Low-grade inflammation from prenatal period to age 6-8 years in a Vitamin D trial.

BACKGROUND: Low-grade systemic inflammation measured as high sensitivity C-reactive protein (hs-CRP) has been associated with non-communicable disease risk. We assessed whether prenatal inflammation and early-childhood vitamin D are associated with inflammation until age 6-8. METHODS: We analyzed blood hs-CRP and 25-hydroxy vitamin D [25(OH)D] in pregnancy, at birth from umbilical cord blood (UCB), from offspring at ages 1, 2, and 6-8 years in the Vitamin D Intervention in Infants (VIDI) study. VIDI was a randomized-controlled trial of vitamin D supplementation of 10 µg/day or 30 µg/day from age 2 weeks until 2 years in 975 infants recruited in 2013-14, with follow-up at age 6-8 in 2019-21 (n = 283). RESULTS: Pregnancy hs-CRP was associated with UCB hs-CRP (r = 0.18, p < 0.001) but not independently with childhood hs-CRP (Estimate [95% CI] 0.04 [<-0.00, 0.09]). Higher UCB hs-CRP was associated independently with higher hs-CRP until 6-8 years (0.20 [0.12, 0.29]). Infant vitamin D dose had no effect on longitudinal hs-CRP (6-8 years, 0.11 [-0.04, 0.25]). Childhood 25(OH)D were associated positively with hs-CRP until age 6-8 (0.01 [>0.00, 0.01]). CONCLUSION: Our results indicate that in children, inflammation, assessed by hs-CRP, persists from birth until 6-8 years. We observed positive associations between 25(OH)D and hs-CRP in vitamin D-sufficient children. IMPACT: High sensitivity C-reactive protein (hs-CRP) concentrations tract from birth to age 8 years Our novel finding suggests a long-lasting pro-inflammatory phenotype in the child Higher vitamin D concentration - but not dose - is associated with higher childhood hs-CRP Chronic disease risk related to inflammation may in part originate from the prenatal period or early childhood Further studies are needed to investigate the effects of inflammation on long-term clinical health outcomes.

Variation in the fibroblast growth factor 23 (FGF23) gene associates with serum FGF23 and bone strength in infants.

Introduction: The effects of genetic variation in fibroblast growth factor 23 (FGF23) are unclear. This study explores the associations of single-nucleotide polymorphisms (SNPs) of FGF23 with phosphate and vitamin D metabolism and bone strength in early childhood. Methods: The study is part of the vitamin D intervention in infant (VIDI) trial (2013-2016), in which healthy term infants born to mothers of Northern European origin received vitamin D3 supplementation of 10 or 30 µg/day from 2 weeks to 24 months of age (ClinicalTrials.gov NCT01723852). Intact and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), parathyroid hormone, phosphate, and peripheral quantitative computed tomography (pQCT)-derived bone strength parameters were analyzed at 12 and 24 months. The study included 622 VIDI participants with genotyping data on FGF23 SNPs rs7955866, rs11063112, and rs13312770. Results: Rs7955866 minor allele homozygotes had lowest cFGF23 at both time-points (mixed model for repeated measurements, pvariant = 0.009). Minor alleles of rs11063112 were associated with a greater age-related decrease in phosphate concentration (pinteraction = 0.038) from 12 to 24 months. Heterozygotes of rs13312770 had the greatest total bone mineral content (total BMC), cross-sectional area (total CSA), and polar moment of inertia (PMI) at 24 months (ANOVA p = 0.005, 0.037, and 0.036, respectively). Rs13312770 minor alleles were associated with a greater increase of total BMC, but a smaller increase of total CSA and PMI, during follow-up (pinteraction <0.001, 0.043, and 0.012, respectively). Genotype of FGF23 did not modify 25-OHD. Conclusion: The study finds that genetic variation in FGF23 modifies cFGF23, phosphate, and pQCT-derived bone strength parameters from 12 to 24 months of age. These findings potentially promote an understanding of the regulation of FGF23 and its role in bone metabolism and temporal changes thereof during early childhood.

Effect of Vitamin D3 Supplementation in the First 2 Years of Life on Psychiatric Symptoms at Ages 6 to 8 Years: A Randomized Clinical Trial.

