A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (ICU) and associated with worse clinical course. Trials in adult ICU demonstrate rapid restoration of vitamin D status using an enteral loading dose is safe and may improve outcomes. There have been no published trials of rapid normalization of VDD in the pediatric ICU. METHODS: We conducted a multicenter placebo-controlled phase II pilot feasibility randomized clinical trial from 2016 to 2017. We randomized 67 critically ill children with VDD from ICUs in Canada, Chile and Austria using a 2:1 randomization ratio to receive a loading dose of enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or placebo. Participants, care givers, and outcomes assessors were blinded. The primary objective was to determine whether the loading dose normalized vitamin D status (25(OH)D > 75 nmol/L). Secondary objectives were to evaluate for adverse events and assess the feasibility of a phase III trial. RESULTS: Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary analyses (40 treatment, 19 placebo). Thirty-one/38 (81.6%) participants in the treatment arm achieved a plasma 25(OH)D concentration > 75 nmol/L versus 1/18 (5.6%) the placebo arm. The mean 25(OH)D concentration in the treatment arm was 125.9 nmol/L (SD 63.4). There was no evidence of vitamin D toxicity and no major drug or safety protocol violations. The accrual rate was 3.4 patients/month, supporting feasibility of a larger trial. A day 7 blood sample was collected for 84% of patients. A survey administered to 40 participating families showed that health-related quality of life (HRQL) was the most important outcome for families for the main trial (30, 75%). CONCLUSIONS: A single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children with VDD, but with significant variability in 25(OH)D concentrations. We established that a phase III multicentre trial is feasible. Using an outcome collected after hospital discharge (HRQL) will require strategies to minimize loss-to-follow-up. CLINICALTRIALS: gov NCT02452762 Registered 25/05/2015.

Effect of Vitamin D Supplementation on Bone Mass in Infants With 25-Hydroxyvitamin D Concentrations Less Than 50 nmol/L: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Importance: The dose of supplemental vitamin D needed in infants born with serum 25-hydroxyvitamin D (25[OH]D) concentrations less than 50 nmol/L (ie, 20 ng/mL) is unclear. Objective: To determine whether a higher dose (1000 IU vs 400 IU per day) is required in infants born with 25(OH)D concentrations less than 50 nmol/L for bone mineral accretion across infancy. Design, Setting, and Participants: In this prespecified secondary analysis of a double-blinded randomized clinical trial, conducted from March 2016 to March 2019 in a single center in Greater Montreal, Quebec, Canada, a consecutive sample of 139 healthy term singletons were recruited from 866 infants screened for vitamin D status at birth. Data were analyzed from June 2021 to November 2022. Interventions: Capillary blood was collected 24 to 36 hours after birth to measure serum total 25(OH)D concentrations. Infants with 25(OH)D concentrations less than 50 nmol/L were randomized to receive either 1000 IU or 400 IU per day of oral vitamin D3 supplementation from age 1 to 12 months. Infants with 25(OH)D concentrations of 50 nmol/L or greater formed a reference group. Main Outcomes and Measures: Measures at age 1, 3, 6, and 12 months were preplanned and included whole-body bone mineral content, lumbar spine bone mineral content, and bone mineral density using dual-energy x-ray absorptiometry, and serum 25(OH)D3 using liquid chromatography tandem mass spectrometry. Results: Of 139 included infants, 81 (58.3%) were male, and the median (IQR) gestational age at birth was 39.6 (38.9-40.6) weeks. A total of 49 infants were included in the 1000 IU per day group, 49 infants in the 400 IU per day group, and 41 in the reference group. Mean (SD) whole-body bone mineral content was not different between trial groups over time (1000 IU per day, 173.09 [2.36] g; 400 IU per day, 165.94 [66.08] g). Similarly, no differences were observed in lumbar spine bone mineral content or density. Mean (SD) serum 25(OH)D3 concentrations were significantly higher in the 1000 IU per day group from age 3 to 12 months (3 months, 115.2 [35.3] nmol/L; 6 months, 121.6 [34.4] nmol/L; 12 months, 99.6 [28.8] nmol/L) compared with the 400 IU per day trial group (3 months, 77.4 [23.3] nmol/L; 6 months, 85.1 [18.6] nmol/L; 12 months, 82.3 [14.3] nmol/L). Conclusions and Relevance: In this study, a higher dose of vitamin D supplementation in infants born with 25(OH)D concentrations less than 50 nmol/L did not present advantages to bone mass in infancy. This study supports a standard dose of 400 IU per day of vitamin D supplementation for breastfed infants in Montreal. Trial Registration: ClinicalTrials.gov Identifier: NCT02563015.

