated (r = 0.434), and the I-FFQ classified 89% of participants into the same or adjacent tertile of intake as the FD. Validity coefficients for the I-FFQ, FD and UIC were 0.542, 0.800 and 0.228, respectively. Though repeatability analyses 10 weeks later (n = 69) showed slight differences in estimates of intake (I-FFQ1: 164 (104, 210) µg/day; I-FFQ2: 132 (67, 237) µg/day), intakes were highly correlated between administrations (r = 0.627, p = 0.001). CONCLUSIONS: The I-FFQ provides a reasonable estimate of habitual iodine intake in young women.

Poor Quality Diets Characterized by Low-Nutrient Density Foods Observed in One-Quarter of 2-Year-Olds in a High Resource Setting.

BACKGROUND: Young children have high nutritional requirements relative to their body size, making healthy diets critical for normal growth and development. OBJECTIVE: We aimed to integrate analysis of dietary patterns among 2-y-old children with indicators of dietary quality, micronutrient status, and body weight status. METHODS: Data from the 2-y follow-up of the Cork BASELINE Birth Cohort included dietary assessment using a 2-d weighed food diary, vitamin D and iron status biomarkers, and anthropometry (n = 468). K-means cluster analysis identified predominant dietary patterns based on energy contributions and associations with nutrient intakes and status and body weight were investigated. RESULTS: Four dietary patterns emerged: "Cows' milk" (unmodified cows' milk: 32% of total energy (TE)); "Traditional" (wholemeal breads, butter, fresh meat, fruit); "Low Nutrient Density (LND) foods" (confectionary, processed meat, convenience foods) and "Formula" (young child formula: 23%TE). The LND pattern was associated with excessive free sugar intake (14%TE) and salt intake (153% of daily limit). No differences in patterns of overweight were observed between the 4 groups; however, the LND group had 3-fold higher odds of being underweight [aOR (95% CI): 3.2 (1.2, 8.5)]. Children consuming >400ml/d of cows' milk or formula exhibited lower dietary variety, fewer family-type meals, and continued use of feeding bottles (75% and 81%, respectively, vs. 35-37% in the other groups). CONCLUSIONS: Unhealthy eating habits are common among young children. Dietary guidance to support families to provide healthy diets needs to maintain currency with eating habits and focus on food choices for meals, snacks, and beverages.

Validation of a touchscreen assessment tool to screen for cognitive delay at 24 months.

AIM: To validate a touchscreen assessment as a screening tool for mild cognitive delay in typically developing children aged 24 months. METHOD: Secondary analysis of data was completed from an observational birth cohort study (The Cork Nutrition & Microbiome Maternal-Infant Cohort Study [COMBINE]), with children born between 2015 and 2017. Outcome data were collected at 24 months of age, at the INFANT Research Centre, Ireland. Outcomes were the Bayley Scales of Infant and Toddler Development, Third Edition cognitive composite score and a language-free, touchscreen-based cognitive measure (Babyscreen). RESULTS: A total of 101 children (47 females, 54 males) aged 24 months (mean = 24.25, SD = 0.22) were included. Cognitive composite scores correlated with the total number of Babyscreen tasks completed, with moderate concurrent validity (r = 0.358, p < 0.001). Children with cognitive composite scores lower than 90 (1 SD below the mean, defined as mild cognitive delay) had lower mean Babyscreen scores than those with cognitive scores equal to or greater than 90 (8.50 [SD = 4.89] vs 12.61 [SD = 3.68], p = 0.001). The area under the receiver operating characteristic curve for the prediction of a cognitive composite score less than 90 was 0.75 (95% confidence interval = 0.59-0.91; p = 0.006). Babyscreen scores less than 7 were equivalent to less than the 10th centile and identified children with mild cognitive delay with 50% sensitivity and 93% specificity. INTERPRETATION: Our 15-minute, language-free touchscreen tool could reasonably identify mild cognitive delay among typically developing children.

ASQ-3 and BSID-III's concurrent validity and predictive ability of cognitive outcome at 5 years.

