Cholesterol Interference in the Assessment of Vitamin D Status: A Canadian Health Measures Survey Biobank Project.

BACKGROUND: Matrix effects are a known problem with immunoassays measuring serum 25-hydroxyvitamin D [25(OH)D]. OBJECTIVES: To determine if the inverse association between serum 25(OH)D and serum cholesterol concentrations is a function of assay method: Diasorin Liaison 25(OH) Vitamin D Total Assay (Liaison Total Assay), an immunoassay, compared with liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS: Canadian Health Measures Survey data and biobank serum (White males aged 20-79 y, n = 392) were evaluated for bias in serum 25(OH)D using Bland-Altman plots. Differences in serum 25(OH)D (Liaison Total Assay - LC-MS/MS) were compared among non-HDL-cholesterol <4.2 (n = 295) compared with ≥4.2 (n = 97) mmol/L and total cholesterol groups <5.2 (n = 256) compared with ≥5.2 (n = 136) mmol/L, and associations tested between 25(OH)D and non-HDL-cholesterol or total cholesterol concentrations, using regression. RESULTS: Serum 25(OH)D measured using Liaison Total Assay ranged from 10.7 to 137.0 nmol/L and 14.4 to 137.9 nmol/L by LC-MS/MS. Liaison Total Assay - LC-MS/MS showed a negative bias of 5.5 (95% limits of agreement -23.8, 12.7) nmol/L. Differences in 25(OH)D were -4.0 ± 9.0 (±SD) nmol/L if non-HDL-cholesterol was <4.2 mmol/L and -10.2 ± 8.7 nmol/L if ≥4.2 mmol/L (P < 0.0001). Differences in 25(OH)D, if total cholesterol was <5.2 mmol/L, were -3.4 ± 8.6 nmol/L and -9.6 ± 9.3 nmol/L if ≥5.2 mmol/L (P < 0.0001). Serum non-HDL-cholesterol (beta -3.17, P = 0.0014) and total cholesterol (beta -2.77, P = 0.0046) were inversely associated with Liaison Total Assay 25(OH)D (adjusted for age, fasting, and body mass index), but not with LC-MS/MS measured 25(OH)D. Interference by these lipoproteins was not eliminated by standardization of the Liaison Total Assay. Similar associations were observed with triglycerides as for the lipoproteins. CONCLUSIONS: Total cholesterol inversely associates with 25(OH)D, which is likely due to elevated non-HDL-cholesterol lipoprotein or triglyceride interference with the Liaison Total Assay. This is important as elevated cholesterol is common, and an underestimation of vitamin D status could be an unnecessary cause for concern.

Adherence to Vitamin D Supplementation Recommendations for Breastfed Infants and Young Children: An Analysis of Canadian Community Health Survey Data Cycles From 2015 to 2018.

BACKGROUND: In Canada, nutrition policy, as outlined in the Nutrition for Healthy Term Infants recommendations, includes a daily vitamin D supplement of 10 µg (400 IU) for breastfed infants and young children to support adequate vitamin D status. OBJECTIVES: This study aimed to report on adherence to vitamin D supplementation recommendations for breastfed infants (≤12 months); and for children breastfed >12 mo. METHODS: Canadian Community Health Survey (paired-cycles 2015/2016 and 2017/2018) maternal experiences data for infants born 2012-2018 who received any breastmilk formed the sample (n = 7079). Whether the infant was given a vitamin D supplement (yes/no) and the frequency (daily/almost every day, 1-2/wk, or <1/wk) were surveyed. Weighted data (95% CI) were summarized according to breastfeeding history (exclusive to 6 mo and continuing; partial to 6 mo and continuing; and stopped ≤6 mo). Correlates of supplement adherence were explored using logistic regression. RESULTS: Overall, 87.1% (95% CI: 85.9%, 88.3%) of participants reported giving their infant (≤12 mo) a vitamin D supplement, and of these, 83.3% (95% CI: 81.9%, 84.7%) did so daily/almost every day, 12.4% (95% CI: 11.1%, 13.7%) did so 1-2/wk, and 4.3% (95% CI: 3.6%, 5.0%) did so <1/wk. Lower adjusted odds of adherence were observed among participants reporting: stopped breastfeeding ≤6 mo, lower education or income, recent immigration, and overweight prepregnancy body mass index; higher odds of adherence were observed in the western provinces. Regarding mothers of children >12 mo and breastfed (n = 2312), 58.0% (95% CI: 54.9%, 61.1%) gave a vitamin D supplement daily/almost every day. CONCLUSIONS: Adherence to providing a vitamin D supplement to breastfed infants is high in Canada. Nonetheless, we estimate that ∼27% of mothers are nonadherent to daily/almost every day administration of a vitamin D supplement and that adherence declines in children breastfed >12 mo. Further promotion to support uptake of the current guidance may be necessary, particularly for parents of recent immigration or lower socioeconomic status.

