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Background: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis., Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D 3 , vitamin D 2 , or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633., Findings: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I 2 =35·6%, p heterogeneity =0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65-0·94]; 19 studies; I 2 =53·5%, p heterogeneity =0·003), at daily dose equivalents of 400-1000 IU (0·70 [0·55-0·89]; ten studies; I 2 =31·2%, p heterogeneity =0·16), for a duration of 12 months or less (0·82 [0·72-0·93]; 29 studies; I 2 =38·1%, p heterogeneity =0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 [0·57-0·90]; 15 studies; I 2 =46·0%, p heterogeneity =0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86-1·07]; 36 studies; I 2 =0·0%, p heterogeneity =0·99). Risk of bias within individual studies was assessed as being low for all but three trials., Interpretation: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation., Funding: None., Competing Interests: Declaration of interests ARM reports grants from the Fischer Family Trust, Pharma Nord, DSM Nutritional Products, the AIM Foundation, Cytoplan, and Thornton & Ross. CG reports grants from the Health Technology Assessment Programme of the UK National Institute of Health Research. WJ reports grants from Chiesi and Astra Zeneca. REN reports grants from the Australian National Health and Medical Research Council. ECG became an employee of GSK Canada in November 2013, after the completion and publication of her vitamin D RCT. AMH reports grants from NHLBI and the Office of Dietary Supplements. JRR reports grants from Dartmouth College, non-financial support (provision of study pills for trial) from Pfizer Consumer Healthcare and has a patent for calcium chemoprevention of adenoma (issued to John Baron & Dartmouth College). HAB-F reports grants from DSM Nutritional Products, travel expenses from Pfizer, and speaker honoraria from Wild Pharma, Mylan, and Roche Diagnostics. All other authors declare no competing interests. DAJ and ARM are the manuscript's guarantors and they affirm that this is an honest, accurate, and transparent account of the study being reported, and that no important aspects of the study have been omitted., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Observational studies support the role of vitamin D in reducing viral upper respiratory tract infection (URTI) symptom severity in adults and children. This study assessed whether wintertime high-dose vitamin D supplementation (2000 IU/day) reduces URTI symptom severity compared with standard-dose (400 IU/day) supplementation in preschool children. Secondary objectives were to assess effects of high-dose supplementation on outpatient physician visits, emergency department (ED) visits and antibiotic prescriptions for URTI., Methods: This was a secondary analysis of a multisite randomized clinical trial involving 703 healthy 1- to 5-year-old children in Toronto, Canada. High-dose or standard-dose oral vitamin D was randomly assigned for 1 winter season. For each URTI, parents completed symptom checklists based on the Canadian Acute Respiratory and Flu Scale. Symptom severity, frequency of outpatient visits, ED visits and antibiotic prescriptions for URTI between groups were analyzed using negative binomial regression., Results: URTI symptom severity was not reduced in the high-dose vs. standard-dose group [incidence rate ratio (IRR) = 0.97; 95% confidence interval (CI): 0.76-1.23]. High-dose vitamin D did not decrease frequency of outpatient visits (IRR = 1.16; 95% CI: 0.84-1.60), ED visits (IRR = 1.17; 95% CI: 0.57-2.40) or antibiotic prescriptions (IRR=1.02; 95% CI: 0.61-1.72). Serum 25-hydroxyvitamin D was higher in the high-dose group (48.7 ng/mL; 95% CI: 46.9-50.5) than the standard-dose group (36.8 ng/mL; 95% CI: 35.4-38.2; P < 0.001)., Conclusions: High-dose vitamin D supplementation did not reduce URTI symptom severity, outpatient visits, ED visits or antibiotic prescriptions relative to standard-dose. These results do not support vitamin D supplementation above the standard recommended dose for reducing URTI symptoms in children.

Background: Asthma is the most common chronic illness of childhood and a common reason for hospital admission. Studies suggest that low vitamin D levels may be associated with health service utilization (HSU) for childhood asthma. The primary objective was to determine if vitamin D serum levels in early childhood were associated with HSU for asthma including: a) hospital admissions; b) emergency department visits; and c) outpatient sick visits. Secondary objectives were to determine whether vitamin D supplementation in pregnancy or childhood were associated with HSU for asthma., Methods: Prospective cohort study of children participating in the TARGet Kids! practice-based research network between 2008 and 2013 in Toronto, Canada. HSU was determined by linking each child's provincial health insurance number to health administrative databases. Multivariable quasi-Poisson and logistic regression were used to evaluate the association between 25-hydroxyvitamin D concentrations, vitamin D supplementation in pregnancy, and childhood and HSU for asthma., Results: A total of 2926 healthy children aged 0-6 years had 25-hydroxyvitamin D data available and were included in the primary analysis. Mean (IQR) 25-hydroxyvitmain D level was 84 nmol/L (65-98 nmol/L), 218 and 1267 children had 25-hydroxyvitamin D concentrations <50 nmol/L and <75 nmol/L, respectively. In the adjusted models, there were no associations between 25-hydroxyvitamin D concentrations (continuously or dichotomized at 50 and 75 nmol/L), vitamin D supplementation in pregnancy or childhood and HSU for asthma., Conclusions: Vitamin D blood values do not appear to be associated with HSU for asthma in this population of healthy urban children., (© 2018 Wiley Periodicals, Inc.)

