Vitamin D deficiency and supplementation : studies from infancy to young adulthood

Vitamin D deficiency in infancy and childhood impairs normal bone development and growth: defective bone mineralization leads to rickets. For many decades in Finland, vitamin D supplementation in infants has been successful in preventing rickets. However, along with increasing knowledge of non-skeletal vitamin D actions, optimal serum 25-hydroxyvitamin D (25OHD) concentration, has been under debate. The optimal vitamin D status and the dose of supplemental vitamin D in different populations may differ considerably. This doctoral thesis aimed to define the prevalence of vitamin D deficiency (serum 25OHD less than 50 nmol/l) in Finnish children, focusing on individuals with high risk of vitamin D deficiency, and studying in chronically ill children the factors that further increase the prevalence of low serum 25OHD concentration. Vitamin D interventions in infants and young adults enabled examination of the effect and safety of higher than currently recommended vitamin D supplementation, and exploring vitamin D and mineral metabolism in more detail. The study populations comprised 113 healthy term newborns and 42 young adults who participated in vitamin D intervention, and 1,335 children followed at Children s Hospital Helsinki between 2007 and 2010 for a chronic illness. The vitamin D interventions were double-blinded controlled randomized trials. The newborns received either 10, 30 or 40 µg of vitamin D3 daily from 2 weeks to 3 months, and blood samples were obtained at baseline and at 3 months. The young adults were either normal weight (n=24), or suffered from severe childhood-onset obesity (n=18). Both groups received either placebo or 50 µg of vitamin D3 daily for 12 weeks. Blood samples were taken at baseline, 6 and 12 weeks. Data on chronically ill children were collected in a retrospective manner from the hospital laboratory database. The prevalence of vitamin D deficiency exceeded 40% in the study cohorts: especially adolescents and obese individuals were at risk for low 25OHD concentration. Seasonal variation was evident in school-age children, with the lowest prevalence of vitamin D deficiency in summer, and the highest prevalence in winter and spring. In younger children, vitamin D deficiency was less prevalent, and seasonal variation was lacking. Daily vitamin D3 supplementation with 30 to 40 µg in infants, and 50 µg in young adults was safe in short-term follow-up. With good adherence to intervention, both 30 and 40 µg dosing increased infant 25OHD concentration to more than 80 nmol/l. The vitamin D3 intervention did not affect serum intact fibroblast growth factor 23 (FGF23) concentrations, but a distinct sex difference was observed, girls having higher concentration than boys at three months of age. Obesity associated with inferior response to vitamin D3 supplementation. Obese individuals receiving 50 µg vitamin D3 daily achieved similar 25OHD concentrations as normal-weight subjects who received placebo. Chronically ill children and obese subjects need individualized vitamin D supplementation and follow-up.D-vitamiinin puute lapsuus- ja nuoruusiässä aiheuttaa luuston puutteellisen mineraalistumisen, riisitaudin, johon liittyy luuston ja kokonaiskasvun häiriintyminen. Suomessa on jo usean vuosikymmenen ajan ehkäisty riisitautia antamalla vastasyntyneille ja pienille lapsille säännöllistä D-vitamiinilisää. Samalla kun tieto luuston ulkopuolisista D-vitamiinivaikutuksista on lisääntynyt, keskustelu parhaasta mahdollisesta veren D-vitamiinipitoisuudesta on kiihtynyt. Ihanteellinen 25OHD-pitoisuus ja tarvittava D-vitamiinilisän suuruus voivat vaihdella huomattavasti eri populaatioiden ja yksilöiden välillä. Tässä vaitöskirjatutkimuksessa selvitettiin D-vitamiinin puutoksen yleisyyttä lapsilla ja nuorilla, joilla on suuri riski kärsiä D-vitamiinin puutoksesta. Seerumin 25OHD-pitoisuus alle 50 nmol/l määriteltiin D-vitamiinin puutteeksi. Tutkimuksessa pyrittiin selvittämään matalalle 25OHD-pitoisuudelle altistavia tekijöitä. Nykyistä suositusta suuremman D-vitamiinilisän tehoa ja turvallisuutta sekä vaikutuksia luuston aineenvaihduntaan tutkittiin vastasyntyneillä ja nuorilla aikuisilla. Helsingin Lastenklinikalla vuosien 2007 ja 2010 välisenä aikana poliklinikkaseurannassa olleiden pitkäaikaissairaiden lasten 25OHD-määritykset poimittiin sairaalan laboratoriotietokannasta. Tämä poikittaistutkimus koostui 1335 lapsen tiedoista. Vastasyntyneiden D-vitamiinitutkimukseen osallistui 113 täysiaikaisena syntynyttä imeväistä, jotka saivat sokkoutetusti joko 10, 30 tai 40 µg D3-vitamiinia päivässä 2 viikon iästä 3 kuukauden ikään saakka. Verinäytteet otettiin napasuonesta syntymän jälkeen ja 3 kuukauden iässä ihopistonäytteenä. Nuorten aikuisten D-vitamiinitutkimukseen osallistui 18 nuorta aikuista, jotka oli vaikea lapsuusiällä alkanut lihavuus, ja 24 heille valittua samanikäistä ja normaalipainoista verrokkia. Molemmat ryhmät arvottiin saamaan sokkoutetusti joko lumevalmistetta tai 50 µg D3-vitamiinia päivässä 12 viikon ajan. Seurantakäynneillä (lähtötilanne, 6 ja 12 viikkoa) otettiin verinäytteet. Yli 40 % kaikista 25OHD-pitoisuuksista oli alle 50 nmol/l, ja jopa yli puolella yli 10-vuotiaista pitkäaikaissairaista ja lihavista nuorista todettiin D-vitamiinin puutos. Kouluikäisillä lapsilla havaittiin merkittävää vuodenaikaisvaihtelua 25OHD-pitoisuudessa. D-vitamiinin puutos oli yleisintä talvella ja keväällä ja harvinaisinta kesällä. Alle kouluikäisillä vuodenaikaisvaihtelua ei havaittu, ja heillä D-vitamiinin puutos oli muita harvinaisempaa. Nykysuositusta korkeampi päivittäinen D3-vitamiinilisä osoittautui turvalliseksi sekä aikuisilla että vastasyntyneillä. Vastasyntyneillä 30 ja 40 µg:n vuorokausiannos D3-vitamiinia nosti 25OHD-pitoisuuden yli 80 nmol/l. D-vitamiinilisä ei vaikuttanut fosfaatin aineenvaihduntaan osallistuvan seerumin fibroblastikasvutekijä 23:n (FGF23) pitoisuuteen, mutta aktiivisen FGF23:n pitoisuuksissa oli selvä ero sukupuolten välillä: kolmen kuukauden iässä pitoisuus oli tytöillä korkeampi kuin pojilla. Lihavuuteen liittyi huonompi vaste D3-vitamiinille: 50 µg:n vuorokausiannos nosti lihavien aikuisten 25OHD-pitoisuuden samalle tasolle kuin lumevalmistetta saaneilla normaalipainoisilla