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.

Parathyroid hormone-vitamin D dynamics vary according to the definition of vitamin D deficiency in newborn infants.

BACKGROUND: Parathyroid hormone (PTH) is an indirect functional indicator of vitamin D status. Risk of vitamin D deficiency, assessed using circulating 25-hydroxyvitamin D (25(OH)D), is defined as <30 nmol/L by the National Academy of Medicine and alternatively <25 nmol/L in the global consensus recommendation on prevention and management of nutritional rickets. OBJECTIVE: To test PTH concentrations and the odds for elevated values according to vitamin D deficiency cut-points (<30 nmol/L, or <25 nmol/L) in newborn infants. METHODS: Healthy term-born infants (n = 858) were recruited from Montreal, Canada (2016-2019). Obstetric data were obtained from medical records, and demographic factors surveyed. Immunoassays were used to measure newborn (24-36 h) serum PTH and 25(OH)D; 25(OH)D was standardized to National Institute of Standards and Technology (NIST) standard reference materials. Serum PTH was log-transformed before comparing serum 25(OH)D groups (<30 vs. ≥30; or <25 vs. ≥25 nmol/L) using ANCOVA adjusted for infant sex, type of delivery, parity, race, and family income. The odds of elevated PTH (>71.48 pg/mL) were tested using logistic regression, adjusted for the same covariates. RESULTS: Infants (50.2 % female) were 39.6 ± 1.0 weeks gestational age (mean ± SD), and 3.41 ± 0.38 kg. Median serum 25(OH)D was 45.4 (IQR 23.2) nmol/L; 20.5 % had serum 25(OH)D < 30 nmol/L, and 12.4 % <25 nmol/L. Median serum PTH was 30.72 (IQR 33.90) pg/mL, elevated in 12.7 % overall, and higher in infants born with serum 25(OH)D < 25 vs. ≥25 nmol/L (35.96 (IQR 39.20) vs. 30.36 (IQR 32.93) pg/mL, p = 0.0158). The odds of elevated PTH were higher when serum 25(OH)D was <25 nmol/L (ORadj 2.13, 95 % CI: 1.23, 3.69). PTH concentration and the odds of being elevated did not differ according to the 30 nmol/L cut-point. CONCLUSIONS: Based on this study, the definition of vitamin D deficiency relative to bone health as set by the National Academy of Medicine (<30 nmol/L) exceeds the threshold at which PTH is elevated in newborn infants.

Association between toxic metals, vitamin D and preterm birth in the Maternal-Infant research on environmental chemicals study.

BACKGROUND: Toxic metals, like lead, are risk factors for preterm birth (PTB), but few studies have examined low levels found in most Canadians. Vitamin D, which may have antioxidant activity, protects against PTB. OBJECTIVES: In this study, we investigated the impact of toxic metals (lead, mercury, cadmium and arsenic) on PTB and examined if maternal plasma vitamin D concentrations modify these associations. METHODS: We investigated whether concentrations of metals in whole blood measured in early and late pregnancy were associated with PTB (<37 weeks) and spontaneous PTB in 1851 live births from the Maternal-Infant Research on Environmental Chemicals Study using discrete time survival analysis. We also investigated whether the risk of PTB was modified by first-trimester plasma 25-hydroxyvitamin D (25OHD) concentrations. RESULTS: Of 1851 live births, 6.1% (n = 113) were PTBs and 4.9% (n = 89) were spontaneous PTB. A 1 µg/dL increase in blood lead concentrations during pregnancy was associated with an increased risk of PTB (relative risk [RR] 1.48, 95% confidence interval [CI] 1.00, 2.20) and spontaneous PTB (RR 1.71, 95% CI 1.13, 2.60). The risk was higher in women with insufficient vitamin D concentrations (25OHD <50 nmol/L) for both PTB (RR 2.42, 95% CI 1.01, 5.79) and spontaneous PTB (RR 3.04, 95% CI 1.15, 8.04). However, an interaction on the additive scale was not present. Arsenic was associated with a higher risk of PTB (RR 1.10, 95% CI 1.02, 1.19) and spontaneous PTB (RR 1.11, 95% CI 1.03, 1.20) per 1 µg/L. CONCLUSIONS: Gestational exposure to low levels of lead and arsenic may increase the risk of PTB and spontaneous PTB; individuals with insufficient vitamin D may be more susceptible to the adverse effects of lead. Given our relatively small number of cases, we encourage testing of this hypothesis in other cohorts, especially those with vitamin D-deficient populations.