Background: Most Canadian children do not meet the recommended dietary intake for vitamin D., Objectives: The aims were to test how much vitamin D from food is needed to maintain a healthy serum 25-hydroxyvitamin D3 [25(OH)D3] status from fall to spring in young children and to examine musculoskeletal outcomes., Design: Healthy children aged 2-8 y (n = 51) living in Montreal, Canada, were randomly assigned to 1 of 2 dietary vitamin D groups (control or intervention to reach 400 IU/d by using vitamin D-fortified foods) for 6 mo, starting October 2014. At baseline and at 3 and 6 mo, anthropometric characteristics, vitamin D metabolites (liquid chromatography-tandem mass spectrometry), and bone biomarkers (IDS-iSYS, Immunodiagnositc Systems; Liaison; Diasorin) were measured and physical activity and food intakes surveyed. At baseline and at 6 mo, bone outcomes and body composition (dual-energy X-ray absorptiometry) were measured. Cross-sectional images of distal tibia geometry and muscle density were conducted with the use of peripheral quantitative computed tomography scans at 6 mo., Results: At baseline, participants were aged 5.2 ± 1.9 (mean ± SD) y and had a body mass index z score of 0.65 ± 0.12; 53% of participants were boys. There were no differences between groups in baseline serum 25(OH)D3 (66.4 ± 13.6 nmol/L) or vitamin D intake (225 ± 74 IU/d). Median (IQR) compliance was 96% (89-99%) for yogurt and 84% (71-97%) for cheese. At 3 mo, serum 25(OH)D3 was higher in the intervention group (P < 0.05) but was not different between groups by 6 mo. Although lean mass accretion was higher in the intervention group (P < 0.05), no differences in muscle density or bone outcomes were observed., Conclusions: The consumption of 400 IU vitamin D/d from fall to spring did not maintain serum 25(OH)D3 concentration or improve bone outcomes. Further work with lean mass accretion as the primary outcome is needed to confirm if vitamin D enhances lean accretion in healthy young children. This trial was registered at www.clinicaltrials.gov as NCT02387892.

Importance: Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown., Objective: To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children., Design, Setting, and Participants: A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice-based research network in Toronto, Ontario, Canada., Interventions: Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May., Main Outcome Measures: The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination., Results: Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, -0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02-5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66-4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88-1.16). At study termination, serum 25-hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9-50.5 ng/mL) in the high-dose group and 36.8 ng/mL (95% CI, 35.4-38.2 ng/mL) in the standard-dose group., Conclusions and Relevance: Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections., Trial Registration: clinicaltrials.gov Identifier: NCT01419262.

Objective: Upper respiratory tract infections (URTI) are the most common and costly condition of childhood. Low vitamin D levels have been hypothesized as a risk factor for URTI. The primary objective was to determine if serum vitamin D levels were associated with health-service utilization (HSU) for URTI including hospital admission, emergency department visits and outpatient sick visits. The secondary objectives were to determine whether oral vitamin D supplementation in pregnancy or childhood was associated with HSU for URTI., Design: Cohort study. HSU was determined by linking each child's provincial health insurance number to health administrative databases. Multivariable quasi Poisson regression was used to evaluate the association between 25-hydroxyvitamin D, vitamin D supplementation and HSU for URTI., Setting: Toronto, Canada., Subjects: Children participating in the TARGet Kids! network between 2008 and 2013., Results: Healthy children aged 0-5 years (n 4962) were included; 52 % were male and mean 25-hydroxyvitamin D was 84 nmol/l (range 11-355 nmol/l). There were 105 (2 %), 721 (15 %) and 3218 (65 %) children with at least one hospital admission, emergency department visit or outpatient sick visit for URTI, respectively. There were no statistically significant associations between 25-hydroxyvitamin D or vitamin D supplementation and HSU for URTI., Conclusions: A clinically meaningful association between vitamin D (continuously and dichotomized at <50 and <75 nmol/l) and HSU for URTI was not identified. While vitamin D may have other benefits for health, reducing HSU for URTI does not appear to be one of them.