D-vitamiinia lapsille - mitä tiedämme annosvastaavuudesta?

Teema : lasten lääkehoit

Miten D-vitamiini vaikuttaa lasten luustossa ja muualla elimistössä?

VertaisarvioituD-vitamiini vaikuttaa luuston ja mineraalien aineenvaihduntaan, mutta sillä on vaikutuksia myös muualla kuin luustossa. Se osallistuu satojen geenien säätelyyn. Aktiivista D-vitamiinia muodostuu munuaisissa. Myös useat kudokset ja solut pystyvät tuottamaan sitä paikallisesti. Vitamiinilisän käyttö suosituksen mukaan turvaa yleensä D-vitamiinin riittävän saannin terveille suomalais¬lapsille. Suuremmasta annoksesta ei näytä olevan lisähyötyä.Peer reviewe

Iron status in early childhood is modified by diet, sex and growth : Secondary analysis of a randomized controlled vitamin D trial

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 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. (C) 2021 The Authors. Published by Elsevier Ltd.Peer reviewe

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

Author summary The effect of vitamin D continues to be highly debated in various health outcomes, including bone health. In this first study of children this young we searched for genes that modify vitamin D metabolism in early childhood using a genome-wide analysis of almost 700,000 genetic variants in a cohort of 761 healthy children participating in a vitamin D intervention study. We show that genetic variation in the genes coding for Vitamin D binding protein (GC) and Vitamin D 25-hydroxylase (CYP2R1) are important determinants for serum 25-hydroxyvitamin D concentration in 2-year-old children. Genetic variants within the GC gene also affect how the child responds to vitamin D supplementation. Moreover, our findings suggest that in 2-year-old children vitamin D concentration, even when within the normal range, influences bone strength as children with genetic constellations associating with lower vitamin D concentration and poorer response to vitamin D supplementation also have weaker bones.Peer reviewe

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 D-3 supplementation of 10 mu g (group 10) or 30 mu g (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 .053), but group 30 had slower growth in length and head circumference between 6 months and 1 year (P 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.Peer reviewe

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

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 Katiloopisto 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.Peer reviewe

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

Publisher Copyright: © 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).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.Peer reviewe

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 mu g (400 IU) or 30 mu g (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.Peer reviewe

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 mu g (400 IU) or 30 mu g (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 mu g vitamin D compared with the 10 mu g 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.Peer reviewe