Vitamin D and extraskeletal effects in children : Studies on infections, allergies and inflammation

Vitamin D is essential for normal childhood growth and bone development. For almost 90 years, vitamin D supplementation has been recommended for children in Finland. Besides its essential effects on bone and mineral metabolism, vitamin D has several extraskeletal actions and is an important modulator of the immune system. Vitamin D status is defined by serum 25-hydroxyvitamin D concentration (25(OH)D), and a 25(OH)D concentration ≥ 50 nmol/L is usually regarded as an indicator of vitamin D sufficiency. However, this may only apply to skeletal health; the optimal vitamin D status for immune defense and overall health remains unestablished. The main aim of this thesis was to study the extraskeletal effects of vitamin D focusing on infections, allergies and inflammation. The effect of high-dose vitamin D supplementation, as compared with the standard recommended dose, in prevention of childhood infections and allergic diseases was evaluated. The study enabled examination of vitamin D status of Finnish children at various ages and determination of factors influencing vitamin D status. The Vitamin D Intervention in Infants study (VIDI) comprised 975 healthy term infants randomized to daily vitamin D3 supplementation of either 10 µg or 30 µg for the first two years of life. Data on infectious diseases were collected prospectively from the parents. Occurrence of allergic diseases was determined by questionnaires and specific IgE antibodies towards common allergens were measured. Serum 25(OH)D was analyzed during pregnancy, at birth from cord blood, and at ages 1 and 2 years. Inflammatory markers were measured from cord blood. In addition, vitamin D status and related dietary and health factors at 10 years of age were assessed from another study sample of 171 fourth graders. The children in both study populations were mostly vitamin D sufficient, as defined by serum 25(OH)D concentration ≥ 50 nmol/L. Over 95% of the children participating in the vitamin D intervention study were vitamin D sufficient throughout the study, from birth up to age 2 years. Of the 10-year-old children, almost 84% were vitamin D sufficient. In the vitamin D intervention study, the incidence of parent-reported infections did not differ between the intervention groups at age 2 years. Allergic sensitization and clinical allergies were not prevented by high-dose vitamin D supplementation during the first year of life. In contrast, higher cord blood 25(OH)D predicted higher concentration of inflammatory markers at birth, and associated with increased risk of allergic sensitization at age 1. In conclusion, in contrast to previous research, most of the participating Finnish children had adequate vitamin D status. We found no additional benefit of high-dose vitamin D supplementation compared with the standard dose in the prevention of infections or allergic diseases. Daily 10 µg vitamin D supplementation was adequate in maintaining vitamin D sufficiency in children from birth to age 2 years.Lapset tarvitsevat D-vitamiinia normaalin kasvun ja luuston kehityksen turvaamiseksi. Suomalaislapsille onkin suositeltu päivittäistä D-vitamiinilisää jo lähes 90 vuoden ajan. D-vitamiinilla on lisäksi useita luuston ulkopuolisia vaikutuskohteita ja se vaikuttaa esimerkiksi elimistön puolustusjärjestelmän toimintaan. Terveyden ja puolustuskyvyn kannalta ihanteellisinta D-vitamiinitasoa ei kuitenkaan tarkkaan tiedetä. Tämän väitöskirjatutkimuksen tavoitteena oli selvittää D-vitamiinin luuston ulkopuolisia vaikutuksia, keskittyen erityisesti pienten lasten infektioihin, allergioihin ja tulehdustilaan. Tutkimuksessa selvitettiin, miten nykysuosituksia korkeampi D-vitamiiniannos vaikuttaa infektiosairastavuuteen ja allergioiden kehittymiseen varhaislapsuudessa. Tutkimuksessa tarkasteltiin myös suomalaislasten D-vitamiinitasoa eri ikäkausina sekä tutkittiin siihen vaikuttavia tekijöitä. D-vitamiini-interventiotutkimukseen osallistui 975 tervettä lasta, jotka satunnaistettiin sokkoutetusti saamaan D-vitamiinilisää joko 10 tai 30 mikrogramman vuorokausiannoksella kahden ensimmäisen elinvuoden ajan. Vanhemmat kirjasivat lapsen sairastamat infektiot ja vastasivat allergiakyselyyn. Lasten allergista herkistymistä tutkittiin mittaamalla seerumin IgE-vasta-aineita tavanomaisille allergeeneille. Elimistön D-vitamiinitilannetta kuvaava seerumin 25-hydroksi-D-vitamiinipitoisuus (25(OH)D) mitattiin raskausaikana, napaverestä syntymähetkellä ja lapsista yhden ja kahden vuoden iässä. Napaverestä tutkittiin myös tulehdustekijöiden pitoisuuksia. Lisäksi toisessa tutkimuksessa 171:ltä kymmenvuotiaalta koululaiselta mitattiin 25(OH)D-pitoisuus ja kartoitettiin terveyteen ja ravitsemukseen liittyviä tekijöitä. Valtaosalla tutkituista lapsista elimistön D-vitamiinitaso oli riittävä (25(OH)D ≥ 50 nmol/l). Interventiotutkimukseen osallistuneista lapsista yli 95 %:lla D-vitamiinitaso oli riittävä syntymästä kaksivuotiaaksi asti. Myös 84 %:lla koululaisista D-vitamiinitaso oli riittävä. D-vitamiini-interventiotutkimuksessa suurempi D-vitamiiniannos ei vähentänyt lasten sairastamien infektioiden lukumäärää kahden ikävuoden aikana. Yhden vuoden iässä allergioissa ei ollut eroa ryhmien välillä. Sen sijaan havaitsimme yhteyden korkean napaveren 25(OH)D-pitoisuuden ja tulehdustekijöiden välillä. Korkea napaveren 25(OH)D-pitoisuus lisäsi myös allergisen herkistymisen riskiä yhden vuoden iässä. Tutkimustulokset osoittavat, että suomalaislasten D-vitamiinitaso oli aiempiin tutkimuksiin verrattuna kohentunut. Nykysuositusten mukaiseen annokseen verrattuna suurempi D-vitamiiniannos ei kuitenkaan suojannut infektioilta tai allergioilta varhaislapsuudessa. Alle kaksivuotiailla lapsilla 10 mikrogramman päivittäinen D-vitamiinilisä oli riittävä hyvän D-vitamiinitason ylläpitämiseksi

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

A History of Cow's Milk Allergy Is Associated with Lower Vitamin D Status in Schoolchildren

Background/Aims: Vitamin D insufficiency is common in children. We aimed to evaluate the main determinants of vitamin D status in Finnish school-aged children, including the history of allergic diseases. Methods: We conducted a cross-sectional study on 171 ten-year-olds where serum 25-hydroxyvitamin D (25[OH] D) levels were measured, and data on food consumption and use of vitamin D supplements were collected. The history of allergic diseases was evaluated with a validated questionnaire. Results: Vitamin D insufficiency (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

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

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

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