Population Iron Status in Canada: Results from the Canadian Health Measures Survey 2012-2019.

BACKGROUND: In Canada, population iron status estimates are dated (2009-2011) and did not consider the presence of inflammation. OBJECTIVES: This study aimed to update iron status estimates in Canada using serum ferrin (SF) and evaluate different correction methods for inflammation based on c-reactive protein (CRP). METHODS: Data from the Canadian Health Measures Survey cycles 3-6 (2012-2019) formed a multiyear, cross-sectional, nationally representative sample (3-79 y) (n = 21,453). WHO cutoffs for SF and hemoglobin were used to estimate iron deficiency (ID), iron deficiency anemia (IDA), anemia, and elevated iron stores. ID was first estimated without considering inflammation. Correction approaches evaluated were excluding individuals with CRP >5 mg/L, using modified SF cutoffs, and regression correction. RESULTS: Total population uncorrected prevalence estimates were 7% (95% CI: 6.2, 7.9) ID, 6.1% (95% CI: 5.2, 7.0) anemia, and 2.0% (95% CI: 1.6, 2.4) IDA. The uncorrected prevalence of ID was the highest among females of reproductive age with 21.3% (95% CI: 17.6, 25.0) and 18.2% (95% CI: 15.4, 21.1) in 14-18 y and 19-50 y, respectively. Corrected ID estimates were higher than the uncorrected values, independent of the correction approach. Regression correction led to a moderate increase in the prevalence to 10.5% for the total population, whereas applying the higher modified SF cutoffs (70 µg/L for those older than 5 y) led to the largest increases in the prevalence, to 12.6%. Applying modified cutoffs led to implausibly high ID estimates among those with inflammation. Elevated iron stores were identified in 17.2% (95% CI: 16.2, 18.2) of the population, mostly in adult males. CONCLUSIONS: Correction methods for estimating population iron status need further research. Considering the fundamental drawbacks of each method, uncorrected and regression-corrected estimates provide a reasonable range for ID in the Canadian population. Important sex-based differences in iron status and a public health ID problem of moderate magnitude among females of reproductive age are evident in Canada.

Vitamin D Status of People 3 to 79 Years of Age from the Canadian Health Measures Survey 2012-2019.

BACKGROUND: Vitamin D is recognized in bone health and the prevention of rickets and osteomalacia. OBJECTIVE: This study aimed to assess vitamin D status of people in Canada and to identify factors associated with vitamin D inadequacy and deficiency. METHODS: Serum 25-hydroxyvitamin D (25(OH)D) from the Canadian Health Measures Survey (cycles 3-6, n = 21,770, 3-79 y) were evaluated for geometric means and proportions <40 (inadequate) and <30 (risk of deficiency) nmol/L. Factors associated with inadequacy or deficiency were tested using logistic regression. RESULTS: Mean serum 25(OH)D was 57.9 (95% CI: 55.4, 60.5) nmol/L; the prevalence of inadequacy was 19.0% (95% CI: 15.7, 22.3) and risk of deficiency was 8.4% (95% CI: 6.5, 10.3). Prominent dietary factors associated with inadequacy in adults included: not consuming fish compared with ≥1/wk (adjusted ORadj: 1.60; 95% CI: 1.21, 2.11), none compared with ≥1/d for cow's milk (ORadj: 1.41; 95% CI: 1.02, 1.94) or margarine (ORadj: 1.42; 95% CI: 1.08, 1.88); or nonuser compared with user of vitamin D supplements (ORadj: 5.21; 95% CI: 3.88, 7.01). Notable demographic factors included: younger adults compared with 71 to 79 y (19-30 y ORadj: 2.33; 95% CI: 1.66, 3.29); BMI ≥30 compared with <25 kg/m2 (ORadj: 2.30; 95% CI: 1.79, 2.95); lower household income quartile 1 compared with 4 (ORadj: 1.46; 95% CI: 1.00, 2.15); and self-reported Black (ORadj: 8.06; 95% CI: 4.71, 13.81), East/Southeast Asian (ORadj: 3.83; 95% CI: 2.14, 6.85), Middle Eastern (ORadj: 4.57; 95% CI: 3.02, 6.92), and South Asian (ORadj: 4.63; 95% CI: 2.62, 8.19) race compared with White. Similar factors were observed in children and for deficiency. CONCLUSIONS: Most people in Canada have adequate vitamin D status; nonetheless, racialized groups have an elevated prevalence of inadequacy. Further research is required to evaluate if current strategies to improve vitamin D status, including increasing vitamin D in fortified foods and supplements, and dietary guidance to include a source of vitamin D every day help to reduce health inequality in Canada.