Correction of neonatal vitamin D status using 1000 IU vitamin D/d increased lean body mass by 12 months of age compared with 400 IU/d: a randomized controlled trial.

BACKGROUND: Intrauterine exposure to maternal vitamin D status <50 nmol/L of serum 25-hydroxyvitamin D [25(OH)D] may adversely affect infant body composition. Whether postnatal interventions can reprogram for a leaner body phenotype is unknown. OBJECTIVES: The primary objective was to test whether 1000 IU/d of supplemental vitamin D (compared with 400 IU/d) improves lean mass in infants born with serum 25(OH)D <50 nmol/L. METHODS: Healthy, term, breastfed infants (Montréal, Canada, March 2016-2019) were assessed for serum 25(OH)D (immunoassay) 24-36 h postpartum. Infants with serum 25(OH)D <50nmol/L at 24-36 h were eligible for the trial and randomly assigned at baseline (1 mo postpartum) to 400 (29 males, 20 females) or 1000 IU/d (29 males, 20 females) of vitamin D until 12 mo. Infants (23 males, 18 females) with 25(OH)D ≥50 nmol/L (sufficient) formed a nonrandomized reference group provided 400 IU/d. Anthropometry, body composition (DXA), and serum 25(OH)D concentrations were measured at 1, 3, 6, and 12 mo. RESULTS: At baseline, mean ± SD serum 25(OH)D concentrations in infants allocated to the 400 and 1000 IU/d vitamin D groups were 45.8 ± 14.1 and 47.6 ± 13.4, respectively; for the reference group it was 69.2 ± 16.4 nmol/L. Serum 25(OH)D concentration increased on average to ≥50 nmol/L in the trial groups at 3-12 mo. Lean mass varied differently between groups over time; at 12 mo it was higher in the 1000 IU/d vitamin D group than in the 400 IU/d group (mean ± SD: 7013 ± 904.6 compared with 6690.4 ± 1121.7 g, P = 0.0428), but not the reference group (mean ± SD: 6715.1 ± 784.6 g, P = 0.19). Whole-body fat mass was not different between the groups over time. CONCLUSIONS: Vitamin D supplementation (400 or 1000 IU/d) during infancy readily corrects vitamin D status, whereas 1000 IU/d modestly increases lean mass by 12 mo. The long-term implications require further research. This trial was registered at clinicaltrials.gov as NCT02563015.

A high-throughput platform for the rapid screening of vitamin D status by direct infusion-MS/MS.

Vitamin D is an important fat-soluble prohormone with pleiotropic effects on human health, such as immunomodulation of the innate and adaptive immune system. There is an unmet clinical need for a rapid screening platform for 25-hydroxyvitamin D (25OH-D) determination without chromatographic separation that offers better precision and accuracy than immunoassays. Here, we introduce a high-throughput method for assessing vitamin D status from blood specimens based on direct infusion-MS/MS (DI-MS/MS) following click derivatization using 2-nitrosopyridine. We developed an optimized liquid-phase extraction protocol to minimize ion suppression when directly infusing serum or plasma extracts via a capillary electrophoresis system for quantitative determination of 25OH-D. Acceptable reproducibility (mean coefficient of variation = 10.9%, n = 412), recovery (mean = 102% at 15, 30, and 45 nmol/l), and linearity (R2 > 0.998) were achieved for 25OH-D with lower detection limits (limit of detection ∼1.2 nmol/l, S/N ∼ 3), greater throughput (∼3 min/sample), and less bias than a commercial chemiluminescence immunoassay prone to batch effects. There was mutual agreement in 25OH-D concentrations from reference blood samples measured by DI-MS/MS as compared with LC-MS/MS (mean bias = 7.8%, n = 18). We also demonstrate that this method could reduce immunoassay misclassification of vitamin D deficiency in a cohort of critically ill children (n = 30). In conclusion, DI-MS/MS offers a viable alternative to LC-MS/MS for assessment of vitamin D status in support of large-scale studies in nutritional epidemiology as well as clinical trials to rapidly screen individual patients who may benefit from vitamin D supplementation.

Maternal excess adiposity and serum 25-hydroxyvitamin D < 50 nmol/L are associated with elevated whole body fat mass in healthy breastfed neonates.

