title: Vitamin D supplementation in breastfed infants from Montréal, Canada: 25-hydroxyvitamin D and bone health effects from a follow-up study at 3 years of age Comparison between daily supplementation doses of 200 versus 400 IU of vitamin D in infants Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: a randomized trial. Randomised controlled trial analysing supplementation with 250 versus 500 units of vitamin D3, sun exposure and surrounding factors in breastfed infants The Change in Plasma 25-Hydroxyvitamin D Did Not Differ between Breast-Fed Infants That Received a Daily Supplement of Ergocalciferol or Cholecalciferol for 3 Months1234 Vitamin D3 Supplementation and Childhood Diarrhea: A Randomized Controlled Trial Combination of bolus dose vitamin D with routine vaccination in infants: a randomised trial. A Treatment Trial of Vitamin D Supplementation in Breast-fed Infants: Universal Supplementation Is Not Necessary for Rickets Prevention in Southern Louisiana Prophylactic vitamin D in healthy infants: assessing the need. High-dose vitamin d intervention in infants--effects on vitamin d status, calcium homeostasis, and bone strength. Vitamin D supplementation trial in infancy: body composition effects at 3 years of age in a prospective follow‐up study from Montréal
abstract: Summary Whether infant vitamin D supplementation may have long-term bone benefits is unclear . In this study , breastfed infants who received vitamin dosages greater than 400 IU/day did not have higher bone mineralization at 3 years . This study provides important data to inform pediatric public health recommendations for vitamin D. Introduction North American health agencies recommend breastfed infants should be supplemented with 400 IU of vitamin D/day to support bone health . Few studies examined the long-term benefits of early life vitamin D supplementation on bone mineralization . The objective of this study was to determine if a dose-response relationship exists between infant vitamin D supplementation , vitamin D status , and bone outcomes at 3 years of age . Methods This was a double-blind r and omized trial of 132 , 1-month-old healthy , breastfed infants from Montréal , Canada , between 2007 and 2010 . In this longitudinal analysis , 87 infants ( 66 % ) returned for follow-up at 3 years of age , between 2010 and 2013 . At 1 month of age , participants were r and omly assigned to receive oral cholecalciferol ( vitamin D3 ) supplements of 400 , 800 , 1200 , or 1600 IU/day until 12 months of age . Lumbar spine vertebrae 1–4 ( LS ) bone mineral density ( BMD ) , LS and whole body bone mineral content ( BMC ) , and mineral accretion were measured by dual-energy x-ray absorptiometry at 3 years . Results At follow-up , the treatment groups were similar in terms of diet , sun exposure , and demographics . There were no significant differences among the groups in LS or whole body BMC , BMD , or accretion . Although , 25(OH)D concentrations were not different among the groups , higher doses ( 1200 and 1600 IU/day ) achieved higher 25(OH)D area under the curve from 1 to 36 months vs. 400 IU/day . Conclusions This is the first longitudinal follow-up of an infant vitamin D dose-response study which examines bone mineralization at 3 years of age . Dosages higher than 400 IU/day do not appear to provide additional benefits to the bone at follow-up . Larger studies with more ethnically diverse groups are needed to confirm these results The daily supplementation of vitamin D is m and atory for infants . However , there are still conflicting opinions about the exact daily dose . Thus , we aim ed to evaluate a daily supplementation dose of 200 IU is sufficient and compared the supplementation doses of 200 and 400 IU per day . One hundred and sixty-nine infants were r and omly assigned to two groups ( group1 , 200 IU/day ; group 2 , 400 IU/day ) and there were 75 infants in group 1 and 64 were in group 2 with a total number of 139 . The median levels of 25-hydroxyvitamin D3 were significantly increased in group 2 at the age of 4 months ( group 1 , 39.60 mcg/L ; group 2 , 56.55 mcg/L ; p < 0.0001 ) . We clearly demonstrated that at the age of 4 months , none of the infants on the group 2 had a serum level of 25-hydroxyvitamin D3 less than 30 mcg/L. However , 21.3 % of the infants in group 1 had a level below 30 mcg/L. Thus , in order to avoid vitamin D deficiency and rickets , we recommend supplementation dose of vitamin D at 400 IU/day as a safe and effective dose IMPORTANCE Vitamin D supplementation in infancy is required to support healthy bone mineral accretion . A supplement of 400 IU of vitamin D per day is thought to support plasma 25-hydroxyvitamin D ( 25[OH]D ) concentrations between 40 and 50 nmol/L ; some advocate 75 to 150 nmol/L for bone health . OBJECTIVE To investigate the efficacy of different dosages of vitamin D in supporting 25(OH)D concentrations in infants . DESIGN , SETTING , AND PARTICIPANTS Double-blind r and omized clinical trial conducted among 132 one-month-old healthy , term , breastfed infants from Montréal , Québec , Canada , between March 2007 and August 2010 . Infants were followed up for 11 months ending August 2011 ( 74 % completed study ) . INTERVENTION Participants were r and omly assigned to receive oral cholecalciferol ( vitamin D3 ) supplements of 400 IU/d ( n=39 ) , 800 IU/d ( n=39 ) , 1200 IU/d ( n=38 ) , or 1600 IU/d ( n=16 ) . MAIN OUTCOMES AND MEASURES The primary outcome was a plasma 25(OH)D concentration of 75 nmol/L or greater in 97.5 % of infants at 3 months . Secondary outcomes included 25(OH)D concentrations of 75 nmol/L or greater in 97.5 % of infants at 6 , 9 , and 12 months ; 25(OH)D concentrations of 50 nmol/L or greater across all times ; growth ; and whole body and regional bone mineral content . Data were analyzed by intention to treat using available data , logistic regression , and mixed-model analysis of variance . RESULTS By 3 months , 55 % ( 95 % CI , 38%-72 % ) of infants in the 400-IU/d group achieved a 25(OH)D concentration of 75 nmol/L or greater vs 81%(95 % CI , 65%-91 % ) in the 800-IU/d group , 92 % ( 95 % CI , 77%-98 % ) in the 1200-IU/d group , and 100 % in the 1600-IU/d group . This concentration was not sustained in 97.5 % of infants at 12 months in any of the groups . The 1600-IU/d dosage was discontinued prematurely because of elevated plasma 25(OH)D concentrations . All dosages established 25(OH)D concentrations of 50 nmol/L or greater in 97 % ( 95 % CI , 94%-100 % ) of infants at 3 months and sustained this in 98 % ( 95 % CI , 94%-100 % ) to 12 months . Growth and bone mineral content did not differ by dosage . CONCLUSIONS AND RELEVANCE Among healthy , term , breastfed infants , only a vitamin D supplement dosage of 1600 IU/d ( but not dosages of 400 , 800 , or 1200 IU/d ) increased plasma 25(OH)D concentration to 75 nmol/L or greater in 97.5 % of infants at 3 months . However , this dosage increased 25(OH)D concentrations to levels that have been associated with hypercalcemia . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00381914 Background The rate of non-compliance with vitamin D supplementation is as high as 45 % . This is why r and omised controlled trials are needed to analyse the response to low doses of vitamin D3 . Objective ( 1 ) To compare supplementation with 250 versus 500 units of vitamin D3 and ( 2 ) to analyse sun exposure time/ultraviolet B ( UVB ) exposure during the first 6 weeks of life . Design 40 breastfed infants ( skin photo-types I , II ) were recruited in Berlin , Germany ( 52.5 ° N ) , during summer ( n=20 ) and winter ( n=20 ) and r and omised into equal groups on either 250 or 500 units of  vitamin D3 per day . Outcome measures were : parameters of vitamin D and bone metabolism at delivery and 6 weeks later , sun exposure time , UVB dosimetry and surrounding factors including maternal diet . Results At delivery 25-hydroxy vitamin D levels were insufficient : 68 ( 53–83 ) nmol/l in each group . 6 weeks later levels were sufficient : 139 ( 114–164 ) nmol/l on 250 units of vitamin D3 per day and 151 ( 126–176 ) nmol/l on 500 units/day . There was no seasonal variation . Daily sun exposure time was 0.4–3.5 h and higher in summer . UVB exposure was 0.01–0.08 minimal erythema dose/day . Calcium levels were within normal . Conclusions In Berlin , Germany , supplementation with 250 units of vitamin D3 is sufficient for breastfed infants during their first 6 weeks of life in summer and winter . UVB exposure is very low throughout the year The biological equivalency of ergocalciferol ( D2 ) and cholecalciferol ( D3 ) has been debated ; several comparisons have appeared in the adult literature but are scarce in pediatrics . The objective of this study was to compare increases in plasma 25-hydroxyvitamin D [ 25(OH)D ] concentrations and attainment of 50 and 75 mol/L status cutoffs following 3 mo of daily supplementation with D2 compared with D3 .  