Importance: Vitamin D is associated with neurodevelopment, but causality, critical windows, and potentials for modification remain unknown. Objective: To determine the impact of high-dose (1200 IU) vs standard-dose (400 IU) vitamin D3 supplementation during the first 2 years on psychiatric symptoms at ages 6 to 8 years and whether the impact is different in children with lower vs higher maternal vitamin D3 levels; lower vs higher levels were defined as 25-hydroxyvitamin D (25[OH]D) less than 30 ng/mL vs 30 ng/mL or greater. Design, Setting, and Participants: This study was a long-term follow-up of the double-blind randomized clinical trial (RCT) Vitamin D Intervention in Infants (VIDI) conducted at a single center in Helsinki, Finland, at 60 degrees north latitude. Recruitment for VIDI took place in 2013 to 2014. Follow-up data for secondary data analysis were collected 2020 to 2021. VIDI originally included 987 term-born infants; 546 of these individuals participated in the follow-up at ages 6 to 8 years, among whom 346 individuals had data on parent-reported psychiatric symptoms. Data were analyzed from June 2022 to March 2023. Interventions: There were 169 infants randomized to receive 400-IU and 177 infants randomized to receive 1200-IU oral vitamin D3 supplementation daily from ages 2 weeks to 24 months. Main Outcomes and Measures: Primary outcomes were internalizing, externalizing, and total problems scores, with clinically significant problems defined as T scores of 64 or greater in the Child Behavior Checklist questionnaire. Results: Among 346 participants (164 females [47.4%]; mean [SD] age, 7.1 [0.4] years), the vitamin D3 dose was 400 IU for 169 participants and 1200 IU for 177 participants. Clinically significant internalizing problems occurred in 10 participants in the 1200-IU group (5.6% prevalence) compared with 20 participants (11.8%) in the 400-IU group (odds ratio, 0.40; 95% CI, 0.17-0.94; P = .04) after adjustment for sex, birth season, maternal depressive symptoms at birth, and parental single status at follow-up. In a post hoc subgroup analysis, 48 children in the 400-IU group with maternal 25(OH)D concentrations less than 30 ng/mL had higher internalizing problems scores compared with children in the 1200-IU group, including 44 children with maternal 25(OH)D concentrations below 30 ng/mL (adjusted mean difference, 0.49; 95% CI, 0.09-0.89; P = .02) and 91 children with maternal concentrations above 30 ng/mL (adjusted mean difference, 0.37; 95% CI, 0.03-0.72; P = .04). Groups did not differ in externalizing or total problems. Conclusions and Relevance: This randomized clinical trial found that higher-than-standard vitamin D3 supplementation in the first 2 years decreased risk of internalizing problems at ages 6 to 8 years. Trial Registration: ClinicalTrials.gov Identifiers: NCT01723852 (VIDI) and NCT04302987 (VIDI2).

Effects of a 2-Year Early Childhood Vitamin D3 Intervention on Tooth Enamel and Oral Health at Age 6-7 Years.

INTRODUCTION: The aim of the study was to compare the effects of a 30 µg/day versus 10 µg/day vitamin D supplementation, given during the two first years of life, on oral health at the age of six to 7 years. METHODS: In 2013-2016, we conducted a randomized, double-blinded, clinical trial from age 2 weeks to 2 years of daily vitamin D3 supplementation (10 vs. 30 µg), including 975 healthy infants. For the present follow-up study at age 6-7 years, a sample of 123 children underwent oral examination by investigators blinded to the intervention group. Tooth enamel defect and caries findings, oral rinse active matrix metalloproteinase-8 levels, and tooth eruption were recorded. The intervention groups were compared with χ2 and Mann-Whitney U tests. Associations of the oral health outcomes were evaluated with correlation analysis and logistic regression. RESULTS: Of the children (median age 7.4 years, 51% boys), 56% belonged to the 30 µg intervention group. Developmental defect of enamel (DDE) was found in 39% of the children in the 10 µg intervention group and in 53% of the 30 µg group (p = 0.104). In total, 94% of children were vitamin D sufficient (25[OH]D ≥50 nmol/L) and 88% had caries-free teeth. No associations were found between vitamin D intervention group in infancy and oral health or the presence of DDE. CONCLUSION: Daily supplementation with 10 µg vitamin D3 in the Northern Hemisphere seems adequate in healthy children younger than 2 years in ensuring good oral health at early school age.

Collagen X Biomarker (CXM), Linear Growth, and Bone Development in a Vitamin D Intervention Study in Infants.