The objective of this study was to evaluate the association of vitamin D intake and serum levels with fracture risk in children under 6 years of age. A case-control study was conducted in Toronto, Ontario, Canada. Cases were recruited from the fracture clinic at the Hospital for Sick Children, and matched controls were obtained from the TARGet Kids! primary-care research network. Controls were matched to cases on age, sex, height, and season. Fracture risk was estimated from conditional logistic regression, with adjustment for skin type, fracture history, waist circumference, outdoor free play, neighborhood income, soda consumption, and child's birth weight. A total of 206 cases were recruited during May 2009-April 2013 and matched to 343 controls. Serum 25-hydroxyvitamin D concentration (per 10-nmol/L increment: adjusted odds ratio (aOR) = 0.95, 95% confidence interval (CI): 0.88, 1.03) and intake of cow's milk (<2 cups/day vs. 2 cups/day: aOR = 0.95 (95% CI: 0.60, 1.52); >2 cups/day vs. 2 cups/day: aOR = 1.39 (95% CI: 0.85, 2.23)) were not significantly associated with reduced odds of fracture. A statistically significant association was observed between child use of vitamin D supplements and decreased odds of fracture (yes vs. no: aOR = 0.42, 95% CI: 0.25, 0.69). Vitamin D supplementation, but not serum 25-hydroxyvitamin D level or milk intake, was associated with reduced fracture risk among these healthy young children., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Fortified cow milk is a material contributor of vitamin D and dietary fat in children. Recommendations for children >2 y of age advise reduced milk-fat consumption to reduce childhood obesity, yet the relation between lower milk fat, vitamin D stores, and body mass index (BMI) is unclear., Objectives: The primary objective was to explore the association between milk-fat percentage and both BMI z score (zBMI) and venous 25-hydroxyvitamin D [25(OH)D]; the secondary objective was to assess whether milk volume consumed modified this relation., Design: This was a cross-sectional analysis. Healthy urban children aged 12-72 mo were recruited from 9 primary health care practices within The Applied Research Group for Kids (TARGet Kids!) research group in Toronto, Canada. We used adjusted bivariate linear regression to examine the relation between milk-fat percentage and child 25(OH)D and zBMI concurrently. Effect modification by milk volume consumed on the evaluated relations was explored with the use of an interaction term in the statistical model., Results: Among the 2745 included children there was a positive association between milk-fat percentage and 25(OH)D (P = 0.006) and a negative association between milk-fat percentage and zBMI (P < 0.0001). Participants who drank whole milk had a 5.4-nmol/L (95% CI: 4.32, 6.54) higher median 25(OH)D concentration and a 0.72 lower (95% CI: 0.68, 0.76) zBMI score than children who drank 1% milk. Milk volume consumed modified the effect of milk-fat percentage on 25(OH)D (P = 0.003) but not on zBMI (P = 0.77)., Conclusions: Whole milk consumption among healthy young children was associated with higher vitamin D stores and lower BMI. Longitudinal and interventional studies are needed to confirm these findings. TARGet Kids! was registered at clinicaltrials.gov as NCT01869530., (© 2016 American Society for Nutrition.)

Current guidelines for cow's milk consumption in children older than age 2 years suggest 1% or 2% milk to reduce the risk of obesity. Given that milk is the main dietary source of vitamin D for North American children and that vitamin D is fat soluble, we hypothesized 25-hydroxyvitamin D (25(OH)D) concentration to be positively associated with the fat content of milk. The objective was to determine the relationship between the fat content of milk consumed and the serum 25(OH)D concentration; our secondary objective was to explore the role that the volume of milk consumed played in this relationship. We completed a cross-sectional study of children aged 12-72 months in the TARGetKids! research network. Multivariable linear regression was used to test the association between milk fat content and child 25(OH)D, adjusted for clinically relevant covariates. The interaction between volume of milk and fat content was examined. Two thousand eight hundred fifty-seven children were included in the analysis. The fat content of milk was positively associated with 25(OH)D (p = 0.03), and the interaction between the volume of milk consumed and the milk fat content was statistically significant (p = 0.005). Children who drank 1% milk needed 2.46 cups (95% confidence interval (CI) 2.38-2.54) of milk to have a 25(OH)D concentration similar to that of children who drank 1 cup of homogenized milk (3.25% fat). Children who consumed 1% milk had 2.05 (95% CI 1.73-2.42) times higher odds of having a 25(OH)D concentration <50 nmol/L compared with children who consumed homogenized milk. In conclusion, recommendations for children to drink lower-fat milk (1% or 2%) may compromise serum 25(OH)D levels and may require study to ensure optimal childhood health.

