Effect of vitamin D supplementation on serum 25-hydroxyvitamin D concentration in children and adolescents: a systematic review and meta-analysis protocol.
ABSTRACT: The importance of vitamin D for bone health as well as its role in non-skeletal functions has long been documented. However, review investigations on the effect of vitamin D supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in children and adolescents are scarce. The aims of the current study were to assess the impact of various doses of vitamin D supplementation on serum 25(OH)D concentrations in children and adolescents, and to identify relevant determinants of variations in the effect of vitamin D supplementation.PubMed, Scopus, ISI Web of Science and Cochrane Central Register of Controlled Trials databases up to 27 September 2017 will systematically be searched for randomised controlled trials of vitamin D supplementation. We considered articles with the following control groups as eligible: placebo control, control group without any supplementation or a comparative arm investigation. Two reviewers will assess articles for eligibility according to prespecified selection criteria, after which data extraction and quality appraisal will be conducted by two independent reviewers. The quality assessment will be assessed using the Jadad scale. Meta-analyses will be conducted where appropriate. We will express continuous measures (ie, serum 25(OH)D concentration) as mean differences with 95% CIs. Heterogeneity of the data will be investigated via visual inspection of the forest plots and using ?2 test on N-1 df, with a significance level of ?=0.1. We will also assess individual study and subgroup characteristics and perform a sensitivity analysis. Publication bias will be assessed using funnel plot and statistical analysis of Egger's test.Ethics approval is not required because the work will be carried out on published documents. The authors will publish findings from this review through peer-reviewed publication or conference presentations.CRD42017067179.
Project description:BACKGROUND:The appropriate dose of vitamin D supplementation in children is still debated. We calculated that the recommended dose of 600-1000?IU vitamin D3/day is not sufficient to reach a serum 25-hydroxyvitamin D (25-OH-D) level of at least 30?ng/ml (75?nmol/l) in north Italian children >?12?months. The aim of this study was to analyse the effect of seasonal supplementation with 1500?IU (=37.5??g) vitamin D3/day. METHODS:DINOS (D-vitamIN Oral Supplementation) study was a pilot, monocentric, non-random case-control register study. It was conducted in a paediatric primary care setting near Padova (North Italy, 45°N latitude). The data of 203 children (girls:boys 1:1,33) aged 2-15?years, collected between November 2010 and January 2015, were analysed. Active group A (n?=?82) were given 1500?IU vitamin D3/day from November to April; control Group B (n?=?121) received no supplementation. The serum 25-OH-D test was part of a laboratory tests panel and performed using a chemiluminescence immunoassay method. RESULTS:Serum 25-OH-D mean level + standard deviation throughout the period was 32 + 13?ng/ml (80 + 32?nmol/l) in group A vs 22 + 10?ng/ml (55 + 25?nmol/l) in group B. In group A 12% had vitamin D deficiency 25-OH-D?<?20?ng/ml (50?nmol/l) and 1.2% severe vitamin D deficiency 25-OH-D?<?10?ng/ml (25?nmol/l). In group B 46% had vitamin D deficiency and 9% severe deficiency (P?<? 0.001). In group A mean levels were normal or near-normal all the year except in May. Group B reached mean 25-OH-D levels close to 30?ng/ml (75?nmol/l) only in late summer. The active group mean 25-OH-D level was normal in preschoolers and schoolers but not in adolescents. Non-white children had a three-times vitamin D deficiency probability despite supplementation. CONCLUSIONS:Vitamin D supplementation with at least 1500?IU vitamin D3/day from November to April was found appropriate for children in North Italy. A prolongation until May could be useful. Higher doses and/or prolonged periods could be more appropriate especially in adolescents and in non-white children. STUDY REGISTRATION:DINOS gained the approval of Padova Ethics Committee (n. 3960/U16/2016).
