Elisa Holmlund-Suila

High-dose vitamin d intervention in infants--effects on vitamin d status, calcium homeostasis, and bone strength.

CONTEXTnGuidelines in Finland recommend 10 μg of vitamin D3 daily for all infants. Recent observations suggest that this may be insufficient to maintain optimal serum 25-hydroxyvitamin D (S-25-OHD).nnnOBJECTIVEnThe aim of the study was to evaluate effects of various vitamin D doses and determine a dose ensuring S-25-OHD of at least 80 nmol/liter in infants without signs of vitamin D excess.nnnDESIGNnWe conducted a randomized double-blind intervention study. Cord blood was obtained at birth for S-25-OHD; 113 infants were randomized to receive vitamin D3 10, 30, or 40 μg/d from age 2 wk to 3 months.nnnSETTINGnAn investigator-initiated study was performed in a single maternity hospital in Helsinki, Finland.nnnMAIN OUTCOME MEASURESnS-25-OHD, calcium homeostasis, and skeletal characteristics were evaluated with peripheral quantitative computed tomography at age 3 months.nnnRESULTSnBaseline S-25-OHD was similar in all three groups (median, 53 nmol/liter). At 3 months, the mean S-25-OHD values were 88, 124, and 153 nmol/liter, and the minimum values were 46, 57, and 86 nmol/liter in the groups receiving 10, 30, and 40 μg (ANOVA; P < 0.001). No hypercalcemia occurred; plasma calcium, serum PTH, and urine calcium excretion was similar between the groups. Peripheral quantitative computed tomography showed a trend toward larger tibial total bone and cortical bone area with higher vitamin D doses.nnnCONCLUSIONnVitamin D3 supplementation with up to 40 μg/d from age 2 wk to 3 months was safe and caused no hypercalcemia or hypercalciuria. The 40-μg dose maintained S-25-OHD above 80 nmol/liter in all infants. More extensive and longer intervention studies are necessary to assess long-term effects.

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 (u200a=u200a 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.

25-hydroxyvitamin D correlates with inflammatory markers in cord blood of healthy newborns

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 20u2009ng/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.

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

BackgroundVitamin 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 strength2.infections and immunity3.allergy, atopy and asthma4.cognitive development5.genetic regulation of mineral homeostasisMethods/DesignVIDI, a randomised controlled double-blinded single-centre intervention study is conducted in infants from the age of 2xa0weeks to 24xa0months. Participants, recruited at Helsinki Maternity Hospital, are randomised to receive daily either 10xa0μg (400xa0IU) or 30xa0μg (1 200xa0IU) of vitamin D3 supplementation. Both groups are assessed at 6xa0months of age for calcium homeostasis, and at 12 and 24xa0months of age for parameters associated with bone strength, growth, developmental milestones, infections, immunity, atopy-related diseases, and genetic factors involved in these functions.DiscussionThe 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 registrationClinicalTrials.gov, NCT01723852, registration date 6.11.2012.

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.

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 (ΔFGF23 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.

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

Sex and Iron Modify Fibroblast Growth Factor 23 Concentration in 1-Year-Old Children

ContextnFibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, but its regulation is inadequately characterized.nnnObjectivenTo examine FGF23 regulators, especially sex and iron status, in early childhood.nnnDesignnA cross-sectional study involving 1-year-old children.nnnSetting and ParticipantsnHealthy 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.nnnMain Outcome MeasuresnIntact and C-terminal FGF23 concentrations and iron status at 1 year of age.nnnResultsnIntact 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).nnnConclusionsnAt 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.

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.

Reply to Letter to the Editor to Maternal vitamin D status during pregnancy in Europe: the two sides of the story

association between 25(OH)D concentration and inflammatory biomarkers in cord blood in vitamin D sufficient population [4]. Although the clinical importance of this cross-sectional finding remains unclear, a possibility for U-shaped relationship between 25(OH)D and the inflammatory state of a newborn could not be abandoned. In Finland, vitamin D food fortification has been proven to be efficient in increasing the vitamin D intake in adult population resulting in a decrease in vitamin D deficiency [5]. The recommended use of vitamin D supplementation during pregnancy has also been well adapted. These public health policies have, in our country, been sufficient to improve maternal and newborn vitamin D status. The coming years will show how this translates to well-being of the mothers and their children. We agree with Karras et al. that prospective randomized studies are needed. While these results are awaited, research to define an optimal vitamin D status in all age groups should continue. It may well be that future findings will allow us to further increase the recommendations, but until then, caution should be exercised. At population level, the emphasis should be in achieving a sufficient maternal vitamin D status by both food fortification and with moderate dose of supplemental vitamin D.