Healthy , breast-fed , 1-mo-old infants ( n = 52 ) received 10 μg ( 400 ic ) of either D2 or D3 daily . At 1 and 4 mo of age , plasma 25-hydroxyergocalciferol and 25-hydroxycholecalciferol concentrations were determined by liquid chromatography t and em MS ( LC-MS/MS ) and total 25(OH)D by chemiluminescent immunoassay ( DiaSorin Liaison ) . Data were analyzed using t tests and χ2 by intent to treat . A total of 23 % of infants were deficient ( ≤24.9 nmol/L ) at baseline and 2 % at follow-up on the basis of LC-MS/MS . At 4 mo , 96 % were breastfed and there were no differences in compliance , breastfeeding rates , or sun exposure among groups . The change in total 25(OH)D measured by LC-MS/MS did not differ between the D2 ( 17.6 ± 26.7 nmol/L ) and D3 ( 22.2 ± 20.2 nmol/L ) groups . In the combined groups , the baseline plasma 25(OH)D concentration was inversely related to the change in total 25(OH)D ( r = −0.52 ; P < 0.001 ) . Overall , 86 % of infants met the 50 nmol/L cutoff at follow-up ; however , fewer infants in the D2 group ( 75 % ) met this level compared with the D3 group ( 96 % ) ( P < 0.05 ) . Similar results were obtained by immunoassay . In conclusion , the increase in the 25(OH)D concentration among the D2 and D3 groups did not differ , suggesting daily intake of either isoform is acceptable for infants < 4 mo OBJECTIVE : To investigate the effect of vitamin D3 supplementation on the incidence and risk for first and recurrent diarrheal illnesses among children in Kabul , Afghanistan . METHODS : This double-blind placebo-controlled trial r and omized 3046 high-risk 1- to 11-month-old infants to receive 6 quarterly doses of oral vitamin D3 ( cholecalciferol 100 000 IU ) or placebo in inner city Kabul . Data on diarrheal episodes ( ≥3 loose/liquid stools in 24 hours ) was gathered through active and passive surveillance over 18 months of follow-up . Time to first diarrheal illness was analyzed by using Kaplan-Meier plots . Incidence rates and hazard ratios ( HRs ) were calculated by using recurrent event Poisson regression models . RESULTS : No significant difference existed in survival time to first diarrheal illness ( log rank P = .55 ) . The incidences of diarrheal episodes were 3.43 ( 95 % confidence interval [ CI ] , 3.28–3.59 ) and 3.59 per child-year ( 95 % CI , 3.44–3.76 ) in the placebo and intervention arms , respectively . Vitamin D3 supplementation was found to have no effect on the risk for recurrent diarrheal disease in either intention-to-treat ( HR , 1.05 ; 95 % CI , 0.98–1.17 ; P = .15 ) or per protocol ( HR , 1.05 ; 95 % CI , 0.98–1.12 ; P = .14 ) analyses . The lack of preventive benefit remained when the r and omized population was stratified by age groups , nutritional status , and seasons . CONCLUSIONS : Quarterly supplementation with vitamin D3 conferred no reduction on time to first illness or on the risk for recurrent diarrheal disease in this study . Similar supplementation to comparable population s is not recommended . Additional research in alternative setting s may be helpful in elucidating the role of vitamin D3 supplementation for prevention of diarrheal diseases INTRODUCTION The present study was design ed to compare two methods of vitamin D supplementation in infants : every two months as a routine vaccination versus a daily dose . METHODS A r and omised clinical trial was performed on 120 healthy breastfed infants between January and September 2007 in Yazd , Iran . The infants were r and omly divided into three groups with different doses of vitamin D3 supplementation : 200 IU daily , 400 IU daily and a bolus of 50,000 IU every two months . A blood sample was taken and evaluated for 25-hydroxy vitamin D and calcium levels when the infants were six months old . The data was reported as the mean and st and ard deviation . RESULTS No significant differences were observed between the serum level of 25-hydroxy vitamin D in the groups administered with 200 IU and 400 IU vitamin D daily . However , the serum level of 25-hydroxy vitamin D reached significance in the third group ( p is less than 0.001 ) . All the blood calcium measured was below 11 mg/dl in the bolus group . A few complications such as diarrhoea and agitation , all of which were self-limited , were seen in the bolus group . No other significant side effects were reported in the other groups . CONCLUSION This study demonstrates that a bolus of 50,000 IU of vitamin D every two months with a routine child vaccination program provides the ideal serum level of vitamin D. This method produces no serious side effects and offers a highly convenient way to supply vitamin D , especially among non-compliant parents This study was conducted to determine if vitamin D supplementation is required to prevent rickets in breast-fed infants . Breast-feeding rates are increasing , and there are concerns about whether the vitamin D content of breast milk is sufficient . There are a few treatment trials of vitamin D supplementation in breast-fed infants ; these were conducted in northern climates . The authors therefore performed a prospect i ve clinical trial comparing vitamin D supplementation with placebo as control in southern Louisiana . Blood sample s and question naires were collected at birth , 2 , 4 , and 6 months of age . There were no cases of rickets observed , and no differences in alkaline phosphatase levels between groups . Thus , there was no evidence that vitamin