Project description:Background:Interpretation of serum vitamin D biomarkers across pregnancy is complex due to limited understanding of pregnancy adaptations in vitamin D metabolism. During pregnancy, both gestational age and serum 25-hydroxyvitamin D [25(OH)D] concentrations may influence the concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D], 24,25-dihydroxyvitamin D [24,25(OH)2D], and parathyroid hormone (PTH). Objective:We aimed to identify predictors of change in serum 25(OH)D across gestation in pregnant adolescents and to assess the contribution made by cholecalciferol (vitamin D3) supplementation. We sought to determine whether gestational age and 25(OH)D concentration interacted to affect serum 1,25(OH)2D, 24,25(OH)2D, or PTH. Methods:Pregnant adolescents (n = 78, 59% African American, mean ± SD age: 17 ± 1 y) living in Rochester, NY (latitude 43°N) were supplemented with 200 IU or 2000 IU vitamin D3/d and allowed to continue their daily prenatal supplement that contained 400 IU vitamin D3. Serum was collected at study entry (18 ± 5 wk of gestation), halfway through study participation, and at delivery (40 ± 2 wk). Serum concentrations of the biochemical markers were modeled with linear mixed-effects regression models. Results:Vitamin D3 supplement intake and season of delivery determined change in 25(OH)D across pregnancy. Fall-winter delivery was associated with a decline in 25(OH)D unless vitamin D3 supplement intake was >872 IU/d. The interaction of gestational age and 25(OH)D affected 24,25(OH)2D concentrations. For a given 25(OH)D concentration, model-predicted serum 24,25(OH)2D increased across gestation except when 25(OH)D was <13 ng/mL. Below this threshold, 24,25(OH)2D was predicted to decline over time. Mean serum 1,25(OH)2D was elevated (>100 pg/mL) throughout the study. Conclusion:Our results suggest that when maternal serum 25(OH)D was low, its catabolism into 24,25(OH)2D decreased or remained stable as pregnancy progressed in order to maintain persistently elevated serum 1,25(OH)2D. Furthermore, in adolescents living at latitude 43°N, standard prenatal supplementation did not prevent a seasonal decline in 25(OH)D during pregnancy. This study was registered at clinicaltrials.gov as NCT01815047.
Project description:INTRODUCTION:Our previous study-level (aggregate data) meta-analysis suggested that vitamin D supplements may be beneficial for bone density specifically in children with vitamin D deficiency. However, the misclassification of vitamin D status inherent in study-level data means that the results are not definitive and cannot provide an accurate assessment of the size of any effect. Therefore, we propose to undertake an individual patient data (IPD) meta-analysis to determine whether the effect of vitamin D supplementation on bone density in children differs according to baseline vitamin D status, and to specifically estimate the effect of vitamin D in children who are vitamin D deficient. METHODS AND ANALYSIS:This study has been designed to adhere to the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement. We will include randomised placebo-controlled trials of vitamin D supplementation reporting bone density outcomes at least 6 months after the study commenced in children and adolescents (aged <20 years) without coexistent medical conditions or treatments causing osteoporosis. We will update the search of the original review to cover the period 2009-2017, using the same methods as the original review. Fully anonymised data on all randomised patients will be requested. Outcomes will be femoral neck, total hip, lumbar spine and proximal and distal forearm bone mineral density, and total body bone mineral content. A two-stage IPD meta-analysis will be used to examine the effect of baseline serum 25-hydroxyvitamin D (25(OH)D) on treatment effect for each bone density outcome. Restricted maximum likelihood will be used to estimate the random-effects meta-analysis models, with 95% CI for summary effects. Heterogeneity will be assessed by I2 and potential publication bias (small-study effects) and availability bias by funnel plots, Egger's test and Peter's test. ETHICS AND DISSEMINATION:Ethics approval will not be required as the data are to be used for the primary purpose for which they were collected and all original individual studies had ethics approval. Results of the IPD meta-analysis will be submitted for publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER:CRD42017068772.