BACKGROUND: Vitamin D status of pregnant women is associated with body composition of the offspring. The objective of this study was to assess whether the association between maternal vitamin D status and neonatal adiposity is modified by maternal adiposity preconception. METHODS: Healthy mothers and their term appropriate weight for gestational age (AGA) infants (n = 142; 59% male, Greater Montreal, March 2016-2019) were studied at birth and 1 month postpartum (2-6 weeks). Newborn (24-36 h) serum was collected to measure total 25-hydroxyvitamin D [25(OH)D] (immunoassay); maternal pre-pregnancy BMI was obtained from the medical record. Anthropometry, body composition (dual-energy X-ray absorptiometry) and serum 25(OH)D were measured at 2-6 weeks postpartum in mothers and infants. Mothers were grouped into 4 categories based on their vitamin D status (sufficient 25(OH)D ≥ 50 nmol/L vs. at risk of being insufficient < 50 nmol/L) and pre-pregnancy BMI (< 25 vs. ≥25 kg/m2): insufficient-recommended weight (I-RW, n = 24); insufficient-overweight/obese (I-OW/O, n = 21); sufficient-recommended weight (S-RW, n = 69); and sufficient-overweight/obese (S-OW/O, n = 28). Partial correlation and linear fixed effects model were used while adjusting for covariates. RESULTS: At birth, infant serum 25(OH)D mean concentrations were below 50 nmol/L, the cut-point for sufficiency, for both maternal pre-pregnancy BMI categories; 47.8 [95%CI: 43.8, 51.9] nmol/L if BMI < 25 kg/m2 and 38.1 [95%CI: 33.5, 42.7] nmol/L if BMI ≥25 kg/m2. Infant serum 25(OH)D concentrations at birth (r = 0.77; P < 0.0001) and 1 month (r = 0.59, P < 0.0001) were positively correlated with maternal postpartum serum 25(OH)D concentrations. Maternal serum 25(OH)D concentration was weakly correlated with maternal percent whole body fat mass (r = - 0.26, P = 0.002). Infants of mothers in I-OW/O had higher fat mass versus those of mothers in S-OW/O (914.0 [95%CI: 766.4, 1061.6] vs. 780.7 [95%CI: 659.3, 902.0] g; effect size [Hedges' g: 0.42]; P = 0.04 adjusting for covariates) with magnitude of difference of 220.4 g or ~ 28% difference. CONCLUSIONS: Maternal and neonatal vitamin D status are positively correlated. In this study, maternal adiposity and serum 25(OH)D < 50 nmol/L are dual exposures for neonatal adiposity. These findings reinforce the importance of vitamin D supplementation early in infancy irrespective of vitamin D stores acquired in utero and maternal weight status.

Disparities in Vitamin D Status of Newborn Infants from a Diverse Sociodemographic Population in Montreal, Canada.

BACKGROUND: Vitamin D status at birth is reliant on maternal-fetal transfer of vitamin D during gestation. OBJECTIVES: We aimed to examine the vitamin D status of newborn infants in a diverse population and to subsequently identify the modifiable correlates of vitamin D status. METHODS: In this cross-sectional study, healthy mother-infant dyads (n = 1035) were recruited within 36 h after term delivery (March 2016-March 2019). Demographic and lifestyle factors were surveyed. Newborn serum 25-hydroxyvitamin D [25(OH)D] was measured (standardized chemiluminescence immunoassay) and categorized as deficient [serum 25(OH)D <30 nmol/L] or adequate (≥40 nmol/L). Serum 25(OH)D was compared among categories of maternal characteristics using ANOVA; each characteristic was tested in a separate model. Subgroups (use of multivitamins preconception and continued in pregnancy compared with during pregnancy only) were matched (n = 352/group) for maternal factors (ancestry, age, income, education, parity, and prepregnancy BMI) using propensity scores; logistic regression models were generated for odds of deficiency or adequacy. RESULTS: Infants' mean serum 25(OH)D was 45.9 nmol/L (95% CI: 44.7, 47.0 nmol/L) (n = 1035), with 20.8% (95% CI: 18.3%, 23.2%) deficient and 60.7% (95% CI: 55.2%, 66.2%) adequate. Deficiency prevalence ranged from 14.6% of white infants to 41.7% of black infants. Serum 25(OH)D was higher (P < 0.0001) in infants of mothers with higher income, BMI < 25 kg/m2, exercise and sun exposure in pregnancy, and use of multivitamins preconception. In the matched-subgroup analysis, multivitamin supplementation preconception plus during pregnancy relative to only during pregnancy was associated with lower odds for vitamin D deficiency (ORadj: 0.55; 95% CI: 0.36, 0.86) and higher odds for adequate vitamin D status (ORadj: 1.47; 95% CI: 1.04, 2.07). CONCLUSIONS: In this study most newborn infants had adequate vitamin D status, yet one-fifth were vitamin D deficient with disparities between population groups. Guidelines for a healthy pregnancy recommend maternal use of multivitamins preconception and continuing in pregnancy. An emphasis on preconception use may help to achieve adequate neonatal vitamin D status.This trial was registered at clinicaltrials.gov as NCT02563015.