Objectives: To determine the association between total breastfeeding duration and serum 25-hydroxyvitamin D (25-OHD) and to explore whether vitamin D supplementation influences this association., Methods: We conducted a cross-sectional study of healthy children between September 2011 and August 2013 through the TARGet Kids! primary health care research network. Of the 4533 eligible children, we included only the 2508 who had 25-OHD measured. We assessed adjusted associations of total breastfeeding duration (in months) with serum 25-OHD and in supplemented versus nonsupplemented children, with the odds of 25-OHD less than 20 nanograms per milliliter., Results: Each 1-month increase in total breastfeeding duration was associated with a 0.12 nanograms per milliliter lower median serum 25-OHD (95% confidence interval [CI] = -0.21 ng/mL, -0.02 ng/mL) among children who were not supplemented. The odds of serum 25-OHD less than 20 nanograms per milliliter increased by 6% (odds ratio [OR] = 1.06; 95% CI = 1.03, 1.10) for every 1-month increase in total breastfeeding duration among nonsupplemented children. The interaction between vitamin D supplementation, duration of breastfeeding, and median serum 25-OHD was statistically significant (P = .04)., Conclusions: Breastfed children who were not supplemented, particularly those breastfed more than 1 year, appear to have lower vitamin D status. Vitamin D supplementation may mitigate this risk. These findings support recommendations for supplementation during breastfeeding of any duration.

Background: Sub-optimal vitamin D status is common worldwide and the condition may be associated with increased risk for various chronic diseases. In particular, low vitamin D status is highly prevalent in indigenous communities in Canada, although limited data are available on the determinants of serum 25-hydroxyvitamin D (25(OH)D) concentrations in this population. The relationship between traditional food consumption and vitamin D status has not been well documented., Objective: To investigate the determinants of serum 25(OH)D status in a First Nations community in Ontario, Canada, with a focus on the role of traditional food consumption and activities., Methods: A cross-sectional analysis was conducted within the Sandy Lake Health and Diabetes Project (2003-2005). A total of 445 participants (>12 years of age) were assessed for serum 25(OH)D status, anthropometric and lifestyle variables, including traditional and non-traditional dietary practices and activities. Diet patterns were identified using factor analysis, and multivariate linear regression analysis was used to analyse the determinants of 25(OH)D concentrations., Results: Mean serum 25(OH)D concentrations were 22.1 nmol/L (16.9, 29.9 nmol/L) in men and 20.5 nmol/L (16.0, 27.3 nmol/L) in women. Multivariate determinants of higher serum 25(OH)D included higher consumption of traditional and healthier market foods, higher wild fish consumption, male gender, spring/summer season of blood collection and more frequent physical activity. Significant negative determinants included hours of TV/day, higher BMI and higher consumption of unhealthy market foods., Conclusions: Traditional food consumption contributed independently to higher 25(OH)D concentrations in a First Nations community with a high prevalence of sub-optimal vitamin D status., Competing Interests: This work was supported by contributions from the Canadian Institutes of Health Research, the Public Health Agency of Canada and the Dairy Research Cluster Initiative (Dairy Farmers of Canada, Agriculture and Agri-Food Canada, the Canadian Dairy Network and the Canadian Dairy Commission); S. Mansuri was supported through a University of Toronto Department of Medicine Graduate Student Award.

Background: Vitamin D is fundamental for bone health. A high proportion of Canadian 2- to 8-y-olds do not meet the Estimated Average Requirement (EAR) of 400 IU/d., Objective: The objective was to determine whether vitamin D intakes consistent with the EAR or Recommended Dietary Allowance (RDA), through fortification of additional dairy products, would result in higher vitamin D status in young children., Design: Participants aged 2-8 y (n = 77; Montreal, Canada) were randomly assigned to 1 of 3 dietary vitamin D targets (control; EAR: 400 IU/d; or RDA: 600 IU/d) for 12 wk (January to April 2014). Anthropometric measurements, demographic characteristics, dietary intakes, fasting serum parathyroid hormone, 25-hydroxyvitamin D [25(OH)D], and ionized calcium were compared by using mixed-model ANOVA., Results: Participants' mean ± SD age was 5.1 ± 1.9 y; 54.5% were boys with body mass index z scores of 0.50 ± 0.85. Compliance was 85% overall. No differences were observed in baseline dietary vitamin D intakes or serum 25(OH)D. At 12 wk, the EAR and RDA groups had significantly higher vitamin D intakes [median (IQR): control, 227 (184-305) IU/d; EAR, 410 (363-516) IU/d; and RDA, 554 (493-653) IU/d; P < 0.05] and serum 25(OH)D concentrations (control: 55.8 ± 12.3 nmol/L; EAR: 64.1 ± 10.0 nmol/L; and RDA: 63.7 ± 12.4 nmol/L; P < 0.05) than the control group. Ninety-six percent of children in the EAR and RDA groups and 67% of the control group had 25(OH)D concentrations ≥50 nmol/L., Conclusion: Increasing the vitamin D intakes of young children through fortification of alternative dairy products results in significantly higher serum concentrations of 25(OH)D and a significantly greater proportion of children with serum 25(OH)D ≥50 nmol/L during periods of minimal ultraviolet B radiation exposure. This trial was registered at clinicaltrials.gov as NCT02097160 and had Health Canada Temporary Marketing Authorization Letters for both products (TM-13-0432 and TM-13-0433)., (© 2016 American Society for Nutrition.)

