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The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer., Competing Interests: Declaration of interests H.H. and I.C.H. received funding from Alzheimer’s Research UK and the Dunhill Medical Trust Foundation. M.A.P. reported receiving grants and personal and travel fees from Roche, Novartis, Merck, and Biogen outside the submitted work. M. Scholz receives funding from Pfizer Inc. for a project not related to this research. C.D. serves as a consultant of Novartis Pharmaceuticals. B.F. has received educational speaking fees from Medice. N.J. and P.M.T. are MPIs of a research grant from Biogen Inc. for work unrelated to the contents of this manuscript. D.J.W. received funding from the Stroke Foundation/British Heart Foundation. D.J.S. has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda, and Vistagen. H.H. received funding from MRC, Wellcome Trust, and NIHR UCLH BRC. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm, and Janssen Cilag as well as research funding from Fresenius Medical Care., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

Context: Childhood hyperphosphatasemia is usually transient and may be associated with infections. It remains less well known how hyperphosphatasemia is related to growth and bone mineralization., Objective: We explored alkaline phosphatase (ALP) concentrations and prevalence of hyperphosphatasemia, and their association with vitamin D, growth, infections, and bone parameters in healthy children., Methods: The study was a secondary analysis of a vitamin D intervention trial. Participants received vitamin D3 10 or 30 µg daily from age 2 weeks to 2 years. Children with data on ALP at 12 and/or 24 months (n = 813, girls 51.9%) were included. Anthropometrics and bone parameters were measured at 12 and 24 months. Infections were recorded prospectively by the parents., Results: Boys had higher ALP than girls at 12 months (median [IQR] 287 [241-345] U/L vs 266 [218-341] U/L; P = .02). At 24 months concentrations were lower than at 12 months (240 [202-284]; P < .001) but without sex difference. The prevalence of hyperphosphatasemia (ALP > 1000 U/L) at 12 months was 5.3% and at 24 months 0.6%. Body size, growth rate, and bone mineral content associated positively with ALP, while vitamin D intervention had no effect. Infants with hyperphosphatasemia were smaller than infants with ALP ≤ 1000 U/L. Hyperphosphatasemia was not associated with previous infections., Conclusion: Approximately 5% of infants had hyperphosphatasemia at 12 months, but <1% at 24 months. ALP concentrations and hyperphosphatasemia were associated with sex, anthropometry, and bone mineralization. Infections did not contribute to hyperphosphatasemia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 D 3 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, p variant = 0.009). Minor alleles of rs11063112 were associated with a greater age-related decrease in phosphate concentration (p interaction = 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 (p interaction <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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Enlund-Cerullo, Holmlund-Suila, Valkama, Hauta-alus, Rosendahl, Andersson, Pekkinen and Mäkitie.)

Higher maternal vitamin D concentration during pregnancy is associated with better child mental health. Negative affectivity, an early-emerging temperamental trait, indicates an increased risk of psychopathology. We investigated if maternal early/mid-pregnancy 25-hydroxyvitamin D (25(OH)D) and neonatal cord blood 25(OH)D concentrations are associated with Negative affectivity in infancy. We studied term-born infants from the vitamin D Intervention in Infants study (VIDI, n = 777, follow-up rate 80%, Finland), and the Generation R Study (n = 1505, follow-up rate 40%, Netherlands). We measured maternal serum 25(OH)D at 6-27 weeks (VIDI) or 18-25 weeks (Generation R) of pregnancy, and cord blood 25(OH)D at birth (both cohorts). Caregivers rated infant Negative affectivity at 11.7 months (VIDI) or 6.5 months (Generation R) using the Revised Infant Behavior Questionnaire. Using linear regression, we tested associations between 25(OH)D and Negative affectivity adjusted for infant age, sex, season of 25(OH)D measurement, maternal age, education, smoking, and body-mass-index. Per 10 nmol/l increase in maternal early/mid-pregnancy 25(OH)D, infant Negative affectivity decreased by 0.02 standard deviations (95% confidence interval [CI] - 0.06, - 0.004) in VIDI, and 0.03 standard deviations (95% CI - 0.03, - 0.01) in Generation R. Cord blood 25(OH)D was associated with Negative affectivity in Generation R (- 0.03, 95% CI - 0.05, - 0.01), but not VIDI (0.00, 95% CI - 0.02, 0.02). Lower maternal 25(OH)D concentrations were consistently associated with higher infant Negative affectivity, while associations between cord blood 25(OH)D concentrations and Negative affectivity were less clear. Maternal vitamin D status during early- and mid-pregnancy may be linked with early-emerging differences in offspring behavior., (© 2021. The Author(s).)