BACKGROUND: Early detection of cognitive disability is challenging. We assessed the domain-specific, concurrent validity of the ages and stages questionnaire (ASQ-3) and the Bayley Scales of Infant and Toddler Development (BSID-III), and their ability to predict cognitive delay at school age. METHODS: Within a longitudinal birth cohort study, a nested cohort of children was assessed using ASQ-3 and BSID-III at 24 months, and at 5 years using the Kaufmann brief IQ test (KBIT). RESULTS: 278 children were assessed using BSID-III and ASQ-3 at 24-months; mean(SD) BW = 3445(506) grams, M:F ratio=52:48. ASQ-3 had reasonable predictive ability (AUROC, p value, sensitivity:specificity) of same domain delay for motor (0.630, p = 0.008, 50%:76.1%) and language (0.623, p = 0.010, 25%:99.5%) at 2 years, but poor ability to detect cognitive delay compared to BSID-III (0.587, p = 0.124, 20.7%/96.8%;). 204/278 children were assessed at 5 years. BSID-III language and cognition domains showed better correlation with verbal and nonverbal IQ (R = 0.435, p < 0.001 and 0.388, p < 0.001 respectively). Both assessments showed high specificity and low sensitivity for predicting delay at 5 years. CONCLUSIONS: The ASQ-3 cognitive domain showed poor concurrent validity with BSID-III cognitive score. Both ASQ-3 and BSID-III at 2 years poorly predict cognitive delay at 5 years. IMPACT: The ASQ-3 does not adequately detect cognitive delay or predict cognitive delay at 5 years, particularly for children with mild to moderate delay. The ASQ-3 shows reasonable concurrent validity with the motor and language subscales of the BSID-III. Neither early screening nor formal developmental testing demonstrated significant predictive validity to screen for cognitive delay at school age. This article highlights the need to analyse our existing model of using the ASQ-3 to screen for cognitive delay in children aged 2 years.

Evidence of low vitamin D intakes in the Australian population points to a need for data-driven nutrition policy for improving population vitamin D status.

BACKGROUND: Nearly one in four Australian adults is vitamin D deficient (serum 25-hydroxyvitamin D concentrations [25(OH)D] < 50 nmol L-1 ) and current vitamin D intakes in the Australian population are unknown. Internationally, vitamin D intakes are commonly below recommendations, although estimates generally rely on food composition data that do not include 25(OH)D. We aimed to estimate usual vitamin D intakes in the Australian population. METHODS: Nationally representative food consumption data were collected for Australians aged ≥ 2 years (n = 12,153) as part of the cross-sectional 2011-2013 Australian Health Survey (AHS). New analytical vitamin D food composition data for vitamin D3 , 25(OH)D3 , vitamin D2 and 25(OH)D2 were mapped to foods and beverages that were commonly consumed by AHS participants. Usual vitamin D intakes (µg day-1 ) by sex and age group were estimated using the National Cancer Institute method. RESULTS: Assuming a 25(OH)D bioactivity factor of 1, mean daily intakes of vitamin D ranged between 1.84 and 3.25 µg day-1 . Compared to the estimated average requirement of 10 µg day-1 recommended by the Institute of Medicine, more than 95% of people had inadequate vitamin D intakes. We estimated that no participant exceeded the Institute of Medicine's Upper Level of Intake (63-100 µg day-1 , depending on age group). CONCLUSIONS: Usual vitamin D intakes in Australia are low. This evidence, paired with the high prevalence of vitamin D deficiency in Australia, suggests that data-driven nutrition policy is required to safely increase dietary intakes of vitamin D and improve vitamin D status at the population level.

Predicting Low Cognitive Ability at Age 5-Feature Selection Using Machine Learning Methods and Birth Cohort Data.

Objectives: In this study, we applied the random forest (RF) algorithm to birth-cohort data to train a model to predict low cognitive ability at 5 years of age and to identify the important predictive features. Methods: Data was from 1,070 participants in the Irish population-based BASELINE cohort. A RF model was trained to predict an intelligence quotient (IQ) score ≤90 at age 5 years using maternal, infant, and sociodemographic features. Feature importance was examined and internal validation performed using 10-fold cross validation repeated 5 times. Results The five most important predictive features were the total years of maternal schooling, infant Apgar score at 1 min, socioeconomic index, maternal BMI, and alcohol consumption in the first trimester. On internal validation a parsimonious RF model based on 11 features showed excellent predictive ability, correctly classifying 95% of participants. This provides a foundation suitable for external validation in an unseen cohort. Conclusion: Machine learning approaches to large existing datasets can provide accurate feature selection to improve risk prediction. Further validation of this model is required in cohorts representative of the general population.