Collagen X biomarker (CXM) is suggested to be a biomarker of linear growth velocity. However, early childhood data are limited. This study examines the relationship of CXM to the linear growth rate and bone development, including the possible modifying effects of vitamin D supplementation. We analyzed a cohort of 276 term-born children participating in the Vitamin D Intervention in Infants (VIDI) study. Infants received 10 µg/d (group-10) or 30 µg/d (group-30) vitamin D3 supplementation for the first 2 years of life. CXM and length were measured at 12 and 24 months of age. Tibial bone mineral content (BMC), volumetric bone mineral density (vBMD), cross-sectional area (CSA), polar moment of inertia (PMI), and periosteal circumference (PsC) were measured using peripheral quantitative computed tomography (pQCT) at 12 and 24 months. We calculated linear growth as length velocity (cm/year) and the growth rate in length (SD unit). The mean (SD) CXM values were 40.2 (17.4) ng/mL at 12 months and 38.1 (12.0) ng/mL at 24 months of age (p = 0.12). CXM associated with linear growth during the 2-year follow-up (p = 0.041) but not with bone (p = 0.53). Infants in group-30 in the highest tertile of CXM exhibited an accelerated mean growth rate in length compared with the intermediate tertile (mean difference [95% CI] -0.50 [-0.98, -0.01] SD unit, p = 0.044) but not in the group-10 (p = 0.062) at 12 months. Linear association of CXM and growth rate until 12 months was weak, but at 24 months CXM associated with both length velocity (B for 1 increment of √CXM [95% CI] 0.32 [0.12, 0.52] cm/yr, p = 0.002) and growth rate in length (0.20 [0.08, 0.32] SD unit, p = 0.002). To conclude, CXM may not reliably reflect linear growth from birth to 12 months of age, but its correlation with growth velocity improves during the second year of life. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Effect of High-Dose vs Standard-Dose Vitamin D Supplementation on Neurodevelopment of Healthy Term Infants: A Randomized Clinical Trial.

Importance: Vitamin D may be important for neurodevelopment. The optimal daily dose of vitamin D for early brain development is not known. Objectives: To test whether a higher (1200 IU) vs standard (400 IU) dose of vitamin D3 has beneficial effects on neurodevelopment in the first 2 years of life and whether serum 25-hydroxyvitamin D concentration is associated with neurodevelopment. Design, Setting, and Participants: This double-blind, interventional randomized clinical trial involved healthy infants born full-term between January 1, 2013, and June 30, 2014, at a maternity hospital in Helsinki, Finland, at the 60th northern latitude. Two-year follow-up was conducted by May 30, 2016. Data analysis was by the intention-to-treat principle. Data were analyzed from November 1, 2020, to May 31, 2021. Interventions: Randomization of 404 infants to receive 400 IU of oral vitamin D3 supplementation daily and 397 infants to receive 1200 IU of oral vitamin D3 supplementation daily from 2 weeks to 24 months of age. Main Outcomes and Measures: Primary outcomes were child total developmental milestone scores at 12 and 24 months of age measured using the Ages and Stages Questionnaire (total score is calculated as a mean of the 5 subscale scores: total score range, 0-60, where 0 indicates delay in all developmental domains and 60 indicates that the child can master all age-specific skills) as well as externalizing, internalizing, and dysregulation problems and competencies scores at 24 months measured using the Infant-Toddler Social and Emotional Assessment (range 0-2, where 0 indicates no problems or no competencies and 2 indicates a high level of problems or a high level of competencies; variables were standardized to the mean [SD] of 0 [1]). Secondary outcomes were specific skills, problems, and competencies derived from these questionnaires. Results: Of the 987 families recruited, 495 children were randomly assigned to receive 400 IU of vitamin D3, and 492 children were randomly assigned to receive 1200 IU of vitamin D3. A total of 801 families participated in the follow-up at 12 and/or 24 months, with 404 children (207 girls [51.2%]) in the 400-IU group and 397 children (198 girls [49.9%]) in the 1200-IU group. All children were of Northern European ethnicity. No differences were found between the 400-IU group and the 1200-IU group in the mean (SD) adjusted Ages and Stages Questionnaire total score at 12 months (45.0 [7.1] vs 46.2 [7.9]; mean difference [MD], 1.17 [95% CI, -0.06 to 2.38]) or 24 months (50.9 [5.3] vs 51.5 [5.5]; MD, 0.48 [95% CI, -0.40 to 1.36]). No differences were found between the 400-IU group and the 1200-IU group at 24 months in the mean (SD) adjusted Infant-Toddler Social and Emotional Assessment externalizing domain score (-0.07 [1.00] vs 0.07 [0.98]; MD, 0.15 [95% CI, -0.01 to 0.31]), internalizing domain score (0.04 [1.06] vs -0.02 [0.98]; MD, -0.07 [95% CI, -0.24 to 0.1.0]), dysregulation domain score (-0.00 [1.04] vs 0.02 [0.96]; MD, 0.02 [95% CI, -0.14 to 0.18]), or competencies score (-0.02 [1.02] vs 0.01 [1.02]; MD, 0.03 [95% CI, -0.13 to 0.20]). The 1200-IU group did have a higher risk in the adjusted model of scoring 1.5 SDs or more on the externalizing domain score (odds ratio, 2.33 [95% CI, 1.19-4.56]; P = .01). Levels of serum 25-hydroxyvitamin D were not associated with the primary outcomes. Conclusions and Relevance: Higher-than-standard vitamin D3 doses provide no systematic benefits for child neurodevelopment up to 2 years of age. However, the potential disadvantageous effects of higher doses could not be fully excluded; even if minimal, the potential nonbeneficial effects of higher-than-standard doses warrant further studies in which both safety and benefits should be evaluated. Trial Registration: ClinicalTrials.gov Identifier: NCT01723852.