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.

Changes in Adiposity without Impacting Bone Health in Nine- to Twelve-Year-Old Children with Overweight and Obesity after a One-Year Family-Centered Lifestyle Behavior Intervention.

Background: Few family-centered lifestyle interventions (FCLIs) for children with overweight or obesity (OW/OB) have assessed regional adiposity and bone health. This study assessed changes in adiposity in 9- to 12-year olds with OW/OB in a 1-year FCLI. Methods: Children were randomized to FCLI (six registered dietitian-led sessions) or no intervention (Control, CTRL). The FCLI focused on physical activity, nutrition education, and behavioral counseling children with families present. Assessments occurred at baseline and every 3 months for 1 year to assess changes in waist circumference (WC), body mass index for age-and-sex Z-scores (BAZ), body composition (dual-energy x-ray absorptiometry), and cardiometabolic biomarkers. Mixed models were used to determine the effects of group and time or group-by-time interactions for all outcomes. Results: Sixty children (age: 11.1 ± 1.1 years, BAZ: 2.7 ± 0.6) were enrolled; 55 participants (n = 28 CTRL, n = 27 FCLI) completed the study. There were no between group differences from baseline to follow-up for any measure. The FCLI group had significant decreases in BAZ over 12 months (-0.18 ± 0.27, p = 0.03) but not CTRL (-0.05 ± 0.32, p = 0.92). WC and android fat mass did not change in FCLI (p > 0.20) but increased in CTRL (p < 0.02). Whole body bone area, content, and areal bone mineral density (aBMD) increased in both groups (p < 0.010); whole body aBMD Z-score decreased by 5.8% and 1.6% in CTRL and FCLI, respectively (p < 0.001). There were no significant within group changes in biomarkers. Conclusion: The FCLI resulted in small reductions in BAZ and a plateau in android fat mass, which suggest that FCLIs are suitable as an intervention for 9- to 12-year-old children with OW/OB. Clinical Trial Registration number: NCT01290016.

SMART goals of children of 6-12 years enrolled in a family-centred lifestyle intervention for childhood obesity: Secondary analysis of a randomized controlled trial.

This study demonstrates how SMART (Specific, Measurable, Attainable, Realistic and Timely) goals set by children in a lifestyle intervention contributed favorably to weight outcomes. Children (6-12 years) set goals with a registered dietitian over six months. Goals were classified according to their type (diet or activity), direction, (increase healthy or decrease unhealthy), and theoretical constructs. Theoretical constructs included the Theory of Planned Behavior's attitudes (i.e., changing beliefs about behaviour outcomes), subjective norm (i.e., incorporation of health recommendations) and perceived behavioural control (i.e., over goal barriers and facilitators). Constructs from a Socio-Ecological Model (family or individual) were also applied. Participants who maintained or decreased their body mass index for-age-and-sex z-scores (BAZ) after six months created significantly more goals related to the subjective norm compared to those whose BAZ increased (p = 0.003). Future interventions using SMART goals should incorporate health recommendations (i.e., the subjective norm) through actionable items among children to promote success.

Perspective: Human Milk Composition and Related Data for National Health and Nutrition Monitoring and Related Research.