Periconceptual and prenatal alcohol consumption and neurodevelopment at age two and five years.

OBJECTIVE: Examine the association between alcohol consumption before and during pregnancy and neurodevelopmental outcomes in the offspring at two and five years. STUDY DESIGN: Retrospective analysis of a prospective longitudinal cohort; SCOPE-BASELINE. Data on pre-conception and prenatal alcohol consumption were obtained at 15 weeks' gestation and categorised as abstinent, occasional-low (1-7units/week) and moderate-heavy (≥8units/week). Binge drinking was defined as ≥6 units/session. Outcome measures (Child Behaviour Checklist and Kaufman Brief Intelligence Test) were obtained at two and five years. Linear regression examined an alcohol consumption and Child Behaviour Checklist and Kaufman Brief Intelligence Test relationship, adjusting for several potential confounders. RESULTS: Data on alcohol consumption was available for 1,507 women. Adjusted linear regression suggested few associations: pre-pregnancy occasional-low alcohol consumption was associated with lower log externalizing Child Behaviour Checklist scores (-0.264, 95% CI: -0.009, -0.520), while pre-pregnancy moderate-high levels of alcohol consumption was associated with lower Kaufman Brief Intelligence Test verbal standard scores (-0.034, 95% CI: -0.001, -0.068) and composite IQ scores (-0.028, 95% CI: -0.056, -0.0004) at five-years. In the first trimester, moderate-high levels of alcohol consumption was associated with lower internalizing Child Behaviour Checklist scores at two-years (-0.252, 95% CI: -0.074, -0.430). No significant associations were observed between number of binge episodes pre-pregnancy or binge drinking in the first trimester and Child Behaviour Checklist or Kaufman Brief Intelligence Test. CONCLUSIONS: We did not find strong evidence of associations between pre-pregnancy and early pregnancy maternal alcohol consumption and adverse neurodevelopmental outcomes at age two and five years overall. Further research examining alcohol consumption (including binge drinking) beyond 15 weeks' gestation and subsequent neurodevelopmental outcomes is needed to examine the potential effect of alcohol consumption in later pregnancy.

Vitamin D Fortification of Milk Would Increase Vitamin D Intakes in the Australian Population, but a More Comprehensive Strategy Is Required.

Low vitamin D status (serum 25-hydroxyvitamin D (25(OH)D) concentration < 50 nmol/L) is prevalent in Australia, ranging between 15% and 32% in the adolescent and adult populations. Vitamin D intakes are also low across the population and were recently estimated at 1.8−3.2 µg/day on average, assuming equal bioactivity of the D vitamers. In combination, these findings strongly suggest that data-driven nutrition policy is needed to increase vitamin D intake and improve status in the Australian population. Food fortification is a potential strategy. We used up-to-date vitamin D food composition data for vitamin D3, 25(OH)D3, vitamin D2, and 25(OH)D2, and nationally representative food and supplement consumption data from the 2011−2013 Australian Health Survey, to model a fortification scenario of 0.8 µg/100 mL vitamin D for fluid dairy milks and alternatives. Under the modelled fortification scenario, the mean vitamin D intake increased by ~2 µg/day from baseline to 4.9 µg/day from food only (7.2 µg/day including supplements). Almost all individual intakes remained substantially below 10 µg/day, which is the Estimated Average Requirement in North America. In conclusion, this modelling showed that fortification of fluid milks/alternatives with vitamin D at the current permitted level would produce a meaningful increase in vitamin D intake, which could be of potential benefit to those with a low vitamin D status. However, this initial step would be insufficient to ensure that most of the population achieves the North American EAR for vitamin D intake. This approach could be included as an effective component of a more comprehensive strategy that includes vitamin D fortification of a range of foods.

Iron deficiency during the first 1000 days of life: are we doing enough to protect the developing brain?