Phosphate Concentrations and Modifying Factors in Healthy Children From 12 to 24 Months of Age.

CONTEXT: Phosphate homeostasis and its modifiers in early childhood are inadequately characterized. OBJECTIVE: To determine physiological plasma phosphate concentration and modifying factors in healthy infants at 12 to 24 months of age. DESIGN: This study included 525 healthy infants (53% girls), who participated in a randomized vitamin D intervention trial and received daily vitamin D3 supplementation of either 10 or 30 µg from age 2 weeks to 24 months. Biochemical parameters were measured at 12 and 24 months. Dietary phosphate intake was determined at 12 months. MAIN OUTCOME MEASURES: Plasma phosphate concentrations at 12 and 24 months of age. RESULTS: Mean (SD) phosphate concentration decreased from 12 months (1.9 ±â€…0.15 mmol/L) to 24 months (1.6 ±â€…0.17 mmol/L) of age (P < 0.001 for repeated measurements). When adjusted by covariates, such as body size, creatinine, serum 25-hydroxyvitamin D, intact and C-terminal fibroblast growth factor 23, mean plasma phosphate was higher in boys than girls during follow-up (P = 0.019). Phosphate concentrations were similar in the vitamin D intervention groups (P > 0.472 for all). Plasma iron was associated positively with plasma phosphate at both time points (B, 0.006 and 0.005; 95% CI, 0.004-0.009 and 0.002-0.008; P < 0.001 at both time points, respectively). At 24 months of age, the main modifier of phosphate concentration was plasma creatinine (B, 0.007; 95% CI 0.003-0.011, P < 0.001). CONCLUSION: Plasma phosphate concentration decreased from age 12 to 24 months. In infants and toddlers, the strongest plasma phosphate modifiers were sex, iron, and creatinine, whereas vitamin D supplementation did not modify phosphate concentrations.

The Effects of Vitamin D Supplementation During Infancy on Growth During the First 2 Years of Life.

CONTEXT: The relationship between maternal and infant vitamin D and early childhood growth remains inadequately understood. OBJECTIVE: This work aimed to investigate how maternal and child 25-hydroxyvitamin D (25[OH]D) and vitamin D supplementation affect growth during the first 2 years of life. METHODS: A randomized, double-blinded, single-center intervention study was conducted from pregnancy until offspring age 2 years. Altogether 812 term-born children with complete data were recruited at a maternity hospital. Children received daily vitamin D3 supplementation of 10 µg (group 10) or 30 µg (group 30) from age 2 weeks to 2 years. Anthropometry and growth rate were measured at age 1 and 2 years. RESULTS: Toddlers born to mothers with pregnancy 25(OH)D greater than 125 nmol/L were at 2 years lighter and thinner than the reference group with 25(OH)D of 50 to 74.9 nmol/L (P < .010). Mean 2-year 25(OH)D concentrations were 87 nmol/L in group 10 and 118 nmol/L in group 30 (P < .001). When group 30 was compared with group 10, difference in body size was not statistically significant (P > .053), but group 30 had slower growth in length and head circumference between 6 months and 1 year (P < .047), and more rapid growth in weight and length-adjusted weight between 1 and 2 years (P < .043). Toddlers in the highest quartile of 25(OH)D (> 121 nmol/L) were shorter (mean difference 0.2 SD score [SDS], P = .021), lighter (mean difference 0.4 SDS, P = .001), and thinner (in length-adjusted weight) (mean difference 0.4 SDS, P = .003) compared with the lowest quartile (< 81.2 nmol/L). CONCLUSION: Vitamin D and early childhood growth may have an inverse U-shaped relationship.

Genetic variation in GC and CYP2R1 affects 25-hydroxyvitamin D concentration and skeletal parameters: A genome-wide association study in 24-month-old Finnish children.