National health and nutrition monitoring is an important federal effort in the United States and Canada, and the basis for many of their nutrition and health policies. Understanding of child exposures through human milk (HM) remains out of reach due to lack of current and representative data on HM's composition and intake volume. This article provides an overview of the current national health and nutrition monitoring activities for HM-fed children, HM composition (HMC) and volume data used for exposure assessment, categories of potential measures in HM, and associated variability factors. In this Perspective, we advocate for a framework for collection and reporting of HMC data for national health and nutrition monitoring and programmatic needs, including a shared vision for a publicly available Human Milk Composition Data Repository (HMCD-R) to include essential metadata associated with HMC. HMCD-R can provide a central, integrated platform for researchers and public health officials for compiling, evaluating, and sharing HMC data. The compiled compositional and metadata in HMCD-R would provide pertinent measures of central tendency and variability and allow use of modeling techniques to approximate compositional profiles for subgroups, providing more accurate exposure assessments for purposes of monitoring and surveillance. HMC and related metadata could facilitate understanding the complexity and variability of HM composition, provide crucial data for assessment of infant and maternal nutritional needs, and inform public health policies, food and nutrition programs, and clinical practice guidelines.

Associations between Body Composition and Vitamin D Status in Children with Overweight and Obesity Participating in a 1-Year Lifestyle Intervention.

Background: To examine associations between body composition and vitamin D status in children participating in a lifestyle intervention. Methods: Children (6−12 y, n = 101) with a body mass index (BMI)-for-age >85th percentile were randomized to six dietitian-led behavior counselling sessions or no intervention. Plasma 25-hydroxyvitamin D (25(OH)D), anthropometry, and body composition using dual-energy X-ray absorptiometry were assessed every 3 months for 1 year. For each anthropometry variable (z-scores), tertiles were created to test for differences in 25(OH)D over time (tertile-by-time), and for changes in the z-score (loss, maintain, gain)-by-time, and according to fat patterning (android vs. gynoid) using mixed effects models. Results: The baseline plasma 25(OH)D was 62.2 nmol/L (95%CI: 58.7−65.7), and none < 30 nmol/L. At 6 mo, children with gynoid fat patterning had higher 25(OH)D concentrations than in those with android fat patterning (64.5 ± 1.1 nmol/L vs. 50.4 ± 1.0 nmol/L, p < 0.003, Cohen's f = 0.20). Children with the lowest lean mass index z-score at 9 mo had higher plasma 25(OH)D concentrations than children with the highest z-score at baseline, 3 mo, and 6 mo (p < 0.05, Cohen's f = 0.20). No other significant differences were observed. Conclusion: In this longitudinal study, vitamin D deficiency was not present in children 6−12 y of age with obesity. Reductions in adiposity did not alter the vitamin D status.

Vitamin D supplementation and gross motor development: A 3-year follow-up of a randomized trial.

BACKGROUND: Vitamin D status during pregnancy, early childhood and season-at-birth are implicated in gross motor development (GMD). AIM: To test whether vitamin D intake in infancy and season-at-birth affect GMD in early childhood. STUDY DESIGN: 3-year follow up study of a single-center trial. SUBJECTS: Healthy infants (n = 116) were allocated to 400 (standard-of-care), 800 or 1200 IU/day of vitamin D3 supplementation from 1 to 12 months; n = 70 returned for follow-up at 3-years. OUTCOME MEASURES: The main outcome was GMD using the Peabody Developmental Motor Scales-2 which includes gross motor quotient (GMQ) and stationary, locomotion and object manipulation subtests. RESULTS: GMQ scores were normal (≥85) in 94 %. An interaction between dosage group and season-at-birth (p = 0.01) was observed for GMQ and stationary standardized score; among winter/spring born children, the 1200 IU/d scored higher vs. 400 and 800 IU/d groups. Object manipulation standardized score was higher (p = 0.04) in children in the 1200 vs. 400 IU/d group, without interaction with season-at-birth. CONCLUSIONS: GMD in young children who received 400 IU/d of supplemental vitamin D in infancy is not influenced by season-at-birth. This dose of vitamin D of 400 IU/d as recommended in North America adequately supports GMD. The modest enhancement in GMD with 1200 IU/d in winter/spring born children requires further study.

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.

Blood metals and vitamin D status in a pregnancy cohort: A bidirectional biomarker analysis.