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 D 3 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)., (© 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).)

Background & Aims: During early childhood the risk of iron deficiency (ID) is high. Serum ferritin serves as a marker of iron status. We explored prevalence of ID and iron deficiency anemia (IDA), and identified determinants of iron status in infants and toddlers., Methods: We performed a secondary analysis of the Vitamin D intervention in infants (VIDI) study in Finnish healthy term infants. According to study protocol, at 12- and 24-months of age iron status, growth and dietary intakes were evaluated. ID was defined as serum ferritin <10 μg/L and IDA as serum ferritin <10 μg/L and Hb <112 g/L. For the present study, altogether 766 children provided data (N = 498 infants at 12 months, N = 508 toddlers at 24 months)., Results: ID prevalence increased from 14% in infants to 20% in toddlers. IDA prevalence was 3% at both time points. In infants, ID and IDA were more common in boys than in girls (19% vs. 9%, p = 0.001 and 5% vs. 1%, p = 0.039) but no sex-difference in toddlers was observed. Of infants, 30% had daily iron intake below average requirement of 5 mg/day. Higher daily iron intake per body weight (mg/kg) independently associated with higher infant serum ferritin (B (95% CI) 0.30 (0.04, 0.56), p = 0.026). Correlation between iron intake and ferritin was stronger in infants with ID than in infants without ID. Breastfeeding was more common (63% vs. 35%, p < 0.001) among ID infants than in infants without ID. In toddlers, frequent consumption of milk products independently associated with lower ferritin (B (95% CI) -0.03 (-0.05, -0.01), p = 0.001). Consumption of meat and fish associated with better iron status. Serum ferritin at both time points associated with duration of gestation and growth. The association of growth and ferritin was age-dependent in boys, while in girls, faster growth associated consistently with lower ferritin., Conclusions: In Northern European healthy infants and toddlers ID is common. The intake of iron remains below recommendations and food consumption and iron intake associate with iron status. Further studies are warranted to assess significance of ID on child development and clinical health outcomes. The project protocol is registered at ClinicalTrials.gov: NCT01723852., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 ± 0.15 mmol/L) to 24 months (1.6 ± 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 Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

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.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Fibroblast growth factor 23 (FGF23) participates in phosphate, calcium and vitamin D metabolism. In children these interactions and modifying factors are largely unknown., Participants and Methods: This study evaluates temporal changes and modifiers of FGF23 concentrations from 12 to 24 months, in healthy children, participating in a randomized vitamin D intervention (VIDI). Participants received vitamin D 3 of 10 or 30 μg/day from age 2 weeks to 24 months. At 12 and 24 months, growth measurements and venous blood samples were obtained for analyses of intact (iFGF23) and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), calcium, phosphate, parathyroid hormone, iron and ferritin. Changes in FGF23 and modifying factors were examined by linear mixed models., Results: The study included 594 infants. Girls had higher iFGF23 than boys (p < 0.001 for both 12 and 24 months), cFGF23 did not differ between the sexes. Adjusted mean iFGF23 decreased from 41.4 to 38.1 pg/mL in boys (p < 0.001) and from 45.2 to 42.5 pg/mL in girls (p = 0.002). Adjusted mean cFGF23 decreased from 2.89 to 2.00 pmol/L in boys (p < 0.001) and from 2.92 to 1.93 pmol/L in girls (p < 0.001). Iron modified FGF23 in both sexes, associating positively with iFGF23 and inversely with cFGF23. In girls, 25-OHD modified iFGF23. In boys, season modified FGF23, possibly through seasonal differences in 25-OHD. Vitamin D intervention dose did not affect FGF23., Conclusions: FGF23 decreases from 12 to 24 months. Girls have higher iFGF23 than boys, at both time points. Iron modifies FGF23 in both sexes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Peripheral quantitative computed tomography (pQCT) is a useful tool to assess detailed bone characteristics. Its utility in infants is however limited due to lack of reference data and technical challenges. The purpose of this study was to provide data on length- and weight-adjusted pQCT values and to present a quality grading system for healthy children aged 12 and 24 months., Material and Methods: As a part of the Vitamin D intervention in Infants (VIDI) trial, we collected pQCT and anthropometric data from 855 children at 12 months and from 784 children at 24 months. Bone mineral content (BMC; mg/mm), volumetric bone mineral density (vBMD; mg/cm 3 ), cross-sectional area (CSA; mm 2 ), polar-moment of inertia (PMI; mm 4 ), and periosteal circumference (PsC; mm) were assessed for total bone at 20% distal site of the left tibia using pQCT (Stratec XCT2000L). We evaluated the impact of scan quality on bone measures. Total bone parameters were assessed for boys and girls separately. The means of the bone parameters were also compared in relation to age. The associations between bone parameters and weight, length, sex and scan quality were analyzed., Results: We included scans with sufficient quality (Grade 1-5) in the final analyses: 679/855 (79%) at 12 months and 709/784 (90%) at 24 months. Altogether 39% of the scans at 12 months and 51% at 24 months were of good or excellent quality (Grade 1-2). Scan quality had an impact on BMCs at 12 and 24 months (p = 0.001 and p = 0.017, respectively) but not on other bone parameters. Boys presented greater total bone BMC, CSA, PMI and PsC values at 12 and 24 months but vBMDs were similar. All bone parameters showed a significant increase between 12 and 24 months for both sexes. When adjusting bone parameters for weight, length and scan quality, differences between sexes disappeared. Weight was the strongest modifier of BMC, CSA, PMI and PsS at 12 and 24 months., Conclusions: This study increases our understanding on bone parameters in young children and demonstrates the suitability of pQCT in bone research in infants. The described pQCT data and scan quality grading system should prove useful in evaluating data reliability in research settings., Clinical Trial Registration Number: NCT1723852., (Copyright © 2020. Published by Elsevier Inc.)