Importance: There is growing evidence that vitamin D plays a role in the pathogenesis of asthma but it is unclear whether supplementation during childhood may improve asthma outcomes., Objectives: The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of vitamin D supplementation as a treatment or adjunct treatment for asthma., Data Sources: We searched MEDLINE, Embase, CENTRAL, and CINAHL through July 2014., Study Selection: We included RCTs that evaluated vitamin D supplementation in children versus active control or placebo for asthma., Data Extraction and Synthesis: One reviewer extracted data and one reviewer verified data accuracy. We qualitatively summarized the main results of efficacy and safety and meta-analyzed data on comparable outcomes across studies. We used GRADE for strength of evidence., Main Outcome Measures: Main planned outcomes measures were ED visits and hospitalizations. As secondary outcomes, we examined measures of asthma control, including frequency of asthma exacerbations, asthma symptom scores, measures of lung function, β2-agonist use and daily steroid use, adverse events and 25-hydroxyvitamin D levels., Results: Eight RCTs (one parallel, one crossover design) comprising 573 children aged 3 to 18 years were included. One study (moderate-quality, n = 100) reported significantly less ED visits for children treated with vitamin D. No other studies examined the primary outcome (ED visits and hospitalizations). There was a reduced risk of asthma exacerbations in children receiving vitamin D (low-quality; RR 0.41, 95% CI 0.27 to 0.63, 3 studies, n = 378). There was no significant effect for asthma symptom scores and lung function. The serum 25(OH)D level was higher in the vitamin D group at the end of the intervention (low-quality; MD 19.66 nmol/L, 95% CI 5.96 nmol/L to 33.37 nmol/L, 5 studies, n = 167)., Limitations: We identified a high degree of clinical diversity (interventions and outcomes) and methodological heterogeneity (sample size and risk of bias) in included trials., Conclusions and Relevance: Randomized controlled trials provide some low-quality evidence to support vitamin D supplementation for the reduction of asthma exacerbations. Evidence on the benefits of vitamin D supplementation for other asthma-related outcomes in children is either limited or inconclusive. We recommend that future trials focus on patient-relevant outcomes that are comparable across studies, including standardized definitions of asthma exacerbations.

Vitamin D is associated with established cardiovascular risk factors such as low density lipoprotein (LDL) in adults. It is unknown whether these associations are present in early childhood. To determine whether serum 25-hydroxyvitamin D (25(OH)D) is associated with serum non-high density lipoprotein (non-HDL) cholesterol during early childhood we conducted a cross-sectional study of children aged 1 to 5 years. Healthy children were recruited through the TARGet Kids! practice based research network from 2008-2011 (n=1,961). The associations between 25(OH)D and non-fasting non-HDL cholesterol (the primary endpoint), total cholesterol, triglycerides, HDL, and low density lipoprotein (LDL) cholesterol, were evaluated using multiple linear regression adjusted for age, sex, skin pigmentation, milk intake, vitamin D supplementation, season, body mass index, outdoor play, and screen time. Each 10 nmol/L increase in 25(OH)D was associated with a decrease in non-HDL cholesterol concentration of -0.89 mg/dl (95% CI: -1.16,-0.50), total cholesterol of -1.08 mg/dl (95%CI: -1.49,-0.70), and triglycerides of -2.34 mg/dl (95%CI: -3.23,-1.45). The associations between 25(OH)D and LDL and HDL were not statistically significant. 25(OH)D concentrations were inversely associated with circulating lipids in early childhood, suggesting that vitamin D exposure in early life may be an early modifiable risk factor for cardiovascular disease.

Background: Vitamin D fortification of non-cow's milk beverages is voluntary in North America. The effect of consuming non-cow's milk beverages on serum 25-hydroxyvitamin D levels in children is unclear. We studied the association between non-cow's milk consumption and 25-hydroxyvitamin D levels in healthy preschool-aged children. We also explored whether cow's milk consumption modified this association and analyzed the association between daily non-cow's milk and cow's milk consumption., Methods: In this cross-sectional study, we recruited children 1-6 years of age attending routinely scheduled well-child visits. Survey responses, and anthropometric and laboratory measurements were collected. The association between non-cow's milk consumption and 25-hydroxyvitamin D levels was tested using multiple linear regression and logistic regression. Cow's milk consumption was explored as an effect modifier using an interaction term. The association between daily intake of non-cow's milk and cow's milk was explored using multiple linear regression., Results: A total of 2831 children were included. The interaction between non-cow's milk and cow's milk consumption was statistically significant (p = 0.03). Drinking non-cow's milk beverages was associated with a 4.2-nmol/L decrease in 25-hydroxyvitamin D level per 250-mL cup consumed among children who also drank cow's milk (p = 0.008). Children who drank only non-cow's milk were at higher risk of having a 25-hydroxyvitamin D level below 50 nmol/L than children who drank only cow's milk (odds ratio 2.7, 95% confidence interval 1.6 to 4.7)., Interpretation: Consumption of non-cow's milk beverages was associated with decreased serum 25-hydroxyvitamin D levels in early childhood. This association was modified by cow's milk consumption, which suggests a trade-off between consumption of cow's milk fortified with higher levels of vitamin D and non-cow's milk with lower vitamin D content., (© 2014 Canadian Medical Association or its licensors.)