Vitamin D is important for normal skeletal homeostasis, especially in growing children. There are no previous genome-wide association (GWA) studies exploring genetic factors that influence vitamin D metabolism in early childhood. We performed a GWA study on serum 25-hydroxyvitamin D (25(OH)D) and response to supplementation in 761 healthy term-born Finnish 24-month-old children, who participated in a randomized clinical trial comparing effects of 10 µg and 30 µg of daily vitamin D supplementation from age 2 weeks to 24 months. Using the Illumina Infinium Global Screening Array, which has been optimized for imputation, a total of 686085 markers were genotyped across the genome. Serum 25(OH)D was measured at the end of the intervention at 24 months of age. Skeletal parameters reflecting bone strength were determined at the distal tibia at 24 months using peripheral quantitative computed tomography (pQCT) (data available for 648 children). For 25(OH)D, two strong GWA signals were identified, localizing to GC (Vitamin D binding protein) and CYP2R1 (Vitamin D 25-hydroxylase) genes. The GWA locus comprising the GC gene also associated with response to supplementation. Further evidence for the importance of these two genes was obtained by comparing association signals to gene expression data from the Genotype-Tissue Expression project and performing colocalization analyses. Through the identification of haplotypes associated with low or high 25(OH)D concentrations we used a Mendelian randomization approach to show that haplotypes associating with low 25(OH)D were also associated with low pQCT parameters in the 24-month-old children. In this first GWA study on 25(OH)D in this age group we show that already at the age of 24 months genetic variation influences 25(OH)D concentrations and determines response to supplementation, with genome-wide significant associations with GC and CYP2R1. Also, the dual association between haplotypes, 25(OH)D and pQCT parameters gives support for vertical pleiotropy mediated by 25(OH)D.

Genetic Variation of the Vitamin D Binding Protein Affects Vitamin D Status and Response to Supplementation in Infants.

CONTEXT: Single nucleotide polymorphisms (SNPs) of the vitamin D binding protein encoding the GC (group component) gene affect 25-hydroxyvitamin D (25OHD) concentrations, but their influence on vitamin D status and response to vitamin D supplementation in infants is unknown. OBJECTIVE: To study GC genotype-related differences in 25OHD concentrations and the response to supplementation during a vitamin D intervention study in infants. DESIGN: In this randomized controlled trial, healthy term infants received vitamin D3 (10 or 30 µg/d) from 2 weeks to 24 months of age. GC SNPs rs2282679, rs4588, rs7041, and rs1155563 were genotyped. rs4588/7041 diplotype and haplotypes of rs2282679, rs4588, and rs7041 (Haplo3SNP) and of all four SNPs (Haplo4SNP) were determined. MAIN OUTCOME MEASURES: 25OHD measured in cord blood at birth and at 12 and 24 months during intervention. RESULTS: A total of 913 infants were included. Minor allele homozygosity of all studied GC SNPs, their combined haplotypes, and rs4588/rs7041 diplotype 2/2 were associated with lower 25OHD concentrations at all time points in one or both intervention groups [analysis of covariance (ANCOVA) P < 0.043], with the exception of rs7041, which did not affect 25OHD at birth. In the high-dose supplementation group receiving 30 µg/d vitamin D3, but not in those receiving 10 µg/d, genotype of rs2282679, rs4588, and rs7041; diplotype; and Haplo3SNP significantly affected intervention response (repeated measurement ANCOVA Pinteraction < 0.019). Minor allele homozygotes had lower 25OHD concentrations and smaller increases in 25OHD throughout the intervention. CONCLUSIONS: In infants, vitamin D binding protein genotype affects 25OHD concentration and efficiency of high-dose vitamin D3 supplementation.

High-Dose Vitamin D Supplementation Does Not Prevent Allergic Sensitization of Infants.

OBJECTIVE: To investigate the effect of vitamin D supplementation dose on allergic sensitization and allergic diseases in infants, and to evaluate whether vitamin D status in pregnancy and at birth are associated with infant allergy outcomes. STUDY DESIGN: Altogether, 975 infants participated in a randomized, controlled trial of daily vitamin D supplementation of 10 µg (400 IU) or 30 µg (1200 IU) from the age of 2 weeks. At 12 months of age, food and aeroallergen IgE antibodies were measured, and the occurrence of allergic diseases and wheezing were evaluated. RESULTS: We found no differences between the vitamin D supplementation groups in food (OR, 0.98; 95% CI, 0.66-1.46) or aeroallergen sensitization at 12 months (OR, 0.76; 95% CI,0.34-1.71). Allergic diseases or wheezing did not differ between groups, except for milk allergy which occurred more often in infants administered 30 µg vitamin D compared with the 10 µg dose (OR, 2.23; 95% CI, 1.00-4.96). Infants with high cord blood 25-hydroxyvitamin D (≥100 nmol/L) had a higher risk of food allergen sensitization compared with those with lower 25(OH)D concentration (75-99.9 nmol/L; OR, 2.00; 95% CI, 1.19-3.39). CONCLUSIONS: High-dose vitamin D supplementation did not prevent allergic sensitization, allergic diseases, or wheezing during the first year of life. In contrast, we observed an increased risk of milk allergy in infants randomized to higher vitamin D supplementation, and an increased risk of allergic sensitization in infants with high cord blood vitamin D status, indicating a possible adverse effect of high concentrations of vitamin D.