Project description:Hypovitaminosis D affects one-third to two-thirds of children and pregnant women from the Middle East and North Africa (MENA) region.To evaluate in infants, children, adolescents and pregnant women, from the MENA region, the effect of supplementation with different vitamin D doses on the change in 25-hydroxyvitamin D [25(OH)D] level reached, and other skeletal and non-skeletal outcomes.This is a systematic review of randomized controlled trials of vitamin D supplementation conducted in the MENA region. We conducted a comprehensive literature search in 7 databases, without language or time restriction, until November 2016. Two reviewers abstracted data from the included studies, independently and in duplicate. We calculated the mean difference (MD) and 95% CI of 25(OH)D level reached when at least 2 studies were eligible in each comparison (low (<800IU), intermediate (800-2000IU) or high (>2000IU) daily dose of vitamin D, or placebo). We pooled data using RevMan version 5.3.We identified a total of 15 eligible trials: one in infants, 4 in children and adolescents and 10 in pregnant women. In children and adolescents, an intermediate vitamin D dose (1901IU/d), resulted in a mean difference in 25(OH)D level of 13.5 (95% confidence interval (CI) 8.1-18.8) ng/ml, compared to placebo, favoring the intermediate dose (p<0.001). The proportion of children and adolescents reaching a 25(OH)D level? 20ng/ml was 74% in the intermediate dose group. In pregnant women, four trials started supplementation at 12-16weeks of gestation and continued until delivery, and six trials started supplementation at 20-28weeks' gestation and stopped it at delivery. The MD in 25(OH)D level reached was 8.6 (95% CI 5.3-11.9) ng/ml (p<0.001) comparing the high dose (3662IU/d) to the intermediate dose (1836IU/d), and 12.3 (95% CI 6.4-18.2) ng/ml (p<0.001), comparing the high dose (3399IU/d) to the low dose (375IU/d). Comparing the intermediate (1832IU/d) to the low dose (301IU/d), the MD in 25(OH)D level achieved was 7.8 (95% CI 4.5-10.8) ng/ml (p<0.001). The proportion of pregnant women reaching a 25(OH)D level?20ng/ml was 80%-90%, 73% and 27%-43% in the high, intermediate, and low dose groups, respectively. The risk of bias in the included studies, for children, adolescents and pregnant women, ranged from low to high across all doamins.In children, adolescents and pregnant women from the MENA, an intermediate vitamin D dose of 1000-2000IU daily may be necessary to allow for the majority of the population to reach a desirable 25(OH)D level of 20ng/ml. Further high quality RCTs are required to confirm/refute the beneficial impact of vitamin D supplementation on various clinically important outcomes.
Project description:Vitamin D deficiency has been shown to affect iron status via decreased calcitriol production, translating to decreased erythropoiesis. The present study aimed to determine for the first time whether vitamin D supplementation can affect iron levels among Arab adolescents. A total of 125 out of the initial 200 Saudi adolescents with vitamin D deficiency (serum 25(OH)D < 50 nmol/L) were selected from the Vitamin D-School Project of King Saud University in Riyadh, Saudi Arabia. Cluster randomization was done in schools, and students received either vitamin D tablets (1000 IU/day) (N = 53, mean age 14.1 ± 1.0 years) or vitamin D-fortified milk (40IU/200mL) (N = 72, mean age 14.8 ± 1.4 years). Both groups received nutritional counseling. Anthropometrics, glucose, lipids, iron indices, and 25(OH)D were measured at baseline and after six months. Within group analysis showed that post-intervention, serum 25(OH)D significantly increased by as much as 50%, and a parallel decrease of -42% (p-values <0.001 and 0.002, respectively) was observed in serum iron in the tablet group. These changes were not observed in the control group. Between-group analysis showed a clinically significant increase in serum 25(OH)D (p = 0.001) and decrease in iron (p < 0.001) in the tablet group. The present findings suggest a possible inhibitory role of vitamin D supplementation in the iron indices of healthy adolescents whose 25(OH)D levels are sub-optimal but not severely deficient, implying that the causal relationship between both micronutrients may be dependent on the severity of deficiency, type of iron disorder, and other vascular conditions that are known to affect hematologic indices. Well-designed, randomized trials are needed to confirm the present findings.
Project description:Background: Hypertension and vitamin D deficiency are prevalent among the elderly. This study evaluated the effects of vitamin D supplementation on changes in serum 25-hydroxyvitamin D (25(OH)D) levels and blood pressure (BP) in the elderly (age > 60 years). Methods: Randomized controlled trials from electronic databases on the elderly taking oral vitamin D, until the end of March 2019, were selected. Two reviewers independently screened the literature on the basis of specific inclusion criteria. The primary outcomes were serum 25(OH)D level, systolic BP (SBP), and diastolic BP (DBP) changes. Results: Our analysis revealed significant differences in serum 25(OH)D level changes between the vitamin D and control groups (mean difference [MD] = 13.84; 95% confidence interval [CI] = 10.21-17.47; P < 0.000). There were no significant differences in SBP and DBP changes between the vitamin D and control groups. Subgroup analysis revealed significant differences in SBP changes between the hypertensive and vitamin D-deficient subgroups (MD = -4.01; 95% CI = -7.45 to -0.57; P = 0.02 and MD = -1.91; 95% CI = -3.48 to -0.34; P = 0.02, respectively), and DBP changes only in the hypertensive subgroup (MD = -2.22; 95% CI = -4.1 to -0.34; P = 0.02). Conclusions: Vitamin D supplementation significantly increases 25(OH)D levels and seems beneficial in lowering BP, specifically in the elderly with elevated BP and vitamin D deficiency.