Objective: To determine if children aged 1-6 years from non-Western immigrant families have lower serum 25-hydroxyvitamin D (25(OH)D) levels than children from Western-born families and examine which factors influence this relationship., Design: Cross-sectional study., Setting: Toronto, Canada., Subjects: Healthy children (n 1540) recruited through the TARGet Kids! practice-based research network. Serum 25(OH)D concentrations of non-Western immigrants were compared with those of children from Western-born families. Children from non-Western immigrant families were defined as those born, or their parents were born, outside a Western country. Univariate and multiple linear regression analyses were used to identify factors which might influence this relationship., Results: Median age was 36 months, 51 % were male, 86 % had 'light' skin pigmentation, 55 % took vitamin D supplements, mean cow's milk intake was 1·8 cups/d and 27 % were non-Western immigrants. Median serum 25(OH)D concentration was 83 nmol/l, with 5 % having 25(OH)D < 50 nmol/l. Univariable analysis revealed that non-Western immigrant children had serum 25(OH)D lower by 4 (95 % CI 1·3, 8·0) nmol/l (P = 0·006) and increased odds of 25(OH)D < 50 nmol/l (OR = 1·9; 95 % CI 1·3, 2·9). After adjustment for known vitamin D determinants the observed difference attenuated to 0·04 (95 % CI -4·8, 4·8) nmol/l (P = 0·99), with higher cow's milk intake (P < 0·0001), vitamin D supplementation (P < 0·0001), summer season (P = 0·008) and increased age (P = 0·04) being statistically significant covariates. Vitamin D supplementation was the strongest explanatory factor of the observed difference., Conclusions: There is an association between non-Western immigration and lower 25(OH)D in early childhood. This difference appears related to known vitamin D determinants, primarily vitamin D supplementation, representing opportunities for intervention.

Background: Vitamin D levels are alarmingly low (<75 nmol/L) in 65-70% of North American children older than 1 year. An increased risk of viral upper respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of 'high dose' (2000 IU/day) vs. 'standard dose' (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of 'high dose' vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI., Methods/design: This study is a pragmatic randomized controlled trial. Over 4 successive winters we will recruit 750 healthy children 1-5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be randomized to the 'standard dose' or 'high dose' oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups., Discussion: Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs. This information will assist in determining practice and health policy recommendations related to vitamin D supplementation in healthy Canadian preschoolers.

Background: Vaccination is an important strategy in the prevention of influenza, but immunologic response to vaccination can vary widely. Recent studies have shown an association between serum 25-hydroxyvitamin D (25[OH]D) levels and immune function. The purpose of this study was to determine if serum 25(OH)D level correlates with influenza vaccine immunogenicity in children and adolescents., Methods: We conducted a prospective cohort study of children age 3 to 15 years of age vaccinated with trivalent influenza vaccine (A/Brisbane/59/2007[H1N1]-like virus, A/Brisbane/10/2007 [H3N2]-like virus and B/Florida/4/2006-like virus) in Hutterite communities in Alberta, Saskatchewan and Manitoba. Serum 25(OH)D levels were measured at baseline and immunogenicity was assessed using hemagluttination inhibition (HAI) titers done at baseline and 3-5 weeks post vaccination. Logistic regression was used to assess the relationship between serum 25(OH)D level as both a continuous and dichotomous variable and seroprotection, seroconversion, fold increase in geometric mean titer (GMT) and post vaccination titer., Results: A total of 391 children and adolescents were included in the study and 221 (57% had post-vaccination HAI titers. The median serum 25(OH)D level was 61.0 nmol/L (Interquartile range [IQR] 50.0, 71.0). No relationship was found between serum 25(OH)D level and seroprotection (post-vaccination titer ≥ 40 and ≥ 320) or seroconversion (post-vaccination titer ≥ 40 for participants with pre-vaccine titer <10 or four-fold rise in post-vaccination titer for those with a pre-vaccine titer ≥ 10)., Conclusion: Serum 25(OH)D level was not associated with influenza vaccine immunogenicity in otherwise healthy children and adolescents. Other strategies to enhance influenza vaccine response should continue to be evaluated in this population. The role of serum 25(OH)D level in vaccine responsiveness in other populations, especially those hyporesponsive to influenza vaccination, requires further study.