Low 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status, is associated with reduced immune function and adverse pregnancy outcomes, such as preterm birth. Observational studies indicate that long-term, high level exposure to metals such as cadmium (Cd) and lead (Pb) can impact a person's vitamin D status. However, the directionality of the association is uncertain, particularly for low-level exposures. We used three distinct longitudinal data analysis methods to investigate cross-sectional, longitudinal and bidirectional relationships of Cd and Pb biomarkers with 25-hydroxyvitamin D (25OHD) in a Canadian pregnancy cohort. Maternal whole blood Cd and Pb and plasma 25OHD concentrations were measured in the 1st (n = 1905) and 3rd (n = 1649) trimester and at delivery (25OHD only, n = 1542). Our multivariable linear regression analysis showed weak inverse associations between Cd and 25OHD concentrations cross-sectionally and longitudinally while the latent growth curve models showed weak associations with Pb on the 25OHD intercept. In the bidirectional analysis, using cross lagged panel models, we found no association between 1st trimester metals and 3rd trimester 25OHD. Instead, 1st trimester 25OHD was associated with 9% (-15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. These findings suggest the 25OHD may modify metal concentrations in pregnancy and demonstrates the value of controlling for contemporaneous effects and the persistence of a biomarker over time, in order to rule out reverse causation.

Iodine Status of Mother-Infant Dyads from Montréal, Canada: Secondary Analyses of a Vitamin D Supplementation Trial in Breastfed Infants.

BACKGROUND: Most pregnant or lactating women in Canada will not meet iodine requirements without iodine supplementation. OBJECTIVES: To assess the iodine status of 132 mother-infant pairs based on secondary analyses of a vitamin D supplementation trial in breastfed infants from Montréal, Canada. METHODS: Maternal iodine status was assessed using the breastmilk iodine concentration (BMIC). Singleton, term-born infants were studied from 1-36 months of age. Usual (adjusted for within-person variation) iodine intakes were estimated from urinary iodine and creatinine concentrations. Iodine status was assessed using median urinary iodine concentrations (UICs) and by estimating inadequate intakes by the cut-point method using a proposed Estimated Average Requirement for infants 0-6 months of age (72 µg/d). RESULTS: At 1, 3, and 6 months of age, 70%, 63%, and 3% of infants, respectively, were exclusively breastfed. From 1-36 months of age (n = 82-129), the median UICs were ≥100 µg/L (range, 246-403 µg/L), which is the cutoff for adequate intakes set by the WHO for children <2 years. Almost all (98%-99%) infants at 1 and 2 months, 2 and 3 months, and 3 and 6 months of age had usual creatinine-adjusted iodine intakes ≥ 72 µg/d. The median BMIC was higher (P < 0.001) at 1 month compared to 6 months of lactation [1 month, 198 µg/kg (IQR, 124-274; n = 105) and 6 months, 109 µg/kg (IQR, 67-168; n = 78)]. At 1 and 6 months, 96% and 79% of mothers, respectively, had a BMIC ≥ 60 µg/kg, the lower limit of a normal reference range. The percentages of mothers that used a multivitamin-mineral (MVM) supplement containing iodine were 90% in pregnancy and 79% and 59% at 1 and 6 months of lactation, respectively. CONCLUSIONS: The iodine status of infants was adequate throughout infancy. These results support a recommendation that all women who could become pregnant, who are pregnant, or who are breastfeeding take a daily MVM supplement containing iodine.

Evaluation of Increasing Dairy Intake on Bone Density in Postpubertal Youth: A Randomized Controlled Trial Using Motivational Interviewing.

BACKGROUND: Adequate nutrition is important for bone health, especially for bone mineral accretion. OBJECTIVES: The primary objective tested whether increasing dairy intake using the motivational interviewing technique (MInt) improves lumbar spine (LS) bone mineral density (BMD) after 2 y in postpubertal adolescents with habitual dairy intake of <2 dairy servings/d. METHODS: Participants (aged 14-18.9 y) were randomly allocated to: group 1 (control), group 2 (target of 3 dairy servings/d), or group 3 (target of ≥4 dairy servings/d) for 12 mo, with groups 2 and 3 using MInt, with an additional 12-mo nonintervention follow-up. The primary outcome was LS BMD, and secondary outcomes were: whole body, total hip (TH), and 33% distal radius BMD using DXA, bone geometry using peripheral quantitative computed tomography, and bone biomarkers. RESULTS: Ninety-four adolescents (16.6 ± 1.5 y) were recruited. Seventy-six (80.9%) completed the 12-mo assessments. From baseline to 12 mo, dairy intake in female groups 2 and 3 increased by 107% and 208%, respectively; and by 48% and 153% in males of groups 2 and 3, respectively. In females, group 3 had greater increases in TH BMD (4.3% to 7.5%) compared with control (3.7% to 4.9%, P = 0.04) and group 2 (0.0% to 1.7%, P = 0.04) at 12 and 24 mo. No effects due to dairy intake were observed for DXA outcomes in males for radial and tibial volumetric BMD in both sexes. None of the bone biomarkers were different among the dairy groups in females or males. CONCLUSIONS: MInt effectively increased dairy intake with benefits to bone health only in female adolescents with previously low calcium intake who consumed ≥4 dairy servings/d for 12 mo. Larger studies are required to explain the lack of intervention effect in males.