Project description:BACKGROUND:There is increasing interest in the extraskeletal effects of vitamin D, particularly in the obese state with regard to the development of insulin resistance and diabetes. OBJECTIVE:The objective of the study was to determine the effect of 2 doses of cholecalciferol (vitamin D3) supplementation on insulin action (Si) and pancreatic ?-cell function in obese adolescents. METHODS:We performed a 12-wk double-blind, randomized comparison of the effect of vitamin D3 supplementation on Si and ?-cell function in obese Caucasian adolescents (body mass index > 95(th) percentile). The subjects were randomly assigned to receive either 400 IU/d (n = 25) or 2000 IU/d (n = 26) of vitamin D3. Each subject underwent a 7-sample 75 g oral glucose tolerance test, with glucose, insulin, and C-peptide measurements, to calculate Si and ?-cell function as assessed by the disposition index (DI), with use of the oral minimal model before and after supplementation. A total of 51 subjects aged 15.0 ± 1.9 y were enrolled. Included for analysis at follow-up were a total of 46 subjects (20 male and 26 female adolescents), 23 in each group. RESULTS:Initial serum 25-hydroxyvitamin D [25(OH)D] was 24.0 ± 8.1 ?g/L. There was no correlation between 25(OH)D concentrations and Si or DI. There was a modest but significant increase in 25(OH)D concentration in the 2000 IU/d group (3.1 ± 6.5 ?g/L, P = 0.04) but not in the 400 IU/d group (P = 0.39). There was no change in Si or DI following vitamin D3 supplementation in either of the treatment groups (all P > 0.10). CONCLUSIONS:The current study shows no effect from vitamin D3 supplementation, irrespective of its dose, on ?-cell function or insulin action in obese nondiabetic adolescents with relatively good vitamin D status. Whether obese adolescents with vitamin D deficiency and impaired glucose metabolism would respond differently to vitamin D3 supplementation remains unclear and warrants further studies. This trial was registered at clinicaltrials.gov as NCT00858247.
Project description:OBJECTIVE:To review the evidence to assess effectiveness of vitamin D supplementation during pregnancy and associations of serum vitamin D levels with perinatal outcomes. DESIGN:Overview of systematic reviews (SRs). DATA SOURCES:Searches conducted in January 2019: Ovid Medline (1946-), Cochrane Library databases. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:Two reviewers independently screened titles and abstracts, and full texts using predefined inclusion criteria: SRs evaluating vitamin D supplementation in pregnant women and/or examining the association between serum vitamin D levels reporting at least one predefined perinatal outcome. Only SRs with high AMSTAR scores were analysed. DATA EXTRACTION AND SYNTHESIS:Data were extracted independently by one reviewer and checked by a second. Results were assessed for quality independently by two reviewers using GRADE criteria. RESULTS:Thirteen SRs were included, synthesising evidence from 204 unique primary studies. SRs of randomised controlled trials (RCTs) with the highest level of evidence showed no significant benefit from vitamin D in terms of preterm birth (RR 1.00 (95% CI 0.77, 1.30); high quality), pre-eclampsia (RR 0.91 (0.45, 1.86); low quality), gestational diabetes (RR 0.65 (0.39, 1.08); very low quality), stillbirth (RR 0.75 (0.50, 1.12); high quality), low birth weight (RR 0.74 (0.47, 1.16); low quality), caesarean section (RR 1.02 (0.93, 1.12); high quality). A significant difference was found for small for gestational age (RR 0.72 (0.52, 0.99); low quality). SRs of observational studies showed associations between vitamin D levels and preterm birth (RR 1.19 (1.08, 1.31); moderate quality), pre-eclampsia (RR 1.57 (1.21, 2.03) for 25-hydroxy vitamin D (25 (OH)D)<50?nmol/L subgroup; low quality), gestational diabetes (RR 1.12 (1.02, 1.22) for 25 (OH)D<50?nmol/L and RR 1.09 (1.03, 1.15)<75?nmol/L; moderate quality) and small for gestational age (RR 1.35 (1.18, 1.54)<50?nmol/L; low quality). SRs showed mixed results for associations between vitamin D and low birth weight (very low quality) and caesarean section (very low quality). CONCLUSION:There is some evidence from SRs of observational studies for associations between vitamin D serum levels and some outcomes; however SRs examining effectiveness from RCTs showed no effect of vitamin D supplementation in pregnancy with the exception of one predefined outcome, which had low quality evidence. Credibility of the evidence in this field is compromised by study limitations (in particular, the possibility of confounding among observational studies), inconsistency, imprecision and potential for reporting and publication biases.