Background: Vitamin D may be important for immune function. Studies to date have shown an inconsistent association between vitamin D and infection with respiratory viruses. The purpose of this study was to determine if serum 25-hydroxyvitamin D (25(OH)D) was associated with laboratory-confirmed viral respiratory tract infections (RTIs) in children., Methods: Serum 25(OH)D levels were measured at baseline and children from Canadian Hutterite communities were followed prospectively during the respiratory virus season. Nasopharyngeal specimens were obtained if symptoms developed and infections were confirmed using polymerase chain reaction. The association between serum 25(OH)D and time to laboratory-confirmed viral RTI was evaluated using a Cox proportional hazards model., Results: Seven hundred forty-three children aged 3-15 years were followed between 22 December 2008 and 23 June 2009. The median serum 25(OH)D level was 62.0 nmol/L (interquartile range, 51.0-74.0). A total of 229 participants (31%) developed at least 1 laboratory-confirmed viral RTI. Younger age and lower serum 25(OH)D levels were associated with increased risk of viral RTI. Serum 25(OH)D levels <75 nmol/L increased the risk of viral RTI by 50% (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.10-2.07, P = .011) and levels <50 nmol/L increased the risk by 70% (HR, 1.67; 95% CI, 1.16-2.40, P = .006)., Conclusions: Lower serum 25(OH)D levels were associated with increased risk of laboratory-confirmed viral RTI in children from Canadian Hutterite communities. Interventional studies evaluating the role of vitamin D supplementation to reduce the burden of viral RTIs are warranted.

OBJECTIVES To determine the effect of modifiable dietary intake variables (current vitamin D supplementation and daily cow's milk intake) on 25-hydroxyvitamin D level in early childhood and to evaluate the relationship between these modifiable dietary factors and other largely nonmodifiable determinants of vitamin D status including skin pigmentation and season. DESIGN Cross-sectional study. SETTING Primary care pediatric and family medicine practices participating in the TARGet Kids! practice-based research network in Toronto, Ontario, Canada. PARTICIPANTS From December 2008 to June 2011, healthy children 1 to 5 years of age were recruited during a routine physician's visit. INTERVENTIONS Survey, anthropometric measurements, and laboratory data were collected. A multivariable linear regression model was developed to examine the independent effects of vitamin D supplementation and daily volume of cow's milk on 25-hydroxyvitamin D level. MAIN OUTCOME MEASURES 25-Hydroxyvitamin D level. RESULTS Blood was obtained in 1898 children. Two modifiable dietary intake variables, vitamin D supplementation and cow's milk, increased 25-hydroxyvitamin D level by 3.4 ng/mL (95% CI, 2-4 ng/mL) and 1.6 ng/mL per 250-mL cup per day (95% CI, 1-2 ng/mL), respectively. Two nonmodifiable variables reflecting cutaneous vitamin D synthesis (skin pigmentation and season) were also strongly associated with 25-hydroxyvitamin D status but accounted for a much smaller proportion of the explained variation in 25-hydroxyvitamin D level. The effect of vitamin D supplementation and milk intake on 25-hydroxyvitamin D level appeared similar regardless of skin pigmentation or season. CONCLUSION Two modifiable dietary intake variables (vitamin D supplementation and cow's milk intake) are the most important determinants of 25-hydroxyvitamin D status in early childhood.

Objective: To examine the association between cow's milk intake on both vitamin D and iron stores in healthy urban preschoolers., Methods: Healthy children 2 to 5 years of age were recruited from December 2008 through December 2010 through the TARGet Kids! practice-based research network. Cow's milk intake was measured by parental report. Vitamin D and iron stores were measured by using serum 25-hydroxyvitamin D and ferritin. Bivariate multivariable linear regression was used to examine the effect of cow's milk intake simultaneously on 25-hydroxyvitamin D and serum ferritin. Analyses were stratified by important clinical variables including skin pigmentation, bottle feeding, vitamin D supplementation, and season., Results: Among 1311 children, increasing cow's milk consumption was associated with decreasing serum ferritin (P < .0001) and increasing 25-hydroxyvitamin D (P ≤ .0001). Two cups (500 mL) of cow's milk per day maintained 25-hydroxyvitamin D >75 nmol/L with minimal negative effect on serum ferritin for most children. Children with darker skin pigmentation not receiving vitamin D supplementation during the winter required 3 to 4 cups of cow's milk per day to maintain 25-hydroxyvitamin D >75 nmol/L. Cow's milk intake among children using a bottle did not increase 25-hydroxyvitamin D and resulted in more dramatic decreases in serum ferritin., Conclusions: There is a trade-off between increasing 25-hydroxyvitamin D and decreasing serum ferritin with increasing milk intake. Two cups of cow's milk per day appears sufficient to maintain healthy vitamin D and iron stores for most children. Wintertime vitamin D supplementation was particularly important among children with darker skin pigmentation.