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., Competing Interests: OM declares consultancy for Kyowa Kirin, Alexion and Sandoz. All other authors declare no conflict of interest.

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., (Copyright © 2019 Endocrine Society.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: The relationship of maternal and infant 25-hydroxyvitamin D concentration [25(OH)D] with infant growth is unclear., Objective: Our objective was to explore whether 25(OH)D in pregnancy, umbilical cord blood (UCB), or in infancy was associated with infant growth., Design: This study involved 798 healthy infants and their mothers in Finland. We assessed 25(OH)D during pregnancy, from UCB at birth, and from the infant at the age of 12 months., Main Outcome Measures: Infant length, weight, length-adjusted weight, and head circumference at 6 and 12 months and midupper-arm circumference at 12 months., Results: Of the mothers and infants, 96% and 99% were vitamin D sufficient [25(OH)D ≥50 nmol/L], respectively. Mothers with pregnancy 25(OH)D >125 nmol/L had the shortest, lightest (in weight), and thinnest (in length-adjusted weight) infants at 6 months (P for all < 0.05). For each 10 nmol/L higher UCB 25(OH)D, the infants were 0.03 SD score (SDS) shorter at 6 months (95% CI -0.05 to -0.01), adjusted for birth size, infant 25(OH)D, and parental height. Higher UCB 25(OH)D associated with smaller head circumference at 6 and 12 months (P for all <0.05) but attenuated after adjustments. Mothers with pregnancy 25(OH)D >125 nmol/L had the thinnest infants at 12 months (P = 0.021). For each 10 nmol/L higher infant 25(OH)D, the infants were 0.03 SDS lighter (-0.05 to -0.01) and 0.03 SDS thinner (-0.05 to 0.00) at 12 months., Conclusions: Our results suggest that high pregnancy, cord blood, and infant vitamin D concentration may have disadvantageous effects on infant growth.

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.

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.