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.

Patterns of Bone Mineral Accretion and Sex Differences in Healthy Term Vitamin D Replete and Breastfed Infants From Montreal, Canada: Bone Mass Reference Data.

Infancy is a period of rapid bone growth and mineral accretion; nonetheless, reference data remain scarce for this age group. The purpose of this report is to generate reference data for bone mass in breastfed vitamin D replete infants and investigate patterns of bone mineral accretion and sex differences. This is a secondary analysis from a double-blinded randomized controlled trial (NCT00381914). Healthy term breastfed (exclusively or mixed) infants were randomized to different doses of oral vitamin D supplementation (400-1600 IU/d) and followed prospectively from 1 to 12 mo. Plasma 25-hydroxyvitamin D (LC-MS/MS), bone mineral content (BMC; whole body (WB) and lumbar spine (LS)) and bone mineral density (BMD; LS) were measured at 1, 3, 6, 9, and 12 mo by dual-energy x-ray absorptiometry (Hologic Discovery 4500A) with no effect of supplementation on bone outcomes. For the purpose of this analysis, 63 infants with adequate plasma 25-hydroxyvitamin D ≥ 50 nmol/L at baseline, were included. Differences over time and between sexes were tested using mixed model repeated measures ANOVA. Infants (31 males, 32 females) were 39.5 ± 1.1 wk gestational age at birth and appropriate for gestational age. WB BMC, LS BMC, and LS BMD increased by 143.2%, 116.8%, and 31.1% respectively across infancy. WB BMC was higher (4.2% - 9.4%; p = 0.03) in males than in females across the study. After adjusting WB BMC for weight, length or head BMC, sex differences were not evident. LS BMC and LS BMD did not vary by sex. LS BMD growth charts for both sexes combined, were generated using LMS chartmaker. WB BMC more than doubles during the first year of life confirming the importance of skeletal growth and the need for age-specific reference data in infancy. Sex differences in BMC, if any, are mostly driven by differences in body size.

Evaluation of Increasing Dairy Intake on Bone Density in Postpubertal Youth: A Randomized Controlled Trial Using Motivational Interviewing.

BACKGROUND: Adequate nutrition is important for bone health, especially for bone mineral accretion. OBJECTIVES: The primary objective tested whether increasing dairy intake using the motivational interviewing technique (MInt) improves lumbar spine (LS) bone mineral density (BMD) after 2 y in postpubertal adolescents with habitual dairy intake of <2 dairy servings/d. METHODS: Participants (aged 14-18.9 y) were randomly allocated to: group 1 (control), group 2 (target of 3 dairy servings/d), or group 3 (target of ≥4 dairy servings/d) for 12 mo, with groups 2 and 3 using MInt, with an additional 12-mo nonintervention follow-up. The primary outcome was LS BMD, and secondary outcomes were: whole body, total hip (TH), and 33% distal radius BMD using DXA, bone geometry using peripheral quantitative computed tomography, and bone biomarkers. RESULTS: Ninety-four adolescents (16.6 ± 1.5 y) were recruited. Seventy-six (80.9%) completed the 12-mo assessments. From baseline to 12 mo, dairy intake in female groups 2 and 3 increased by 107% and 208%, respectively; and by 48% and 153% in males of groups 2 and 3, respectively. In females, group 3 had greater increases in TH BMD (4.3% to 7.5%) compared with control (3.7% to 4.9%, P = 0.04) and group 2 (0.0% to 1.7%, P = 0.04) at 12 and 24 mo. No effects due to dairy intake were observed for DXA outcomes in males for radial and tibial volumetric BMD in both sexes. None of the bone biomarkers were different among the dairy groups in females or males. CONCLUSIONS: MInt effectively increased dairy intake with benefits to bone health only in female adolescents with previously low calcium intake who consumed ≥4 dairy servings/d for 12 mo. Larger studies are required to explain the lack of intervention effect in males.