Several studies have suggested an association between vitamin D in childhood and autism spectrum disorder. No prospective studies have evaluated whether lower vitamin D levels precede ASD diagnoses – a necessary condition for causality. The objective of this study was to prospectively evaluate whether vitamin D serum levels in early childhood was associated with incident physician diagnosed ASD. A prospective cohort study was conducted using data from preschool-aged children in the TARGet Kids! practice-based research network in Toronto, Canada, from June 2008 to July 2015. 25-hydroxyvitamin D concentration was measured through blood samples and vitamin D supplementation from parent report. Autism spectrum disorder diagnosis was determined from medical records at follow-up visits. Covariates included age, sex, family history of autism spectrum disorder, maternal ethnicity, and neighborhood household income. Unadjusted and adjusted relative risks and 95% confidence intervals were estimated using Poisson regression with a robust error variance. In this study, 3852 children were included. Autism spectrum disorder diagnosis was identified in 41 children (incidence = 1.1%) over the observation period (average follow-up time = 2.5 years). An association between 25-hydroxyvitamin D concentration and autism spectrum disorder was not identified in the unadjusted (relative risk = 1.04, 95% confidence interval: 0.97, 1.11 per 10 nmol/L increase in 25-hydroxyvitamin D concentration) or adjusted models (adjusted relative risk = 1.06; 95% confidence interval: 0.95, 1.18). An association between vitamin D supplementation in early childhood and autism spectrum disorder was also not identified (adjusted relative risk = 0.86, 95% confidence interval: 0.46, 1.62). Vitamin D in early childhood may not be associated with incident physician diagnoses of autism spectrum disorder. [ABSTRACT FROM AUTHOR]

Objectives: Studies in Canada have reported varying prevalences of low serum 25-hydroxyvitamin D (25(OH)D) levels, but none have been conducted in rural paediatric populations. The purpose of this study was to determine the prevalence and predictors of low vitamin D levels in rural communities. Methods: We conducted a cross-sectional study of children aged 3 to 15 living in Canadian Hutterite communities. Serum 25(OH)D levels were measured between October 2008 and April 2009 using a chemiluminescence assay. Predictors of vitamin D levels were evaluated using multivariable linear regression. A multilevel model was used to evaluate the impact of individual, household and colony factors on the variation in vitamin D levels. Results: Serum 25(OH)D levels were available on 743 children/adolescents. The median was 62.0 nmol/L (interquartile range 51.0, 74.0). Levels lower than 50 nmol/L and 75 nmol/L were found in 152 (20.5%) and 565 (76%) children, respectively. Adolescents were at highest risk for levels <75 nmol/L (odds ratio 3.38, 95% confidence interval 2.00, 5.80). Age and latitude were negatively correlated with serum 25(OH)D level. In the multilevel model, most of the variation in levels was associated with individual children. Conclusion: Low vitamin D levels are a significant problem in rural Hutterite communities in Canada. Adolescents were at greatest risk for low levels and represent an important target group for supplementation. Variation in serum 25(OH)D levels was explained mostly at the individual level. Additional studies are needed to explore factors associated with individuals (e.g., genetics) leading to lower 25(OH)D levels. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The primary objective of this study was to examine the relationships between vegetarian diet and growth, micronutrient stores, and serum lipids among healthy children. Secondary objectives included exploring whether cow's milk consumption or age modified these relationships. METHODS: A longitudinal cohort study of children aged 6 months to 8 years who participated in the TARGet Kids! cohort study. Linear mixed-effect modeling was used to evaluate the relationships between vegetarian diet and BMI z-score (zBMI), height-for-age z-score, serum ferritin, 25-hydroxyvitamin D, and serum lipids. Generalized estimating equation modeling was used to explore weight status categories. Possible effect modification by age and cow's milk consumption was examined. RESULTS: A total of 8907 children, including 248 vegetarian at baseline, participated. Mean age at baseline was 2.2 years (SD 1.5). There was no evidence of an association between vegetarian diet and zBMI, height-for-age z-score, serum ferritin, 25-hydroxyvitamin D, or serum lipids. Children with vegetarian diet had higher odds of underweight (zBMI <-2) (odds ratio 1.87, 95% confidence interval 1.19 to 2.96; P = .007) but no association with overweight or obesity was found. Cow's milk consumption was associated with higher nonhigh-density lipoprotein cholesterol (P 5 .03), total cholesterol (P = .04), and low-density lipoprotein cholesterol (P = .02) among children with vegetarian diet. However, children with and without vegetarian diet who consumed the recommended 2 cups of cow's milk per day had similar serum lipids. CONCLUSIONS: Evidence of clinically meaningful differences in growth or biochemical measures of nutrition for children with vegetarian diet was not found. However, vegetarian diet was associated with higher odds of underweight. [ABSTRACT FROM AUTHOR]