Iron is essential for the functioning of all cells and organs, most critically for the developing brain in the fundamental neuronal processes of myelination, energy and neurotransmitter metabolism. Iron deficiency, especially in the first 1000 days of life, can result in long-lasting, irreversible deficits in cognition, motor function and behaviour. Pregnant women, infants and young children are most vulnerable to iron deficiency, due to their high requirements to support growth and development, coupled with a frequently inadequate dietary supply. An unrecognised problem is that even if iron intake is adequate, common pregnancy-related and lifestyle factors can affect maternal-fetal iron supply in utero, resulting in an increased risk of deficiency for the mother and her fetus. Although preterm birth, gestational diabetes mellitus and intrauterine growth restriction are known risk factors, more recent evidence suggests that maternal obesity and delivery by caesarean section further increase the risk of iron deficiency in the newborn infant, which can persist into early childhood. Despite the considerable threat that early-life iron deficiency poses to long-term neurological development, life chances and a country's overall social and economic progress, strategies to tackle the issue are non-existent, too limited or totally inappropriate. Prevention strategies, focused on improving the health and nutritional status of women of reproductive age are required. Delayed cord clamping should be considered a priority. Better screening strategies to enable the early detection of iron deficiency during pregnancy and early-life should be prioritised, with intervention strategies to protect maternal health and the developing brain.

Individual participant data (IPD)-level meta-analysis of randomised controlled trials to estimate the vitamin D dietary requirements in dark-skinned individuals resident at high latitude.

CONTEXT AND PURPOSE: There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. METHODS: IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5-86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. RESULTS: To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. CONCLUSIONS: Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose-response relationship and risk characterisation for health outcomes. TRAIL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260).

Implementation strategies for improving vitamin D status and increasing vitamin D intake in the UK: current controversies and future perspectives: proceedings of the 2nd Rank Prize Funds Forum on vitamin D.

A multi-disciplinary expert group met to discuss vitamin D deficiency in the UK and strategies for improving population intakes and status. Changes to UK Government advice since the 1st Rank Forum on Vitamin D (2009) were discussed, including rationale for setting a reference nutrient intake (10 µg/d; 400 IU/d) for adults and children (4+ years). Current UK data show inadequate intakes among all age groups and high prevalence of low vitamin D status among specific groups (e.g. pregnant women and adolescent males/females). Evidence of widespread deficiency within some minority ethnic groups, resulting in nutritional rickets (particularly among Black and South Asian infants), raised particular concern. Latest data indicate that UK population vitamin D intakes and status reamain relatively unchanged since Government recommendations changed in 2016. Vitamin D food fortification was discussed as a potential strategy to increase population intakes. Data from dose-response and dietary modelling studies indicate dairy products, bread, hens' eggs and some meats as potential fortification vehicles. Vitamin D3 appears more effective than vitamin D2 for raising serum 25-hydroxyvitamin D concentration, which has implications for choice of fortificant. Other considerations for successful fortification strategies include: (i) need for 'real-world' cost information for use in modelling work; (ii) supportive food legislation; (iii) improved consumer and health professional understanding of vitamin D's importance; (iv) clinical consequences of inadequate vitamin D status and (v) consistent communication of Government advice across health/social care professions, and via the food industry. These areas urgently require further research to enable universal improvement in vitamin D intakes and status in the UK population.

Safety of Vitamin D Food Fortification and Supplementation: Evidence from Randomized Controlled Trials and Observational Studies.

The safety considerations of food-based solutions for vitamin D deficiency prevention, such as fortification and supplementation, are critical. On the basis of collective data from 20 randomized controlled trials (RCTs) and 20 national healthy surveys, as well as prospective cohort studies (PCSs) across the ODIN project ("Food-based solutions for optimal vitamin D nutrition and health through the life cycle", FP7-613977), we analyzed the potential safety issues arising from vitamin D intakes and/or supplementation. These adverse consequences included high serum 25-hydroxyvitamin D (S-25(OH)D) concentrations (>125 nmol/L), high serum calcium concentrations, and vitamin D intakes in excess of the tolerable upper intake levels (ULs). In the RCTs (n = 3353, with vitamin D doses from 5-175 µg/day), there were no reported adverse effects. The prevalence of high S-25(OH)D was <10% when vitamin D supplements were administered, and <0.1% for fortified foods. Elevated serum calcium was observed among <0.5% in both administration types. No ODIN RCT participants exceeded the age-specific ULs. In observational studies (n = 61,082), the prevalence of high 25(OH)D among children/adolescents, adults, and older adults was <0.3%, with no evidence of adverse effects. In conclusion, high S-25(OH)D concentrations >125 nmol/L were rare in the RCTs and PCSs, and no associated adverse effects were observed.