Effect of Higher vs Standard Dosage of Vitamin D3 Supplementation on Bone Strength and Infection in Healthy Infants: A Randomized Clinical Trial.

Importance: Although guidelines for vitamin D supplementation in infants have been widely implemented, they are mostly based on studies focusing on prevention of rickets. The optimal dose for bone strength and infection prevention in healthy infants remains unclear. Objective: To determine whether daily supplementation with 1200 IU of vitamin D3 increases bone strength or decreases incidence of infections in the first 2 years of life compared with a dosage of 400 IU/d. Design, Setting, and Participants: A randomized clinical trial involving a random sample of 975 healthy term infants at a maternity hospital in Helsinki, Finland. Study recruitment occurred between January 14, 2013, and June 9, 2014, and the last follow-up was May 30, 2016. Data analysis was by the intention-to-treat principle. Interventions: Randomization of 489 infants to daily oral vitamin D3 supplementation of 400 IU and 486 infants to 1200 IU from age 2 weeks to 24 months. Main Outcomes and Measures: Primary outcomes were bone strength and incidence of parent-reported infections at 24 months. Results: Of the 975 infants who were randomized, 485 (49.7%) were girls and all were of Northern European ethnicity. Eight hundred twenty-three (84.4%) completed the 24-month follow-up. We found no differences between groups in bone strength measures, including bone mineral content (mean difference, 0.4 mg/mm; 95% CI, -0.8 to 1.6), mineral density (mean difference, 2.9 mg/cm3; 95% CI, -8.3 to 14.2), cross-sectional area (mean difference, -0.9 mm2; 95% CI, -5.0 to 3.2), or polar moment of inertia (mean difference, -66.0 mm4, 95% CI, -274.3 to 142.3). Incidence rates of parent-reported infections did not differ between groups (incidence rate ratio, 1.00; 95% CI, 0.93-1.06). At birth, 914 of 955 infants (95.7%) were vitamin D sufficient (ie, 25-hydroxyvitamin D [25(OH)D] concentration ≥20.03 ng/mL). At 24 months, mean 25(OH)D concentration was higher in the 1200-IU group than in the 400-IU group (mean difference, 12.50 ng/mL; 95% CI, 11.22-13.78). Conclusions and Relevance: A vitamin D3 supplemental dose of up to 1200 IU in infants did not lead to increased bone strength or to decreased infection incidence. Daily supplementation with 400 IU vitamin D3 seems adequate in maintaining vitamin D sufficiency in children younger than 2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01723852.

Season, dietary factors, and physical activity modify 25-hydroxyvitamin D concentration during pregnancy.

PURPOSE: The objectives of this cross-sectional study were to define maternal and umbilical cord blood (UCB) 25-hydroxyvitamin D (25(OH)D) to characterize maternal factors modifying 25(OH)D during pregnancy and predict UCB 25(OH)D in two subgroups with Declined [Δ25(OH)D <0 nmol/l] and Increased [Δ25(OH)D >0 nmol/l] 25(OH)D concentration. METHODS: A complete dataset was available from 584 women. 25(OH)D was determined at gestational weeks 6-13 and in UCB. Baseline characteristics were collected retrospectively using questionnaires. Δ25(OH)D was calculated as UCB 25(OH)D-early pregnancy 25(OH)D. Dietary patterns were generated with principal component analysis. Multivariate regression models were applied. RESULTS: Vitamin D deficiency was scarce, since only 1% had 25(OH)D concentration <50 nmol/l both in early pregnancy and in UCB. Shared positive predictors of UCB 25(OH)D in the subgroups of Declined and Increased, were early pregnancy 25(OH)D (P < 0.001) and supplemental vitamin D intake (P < 0.04). For the Increased subgroup summer season at delivery (P = 0.001) and "sandwich and dairy" dietary pattern characterized with frequent consumption of vitamin D fortified margarine and milk products (P = 0.009) were positive predictors of UCB 25(OH)D. Physical activity (P = 0.041) and maternal education (P = 0.004) were additional positive predictors in the Declined group CONCLUSIONS: Maternal and newborn vitamin D status was sufficient, thus public health policies in Finland have been successful. The key modifiable maternal determinants for 25(OH)D during pregnancy, and of the newborn, were supplemental vitamin D intake, frequent consumption of vitamin D fortified foods, and physical activity.

Food and Nutrient Intake and Nutrient Sources in 1-Year-Old Infants in Finland: A Cross-Sectional Analysis.