Background: Maternal vitamin D status has been associated with both gestational diabetes mellitus (GDM) and fetal growth restriction, however, the evidence is inconsistent. In Finland, maternal vitamin D status has improved considerably due to national health policies. Our objective was to compare maternal 25-hydroxy vitamin D concentrations [25(OH)D] between mothers with and without GDM, and to investigate if an association existed between maternal vitamin D concentration and infant birth size., Methods: This cross-sectional study included 723 mother-child pairs. Mothers were of Caucasian origin, and infants were born at term with normal birth weight. GDM diagnosis and birth size were obtained from medical records. Maternal 25(OH)D was determined on average at 11 weeks of gestation in pregnancy and in umbilical cord blood (UCB) at birth., Results: GDM was observed in 81 of the 723 women (11%). Of the study population, 97% were vitamin D sufficient [25(OH)D ≥ 50 nmol/L]. There was no difference in pregnancy 25(OH)D concentration between GDM and non-GDM mothers (82 vs 82 nmol/L, P = 0.99). Regression analysis confirmed no association between oral glucose tolerance test results and maternal 25(OH)D (P > 0.53). Regarding the birth size, mothers with optimal pregnancy 25(OH)D (≥ 80 nmol/L) had heavier newborns than those with suboptimal pregnancy 25(OH)D (P = 0.010). However, mothers with optimal UCB 25(OH)D had newborns with smaller head circumference than those with suboptimal 25(OH)D (P = 0.003), which was further confirmed as a linear association (P = 0.024)., Conclusions: Maternal vitamin D concentration was similar in mothers with and without GDM in a mostly vitamin D sufficient population. Associations between maternal vitamin D status and birth size were inconsistent. A sufficient maternal vitamin D status, specified as 25(OH)D above 50 nmol/L, may be a threshold above which the physiological requirements of pregnancy are achieved., Trial Registration: The project protocol is registered in ClinicalTrials.gov in November 8, 2012 ( NCT01723852 ).

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., Competing Interests: Liisa Korkalo is a board member of the company TwoDads Oy and has received a lecture fee from the company Valio Oy. Other authors declare no conflicts of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Context: Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, but its regulation is inadequately characterized., Objective: To examine FGF23 regulators, especially sex and iron status, in early childhood., Design: A cross-sectional study involving 1-year-old children., Setting and Participants: Healthy term infants with a birth weight appropriate for gestational age were recruited to an ongoing vitamin D trial at Kätilöopisto Maternity Hospital, Helsinki, Finland. At 12-month follow-up visits, serum FGF23, 25-hydroxyvitamin D (25OHD), phosphate, ionized calcium, parathyroid hormone, and iron status were measured. All 721 children (51% girls) with complete data were included., Main Outcome Measures: Intact and C-terminal FGF23 concentrations and iron status at 1 year of age., Results: Intact FGF23 was greater in girls than in boys [median, 44.4 pg/mL; interquartile range (IQR), 36.8 to 51.9; median, 40.9 pg/mL; IQR, 34.5 to 49.0, respectively; P < 0.001]. C-terminal FGF23 was similar in boys and girls (median, 2.8 pmol/L; IQR, 2.1 to 3.7; median, 2.9 pmol/L; IQR, 2.2 to 3.7, respectively; P = 0.393). The iron concentration was positively associated with intact FGF23 and was the strongest modifier of intact FGF23 (regression coefficient, 0.498; 95% confidence interval, 0.333 to 0.663; P < 0.001) with ferritin, season, ionized calcium, 25OHD, and sex as other covariates. The association between iron and C-terminal FGF23 was inversely related (regression coefficient, -0.072; 95% confidence interval, -0.092 to -0.051; P < 0.001)., Conclusions: At 1 year of age, FGF23 status was different in girls and boys, with intact FGF23 concentrations higher in girls. Iron modified FGF23 concentrations, with intact FGF23 higher and C-terminal lower, in those with greater iron concentrations., (Copyright © 2017 Endocrine Society)

Background: Vitamin D is a potent immunomodulator and may play a role in the development of the fetal innate immune functions. The aim of our study was to evaluate inflammatory markers in cord blood of healthy newborns in relation to vitamin D status at birth., Methods: We studied the concentrations of inflammatory markers, matrix metalloproteinase 8 (MMP-8) and high sensitivity CRP (hs-CRP), and 25-hydroxyvitamin D (25(OH)D) in cord blood of 939 healthy term infants born to mothers of Caucasian origin. We evaluated perinatal factors that affect the concentrations of MMP-8 and hs-CRP, and further explored associations between cord blood 25(OH)D and these inflammatory biomarkers., Results: Majority (99%) of the cohort was vitamin D sufficient (>50 nmol/l or 20 ng/ml). We observed a positive correlation between cord blood 25(OH)D and MMP-8 concentrations, and between 25(OH)D and hs-CRP concentrations. After adjustment for potential confounders (parity, antenatal antibiotic treatment, gestational age, mode of delivery, and maternal prepregnancy BMI), the association of 25(OH)D with MMP-8 and hs-CRP remained significant., Conclusion: Cord blood 25(OH)D correlates with inflammatory markers MMP-8 and hs-CRP. The findings may reflect the diverse immunomodulatory functions of vitamin D in the innate immune response of the newborn.

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.

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., (© 2017 S. Karger AG, Basel.)