Project description:Vitamin D deficiency is prevalent in human populations and has been linked to immune dysfunction. Here we explored the effects of cholecalciferol supplementation on circulating cytokines in severely vitamin D deficient [blood 25(OH)D << 30 nmol/L] adolescents aged 12-15 from Mongolia. The study included 28 children receiving 800 IU daily cholecalciferol for 6 months spanning winter and spring, and 30 children receiving placebo during the same period. The levels of 25(OH)D were assessed at baseline, 3 and 6 months. Twenty-one cytokines were measured in serum at baseline and at 6 months. Changes in 25(OH)D and cytokines were assessed using paired parametric tests. The median blood 25(OH)D concentration at baseline was 13.7 nmol/L (IQR = 10.0-21.7). Supplementation tripled blood 25(OH)D levels (p < 0.001) and was associated with elevated interleukin (IL)-6 (p = 0.043). The placebo group had reduced macrophage inflammatory protein (MIP)-1? (p = 0.007) and IL-8 (p = 0.034) at 6 months. Although limited by a small sample size, these findings suggest that cholecalciferol supplementation and seasonality may impact systemic immunity in adolescents, identifying chemokines as potentially important biomarkers of vitamin D status in this Northeast Asian population. Larger clinical trials are warranted to validate these results. Clinical Trial Registration: www.ClinicalTrial.org, Identifier: NCT01244204.
Project description:Serum free 25-hydroxyvitamin D (25(OH)D) rather than total 25(OH)D may better indicate vitamin D status during pregnancy given the pregnancy-associated increase in serum vitamin D binding protein (DBP) concentration. Our aims were to assess changes in DBP and free 25(OH)D across gestation and to determine whether free compared with total 25(OH)D more strongly correlates with markers of vitamin D and calcium metabolism during pregnancy. This ancillary study included 58 pregnant adolescents (53% African American, 47% White) who completed a vitamin D3 supplementation study in Rochester, NY. Blood was collected at entry, mid-study, and delivery (median 17, 29, and 40 weeks' gestation). Mixed-effects regression was used to test for differences in DBP, directly measured free 25(OH)D, and other serum markers by study visit and race. Free and total 25(OH)D were evaluated in relation to serum PTH, 1,25(OH)2D, 24,25(OH)2D, and calcium. The mean DBP concentration was above nonpregnant reference values at entry and increased across gestation (P < 0.0001). Total 25(OH)D explained most of the variance in free 25(OH)D (r ? 0.67; P < 0.0001). Holding total 25(OH)D constant, each 100?mg/L increase in DBP was associated with a 0.4?pg/mL decrease in free 25(OH)D (P < 0.01). The percent free 25(OH)D was inversely related to both DBP and total 25(OH)D at each visit. Regardless of race or visit, total 25(OH)D was a stronger correlate of PTH, 1,25(OH)2D, and 24,25(OH)2D, and neither total nor free 25(OH)D was related to serum calcium. African Americans had lower total 25(OH)D (P?<? 0.0001), but free 25(OH)D did not significantly differ by race (P?=? 0.2). In pregnant adolescents, DBP concentration was elevated and inversely associated with percent free 25(OH)D, but measured free 25(OH)D provided no advantage over total 25(OH)D as a predictor of PTH, 1,25(OH)2D, 24,25(OH)2D, or calcium. The clinical relevance of the small racial difference in percent free 25(OH)D requires further investigation.