Trying to identify who may benefit most from future vitamin D intervention trials: a post hoc analysis from the VITDAL-ICU study excluding the early deaths.

BACKGROUND: Vitamin D supplementation has shown promise for reducing mortality in the intensive care setting. As a steroid prohormone with pleiotropic effects, there may be a lag between administration and observing clinical benefit. This secondary analysis of the VITdAL-ICU study sought to explore whether the effect size of vitamin D on mortality was different when study participants who died or were discharged early were excluded. METHODS: The VITdAL-ICU study was a randomized, placebo-controlled trial in critically ill adults who received placebo or 540,000 IU cholecalciferol followed by monthly supplementation. The effect of vitamin D on 28-day mortality was evaluated after exclusion of participants who died or were discharged within 7 days from study drug administration, according to vitamin D concentrations on day 3, using a bivariate analysis adjusted for confounders and in a stepwise multiple analysis. RESULTS: Of 475 study participants, 65 died or were discharged within the first 7 days. In the remaining 410 patients, vitamin D supplementation was associated with a reduction in 28-day mortality [OR 0.58 (95% CI 0.35-0.97) p value = 0.035]. The effect on mortality was not significant after adjusting for age, severity scores, female gender, chronic liver and kidney disease, COPD, diagnosis of the tumor, mechanical ventilation, and vasopressors at enrollment (all p > 0.05). In a multiple model, the mortality reduction by vitamin D supplementation did not remain independently significant [OR 0.61 (95% CI 0.35-1.05) p = 0.075]. Vitamin D metabolite response, in the treatment group, demonstrated that survivors at 28 days, had higher levels of 25-hydroxyvitamin D (34.4 vs 25.4 ng/ml, p = 0.010) and 1,25-dihydroxyvitamin D (107.6 vs 70.3 pg/ml, p = 0.049) on day 3. The increase of plasma metabolites after vitamin D oral supplementation, independent of the baseline value, was associated with lower odds of death [OR 0.48 (95% CI 0.27-0.87) p value = 0.016]. CONCLUSIONS: High-dose vitamin D3 supplementation was associated with a reduction of 28-day mortality in a mixed population of critically ill adults with vitamin D deficiency when excluding patients who died or were discharged within 7 days after study inclusion. However, this survival benefit was not independently confirmed when adjusted for other factors strongly associated with mortality.

Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

BACKGROUND: Clinical research has recently demonstrated that vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (PICU) and associated with worse clinical course. Multiple adult ICU trials have suggested that optimization of vitamin D status through high-dose supplementation may reduce mortality and improve other clinically relevant outcomes; however, there have been no trials of rapid normalization in the PICU setting. The objective of this study is to evaluate the safety and efficacy of an enteral weight-based cholecalciferol loading dose regimen in critically ill children with VDD. METHODS/DESIGN: The VITdAL-PICU pilot study is designed as a multicenter placebo-controlled phase II dose evaluation pilot randomized controlled trial. We aim to randomize 67 VDD critically ill children using a 2:1 randomization schema to receive loading dose enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or a placebo solution. Participants, caregivers and outcome assessors will be blinded to allocation. Eligibility criteria include ICU patient, aged 37 weeks to 18 years, expected ICU length of stay more than 48 h, anticipated access to bloodwork at 7 days, and VDD (blood total 25 hydroxyvitamin D < 50 nmol/L). The primary objective is to determine whether the dosing protocol normalizes vitamin D status, defined as a blood total 25(OH)D concentration above 75 nmol/L. Secondary objectives include an examination of the safety of the dosing regimen (e.g. hypercalcemia, hypercalciuria, nephrocalcinosis), measures of vitamin D axis function (e.g. calcitriol levels, immune function), and protocol feasibility (eligibility criteria, protocol deviations, blinding). DISCUSSION: Despite significant observational literature suggesting VDD to be a modifiable risk factor in the PICU setting, there is no robust clinical trial evidence evaluating the benefits of rapid normalization. This phase II clinical trial will evaluate an innovative weight-based dosing regimen intended to rapidly and safely normalize vitamin D levels in critically ill children. Study findings will be used to inform the design of a multicenter phase III trial evaluating the clinical and economic benefits to rapid normalization. Recruitment for this trial was initiated in January 2016 and is expected to continue until November 30, 2017. TRIAL REGISTRATION: Clinicaltrials.gov NCT02452762.