D supplementation reduced rickets risk in the authors ’ study population . This suggests that the current recommendations for universal vitamin D supplementation of breast-fed infants throughout the United States may need to be revised The objective was to evaluate the need for vitamin D prophylaxis in healthy infants . This was a prospect i ve and r and omized study performed at primary care clinics . Eighty-eight full-term 1-month-old healthy infants were r and omly assigned to receive ( n = 41 ) or not ( n = 47 ) 402 IU/d of vitamin D for 1 year . Primary outcome measures were serum 25-hydroxyvitamin D ( 25OHD ) and parathyroid hormone ( PTH ) concentrations at 3 , 6 , and 12 months of age ; secondary measures included data on feeding , habitat , season of birth , sun exposure , and physical examination . At 3 and 6 months of age , serum 25OHD levels ( ±SD ) were significantly higher ( P < .001 ) in the prophylaxis group . In the group without prophylaxis , serum 25OHD increased with age ; and breast-fed infants aged 3 months had the lowest value ( 20.2 ± 9.4 ng/mL ) , which was significantly ( P = .001 ) lower than that of formula-fed infants ( 35.0 ± 9.7 ng/mL ) . The PTH levels were not influenced by the prophylaxis or feeding . No influence of either the habitat or season of birth on serum 25OHD concentrations was demonstrated . No infant had clinical signs of vitamin D deficiency . Serum 25OHD and PTH concentrations were weakly but significantly correlated ( r = -0.29 , P = .009 ) at 3 months of age . Healthy infants  without vitamin D prophylaxis had lower circulating concentrations of 25OHD at 3 and 6 months of age , the lowest value being found in 3-month breast-fed infants . The clinical relevance of these findings is probably negligible because serum 25OHD levels spontaneously increased with age and were not associated with high serum PTH . Clinical manifestations of rickets were not observed CONTEXT Guidelines in Finl and 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 ) . OBJECTIVE The 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 . DESIGN We conducted a r and omized double-blind intervention study . Cord blood was obtained at birth for S-25-OHD ; 113 infants were r and omized to receive vitamin D3 10 , 30 , or 40 μg/d from age 2 wk to 3 months . SETTING An investigator-initiated study was performed in a single maternity hospital in Helsinki , Finl and . MAIN OUTCOME MEASURES S-25-OHD , calcium homeostasis , and skeletal characteristics were evaluated with peripheral quantitative computed tomography at age 3 months . RESULTS Baseline 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 . CONCLUSION Vitamin 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 BACKGROUND The impact of vitamin D status on body composition is not well understood . OBJECTIVES Evaluate how vitamin D supplementation in infancy affects body composition at 3 years of age . METHODS Double-blind r and omized trial of 132 , 1-month-old healthy , breastfed infants r and omly assigned to receive oral vitamin D3 supplements of 400 , 800 , 1200 or 1600 IU d-1 for 11 months . In the present analysis , 87 ( 66 % ) returned at 3 years of age .  Body composition was measured using dual-energy x-ray absorptiometry and  plasma 25-hydroxyvitamin D [ 25(OH)D ] concentrations by liquid chromatography t and em mass spectrometry . RESULTS Anthropometry , body composition , diet , activity and demographics were similar across dosage groups at 3 years . Mean 25(OH)D concentration from 1 month to 3 years was higher ( P < 0.001 ) in the 1200 IU group than 800 and 400 IU groups . Children with 25(OH)D concentrations above 75 nmol L-1 had lower fat mass ( ~450 g ; P = 0.049 ) . In multiple linear regression , mean 25(OH)D was associated with lean mass percent ( β = 0.06 ; CI : 0.00 , 0.12 ; P = 0.042 ) , fat mass ( β = -11.29 ; CI : -22.06 , -0.52 ; P = 0.048 ) and body fat percent ( β = -0.06 ; CI : -0.12 , -0.01 ; P = 0.045 ) . CONCLUSIONS Higher vitamin D status from infancy through to 3 years of age associates with leaner body composition
target: They do not provide any additional evidence that larger , more generous amounts of daily vitamin D beyond the customary recommended 400 IU daily dose , affect any significant outcome .
  Larger amounts may lead to serum 25 hydroxy vitamin D concentrations that have been reported to be potentially associated with adverse effects .
  Summary There are still many unanswered questions left , in particular whether or not more ‘ generous ’ amounts of vitamin D in infancy may improve long-term health outcomes such as prevention of osteoporosis , allergies , or cancer
background: Purpose of review New evidence for recommendations for vitamin D supplementation in healthy infants based upon recent literature .