The infant diet has short- and long-term health consequences. Updated data regarding the dietary intake of Finnish infants are lacking. The objectives of this study were to describe infant food and nutrient intake and to identify food sources of the nutrients. Altogether, 739 healthy infants were studied. Dietary intake and breastfeeding frequency were assessed with a three-day food record at 1 year of age. Dietary intake was calculated separately for non-breastfed and breastfed infants. One-third (36%) of the infants were partially breastfed and 95% consumed mass-produced baby foods. The infants' diet consisted mainly of infant formula, dairy milk, porridges, fruit and berry foods, and meat dishes. The mean vegetable, fruit and berry consumption was 199 g/day. Most nutrient intakes were adequate except for fat, linoleic acid, vitamin D and iron from food. Mean sucrose intake, as a percentage of total energy intake (E%), was 5-6 E%. High protein intake (>20 E%) was observed in 19% of non-breastfed infants. Overall, the infants' diet was favorable since vegetable and fruit consumption was reasonably high and nutrient intake was mostly adequate. However, the fat intake was lower, and protein intake higher than recommended. Increasing the consumption of vegetable oils and reducing the intake of red meat and dairy milk may further improve the diet of 1-year-olds.

No Severe Hypercalcemia with Daily Vitamin D3 Supplementation of up to 30 µg during the First Year of Life.

BACKGROUND: Vitamin D supplementation is widely recommended for infants, but the optimal dose remains unclear. High intake may result in hypercalcemia. METHODS: We evaluated the incidence of hypercalcemia during the first year of life in a cohort of 987 healthy children who received 10 or 30 µg of vitamin D3 supplementation daily. Ionized calcium (Ca-ion) was analyzed at 6 and 12 months, and serum 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentration at 12 months. Severe hypercalcemia was defined as Ca-ion exceeding the reference limit (1.16-1.39 mmol/L) by 10%. RESULTS: No severe hypercalcemia occurred. Mild hypercalcemia (1.40-1.52 mmol/L) was present at 6 months in 28% and at 12 months in 2% of infants. At 12 months, 25-OHD ranged between 23 and 241 nmol/L (median 97), and PTH was between undetectable and 104 pg/mL (median 24) and was below the reference range (11.5-78.4 pg/mL) in 11%. 25-OHD and Ca-ion correlated positively (r = 0.149), and 25-OHD was slightly higher in the 12 infants with mild hypercalcemia (median 97 vs. 110 nmol/L, p = 0.046). CONCLUSIONS: Vitamin D3 supplementation of 10 or 30 µg did not cause severe hypercalcemia. Mild hypercalcemia was more prevalent at 6 months than at 12 months, and was associated weakly with 25-OHD at 12 months.

Towards evidence-based vitamin D supplementation in infants: vitamin D intervention in infants (VIDI) - study design and methods of a randomised controlled double-blinded intervention study.

BACKGROUND: Vitamin D is important for bone mass accrual during growth. Additionally, it is considered a requirement for a multitude of processes associated with, for example, the development of immunity. Many countries apply vitamin D supplementation strategies in infants, but the guidelines are not based on scientific evidence and aim at prevention of rickets. It remains unclear whether the recommended doses are sufficient for the wide array of other effects of vitamin D. The VIDI trial performed in Finland is the first large randomised controlled study for evaluation of the effects of different vitamin D supplemental doses in infancy on: 1. bone strength 2. infections and immunity 3. allergy, atopy and asthma 4. cognitive development 5. genetic regulation of mineral homeostasis METHODS/DESIGN: VIDI, a randomised controlled double-blinded single-centre intervention study is conducted in infants from the age of 2 weeks to 24 months. Participants, recruited at Helsinki Maternity Hospital, are randomised to receive daily either 10 µg (400 IU) or 30 µg (1 200 IU) of vitamin D3 supplementation. Both groups are assessed at 6 months of age for calcium homeostasis, and at 12 and 24 months of age for parameters associated with bone strength, growth, developmental milestones, infections, immunity, atopy-related diseases, and genetic factors involved in these functions. DISCUSSION: The study enables evaluation of short and long term effects of supplemental vitamin D on growth, immune functions and skeletal and developmental parameters in infants, and the effects of genetic factors therein. The results enable institution of evidence-based guidelines for vitamin D supplementation in infancy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01723852 , registration date 6.11.2012.

Obese young adults exhibit lower total and lower free serum 25-hydroxycholecalciferol in a randomized vitamin D intervention.