Vitamin D Food Fortification and Biofortification Increases Serum 25-Hydroxyvitamin D Concentrations in Adults and Children: An Updated and Extended Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Low vitamin D status is a global public health issue that vitamin D food fortification and biofortification may help to alleviate. OBJECTIVES: We investigated the effect of vitamin D food fortification and biofortification on circulating 25-hydroxyvitamin D (25(OH)D) concentrations. We expanded the scope of earlier reviews to include adults and children, to evaluate effects by vitamin D vitamer, and investigate linear and nonlinear dose-response relations. METHODS: We conducted a systematic review and meta-analysis. We searched CINAHL, MEDLINE, PubMed, Embase, the Cochrane Library, and gray and unpublished literature sites for randomized controlled trials, including people of all ages, with the criteria: absence of illness affecting vitamin D absorption, duration ≥4 wk, equivalent placebo food control, dose quantification, dose ≥5 µg/d, baseline and endpoint or absolute change in 25(OH)D concentrations reported, random allocation, and participant blinding. Quality was assessed using the Jadad Scale. RESULTS: Data from 34 publications (2398 adults: 1345 intervention, 1053 controls; 1532 children: 970 intervention, 562 controls) were included. Random-effects meta-analysis of all studies combined (mean dose 16.2 µg/d) indicated a pooled treatment effect of 21.2 nmol/L (95% CI: 16.2, 26.2), with a greater effect for studies using cholecalciferol than ergocalciferol. Heterogeneity was high (I2  > 75%). Metaregression analyses for all studies combined suggested positive effect differences for baseline circulating 25(OH)D concentrations <50 nmol/L, dose ≥10 µg/d and a negative effect difference when the intervention arm included a calcium dose ≥500 mg/d greater than the control arm. Dose-response rates were found to be nonlinear (Wald test for nonlinearity P < 0.001). For all studies combined, a threshold occurred at ∼26 nmol/L for a dose of ∼21 µg/d. CONCLUSIONS: These results support use of vitamin D food fortification to improve circulating 25(OH)D circulations in populations. This work was registered with PROSPERO as CRD42020145497.

Vitamin D composition of Australian foods.

Australia needs accurate vitamin D food composition data to support public health initiatives. Previously, limitations in analytical methodology have precluded development of a comprehensive database. We used liquid chromatography with triple quadrupole mass spectrometry (LC-QQQ) to analyse 149 composite samples representing 98 foods (primary samples n = 896) in duplicate for vitamin D3, 25-hydroxyvitamin D3 (25(OH)D3), vitamin D2, 25(OH)D2. The greatest concentrations of vitamin D3 were found in canned salmon and a malted chocolate drink powder (fortified); chicken eggs and chicken leg meat contained the most 25(OH)D3. Margarine (fortified) and chocolate contained the greatest concentrations of vitamin D2, with smaller amounts found in various meat products. 25(OH)D2 was detected in various foods, including meats, and was quantitated in lamb liver. These data advance knowledge of dietary vitamin D in Australia and highlight the importance of analysis of these four forms of vitamin D to accurately represent the vitamin D content of food.

Iron, iodine and vitamin D deficiencies during pregnancy: epidemiology, risk factors and developmental impacts.

Micronutrient deficiency persists throughout the world, and although the burden is higher in low-resource settings, it is also prevalent in wealthy countries, a phenomenon termed 'hidden hunger'. Due to their high requirements for vitamins and minerals relative to their energy intake, young women and children are particularly vulnerable to hidden hunger. As they share several risk factors and impact on overlapping outcomes, we consider how deficiency of iron, iodine and vitamin D can have profound impacts on perinatal health and infant development. We review the epidemiology of these micronutrient deficiencies during pregnancy, including social, environmental and dietary risk factors. We identify the main challenges in defining nutritional status of these nutrients using validated diagnostic criteria linked with meaningful clinical outcomes. Public health strategies are urgently required to improve the overall health and nutritional status of women of reproductive age. Obesity prevention and early detection of malnutrition with standardised screening methods would detect pregnant women at increased risk of iron deficiency. Development of sensitive, individual biomarkers of iodine status is required to protect maternal health and fetal/infant brain development. Risk assessments of vitamin D requirements during pregnancy need to be revisited from the perspective of fetal and neonatal requirements. International consensus on standardised approaches to micronutrient assessment, analysis and reporting as well as sensitive, clinically validated infant and child neuro-behavioural outcomes will enable progression of useful observational and intervention studies.