OBJECTIVE: Although obesity is a risk factor for vitamin D insufficiency, its impact on vitamin D-binding protein (DBP) concentration, and thereby possibly also on free 25OHD, is less well known. Our aim was to compare total and free serum 25OHD, and DBP concentrations between obese and normal-weight young adults at baseline and their responses to cholecalciferol supplementation. DESIGN: A 12-week randomized, double-blinded clinical trial. PATIENTS: Obese subjects N = 18 (BMI = 38, 67% men) with severe childhood-onset obesity and 24 normal-weight subjects (BMI = 23, 46% men), age between 15 and 25 years, were randomized into two groups to receive either placebo or cholecalciferol 50 µg (2000 IU) daily. MEASUREMENTS: At baseline, 6-week and 12-week blood samples and anthropometric measurements were collected; baseline body composition was assessed by dual-energy X-ray absorptiometry. RESULTS: At baseline, obese subjects had, compared with normal-weight, lower total and free serum 25OHD (49 vs 62 nmol/l, P = 0·041; 2·8 vs 4·7 pg/ml, P = 0·001), without differences in DBP concentrations (309 vs 346 µg/ml, P = 0·212). Cholecalciferol 50 µg per day increased both total and free 25OHD (ancova P < 0·001 and P = 0·021). The response of total 25OHD to supplementation was inferior in the obese compared with normal-weight subjects (P = 0·027). On the contrary, the change in free 25OHD concentration was similar in groups (P = 0·487). CONCLUSIONS: Obese young adults exhibit lower total and free 25OHD concentration, which is not directly explained by differences in DBP status. The response of free 25OHD to supplementation did not differ between obese and normal-weight subjects.

Fibroblast Growth Factor 23 Concentrations Reflect Sex Differences in Mineral Metabolism and Growth in Early Infancy.

BACKGROUND: The role of fibroblast growth factor 23 (FGF23) in the regulation of mineral homeostasis in early life is inadequately understood. We aimed to explore the effects of vitamin D supplementation on serum FGF23 and to elucidate longitudinal changes in FGF23, in addition to studying its association with mineral metabolism in early infancy. METHODS: Altogether 113 healthy infants received vitamin D3 10, 30 or 40 µg/day from age 0.5 to 3.0 months. Cord blood at birth and capillary blood samples at 3 months were analyzed for serum 25-hydroxyvitamin D, parathyroid hormone, phosphate, calcium and intact and C-terminal FGF23. RESULTS: In repeated-measures ANCOVA, intact FGF23 concentration increased with time (p < 0.001) and C-terminal FGF23 decreased (p < 0.001). At 3 months, girls had a higher concentration of intact FGF23 (51 vs. 26 pg/ml, p < 0.001) and a greater increase over time (x0394;FGF23 intact 45 vs. 16 pg/ml, p = 0.001) than boys. Vitamin D did not affect serum intact or C-terminal FGF23 concentrations. Girls showed a positive correlation between phosphate and intact FGF23 (p = 0.004), whereas in boys phosphate and C-terminal FGF23 correlated inversely (p = 0.006). CONCLUSIONS: A substantial sex-related difference in intact FGF23 concentration exists during early infancy, possibly related to differences in skeletal growth between boys and girls.

Vitamin D deficiency in children with a chronic illness-seasonal and age-related variations in serum 25-hydroxy Vitamin D concentrations.

INTRODUCTION: Children and adolescents with a chronic illness have potential risk factors for vitamin D deficiency. An optimal vitamin D status might have multiple health effects. This study evaluated vitamin D status and its association with age, gender, and season in a large cohort of chronically ill Finnish patients at a tertiary pediatric outpatient clinic. A cross-sectional register-based study was carried out, involving altogether 1351 children (51% boys, age range 0.2-18 years), who visited the outpatient clinic during 2007-2010 and had their vitamin D status (S-25-OHD) determined. A post-doc analysis was conducted to identify predisposing and preventing factors for vitamin D deficiency. RESULTS: Almost half (47%) of the S-25-OHD values were consistent with subnormal vitamin D status (S-25-OHD <50 nmol/L) while only 12% were >80 nmol/L. Age and season were the most important determinants for S-25-OHD concentration. Mean S-25-OHD concentration differed between age groups (Kruskal-Wallis; p<0.001), adolescents being at highest risk for vitamin D insufficiency. Young age and vitamin D supplementation were preventive factors for deficiency, while non-Finnish ethnic background was a predisposing factor. S-25-OHD showed significant seasonal variation in children older than 6 years. In the whole cohort, S-25-OHD was on average 13 nmol/L higher in summer than in winter, and the prevalence of vitamin D deficiency ( =  S-25-OHD <37.5 nmol/l) varied from 11% in summer to 29% in winter. CONCLUSIONS: The finding that almost half of the studied Finnish children with a chronic illness had suboptimal vitamin D status is alarming. Inferior vitamin D status was noted in adolescents compared with younger children, suggesting that imbalance between intake and requirement evolves with age. Although less common during summer, subnormal vitamin D status was still observed in 28% of those evaluated in summer. Clinicians should identify individuals at risk and actively recommend vitamin D supplementation.