SYMPOSIUM ON PEDIATRIC ENDOCRINOLOGY

Vitamin D Deficiency in a Tropical Country — Treatmentand Prevention in Children

Kriti Joshi & Vijayalakshmi Bhatia

Received: 23 May 2013 /Accepted: 29 August 2013 /Published online: 6 November 2013# Dr. K C Chaudhuri Foundation 2013

Abstract Vitamin D has an important role to play in skeletaland extraskeletal health. Inspite of being a sun rich country,India has widespread vitamin D deficiency. Vitamin D defi-ciency can lead to serious consequences like hypocalcemicseizures and increased risk of respiratory tract infections inneonates and infants. International expert groups advocateuniversal supplementation for non-formula fed infants, preg-nant and lactating women and those at risk of deficiency. Abody of literature on vitamin D status in India is being gener-ated, which may guide clinical practice in our country. Treat-ment of deficiency must be undertaken with minimally effec-tive doses to avoid the risk of toxicity. Sensible sunshineexposure should be encouraged to facilitate vitamin D pro-duction from natural sources.

Keywords VitaminD . Cholecalciferol . Sunshine . Rickets

Introduction

VitaminD has a wide spectrum of actions ranging from its rolein bone health and calcium homeostasis, to extraskeletal ef-fects on the immune system and cell proliferation. Rickets ingrowing children and osteomalacia in adults are the moststriking features of its deficiency. Vitamin D is mainlyobtained from sunlight exposure as most dietary sources arepoor in vitamin D. India, inspite of being a sun rich country,has been demonstrated to have rampant vitamin D deficiencyacross all age-groups. Our modest tradition of clothing, darkerskin pigmentation and poor nutritional status are factors im-plicated in causing this deficiency. This review examines the

issue of pharmacological supplementation of vitamin D in ourcountry, vulnerable groups which require it and the variousdoses and regimens for optimal treatment of deficiency andprevention of toxicity. Also reviewed is the information onhow much sunshine may be adequate for generation of suffi-cient vitamin D.

Sunlight and Vitamin D

The main source of vitamin D in humans is cutaneous syn-thesis. Exposure of skin to ultraviolet B (UVB) radiationinitiates the conversion of 7-dehydrocholesterol (provitaminD) into previtamin D which is isomerised to the more ther-mostable cholecalciferol or vitamin D. Vitamin D undergoes25 hydroxylation in the liver to 25 hydroxyvitamin D(25 OHD). This 25 OHD, considered the storage form of thevitamin, undergoes 1-hydroxylation in the kidney to 1,25dihydroxyvitamin D (calcitriol, the active form) [1]. Onprolonged exposure to UVB there is no risk of toxicity,because excess previtamin D is converted to inactive metab-olites like lumisterol and tachysterol [2].

Early humans were hunters and gatherers and had a pre-dominant outdoor life with limited clothing. However, withcivilization came the attendant lifestyle changes of clothingand shelter. Industrialization brought reduced outdoor activityand increasing pollution, thereby leading to impaired cutane-ous vitamin D synthesis. Rickets became famous as “theEnglish disease” during the 17th to the early 20th century inthe industrialized cities of Europe. Most temperate countriesthen started food fortification with vitamin D to prevent defi-ciency. Subsequently, studies showed that if adequate UVBexposure is provided, a state of vitamin D sufficiency caneasily be obtained. Haddock et al. demonstrated that PuertoRican farmers (Latitude18.3°S) who had sufficient sunshineexposure had mean serum 25 OHD of 54 ng/mL [3]. A similar

K. Joshi :V. Bhatia (*)Department of Endocrinology, Sanjay Gandhi Postgraduate Instituteof Medical Sciences, Lucknow 226014, Uttar Pradesh, Indiae-mail: vbhatia@sgpgi.ac.in

Indian J Pediatr (January 2014) 81(1):84–89DOI 10.1007/s12098-013-1241-2

study on lifeguards also showed abundant endogenous vita-min D production with mean 25 OHD of 65.2 ng/mL [3].Goswami et al. (working in Delhi, latitude 29°N) also dem-onstrated that healthy soldiers with abundant outdoor activityhad a mean 25 OHD of 47.2±11.7 ng/mL (in winter), whichwas significantly higher (and within normal range) comparedwith that of physicians and nurses in the same season (7.9±3.5 ng/mL) [4]. Thus, people working and living in sun richenvironments have been shown to produce adequate amountsof vitamin D.

How Much Sunlight is Needed for Adequate Vitamin DProduction?

Cutaneous vitamin D production depends upon a multitude offactors, the most important being skin pigmentation. Individ-uals with darker skin types require about 3–6 times the UVBexposure to produce the same amount of vitamin D as Cau-casians [2]. Goswami et al. showed patients with vitiligo (i.e.,cutaneous depigmentation) to have significantly higher25 OHD (18.2±11.2 ng/mL) in winter when compared to thephysician and nurse group (7.9±3.5 ng/mL) [4].

Studies on individuals treated with external UVB radiationhave shown that full body exposure to one MED (minimalerythemal dose, which leads to slight pinkness of the skin) ofUVB leads to production of 25 OHD equivalent to a single oraldose of 10,000 – 25,000 IU of vitamin D3 [3, 5]. By extrapo-lation, exposure of 25 % of body surface area (face, neck, armsand hands) to one MED should suffice for the production ofapproximately 2,500–6,000 IU of vitamin D. One MED forCaucasian skin (Fitzpatrick type I, II and III) is achieved withUVB exposure of 10–15 min. Indians would correspondinglyrequire exposure time of 30–60 min for the same. Therefore inpractical terms, for the synthesis of about 1,000 IU vitamin DIndians would need sunshine exposure of 15–20 min if 25 %surface area is exposed (face, neck, hand and arms) and 20–30 min if 15 % (face, neck, hands) skin is exposed to sunlight.

The other important factors which influence vitamin Dsynthesis are latitude, season, cloud cover and pollution. Inwinters, at latitudes greater than 37°, vitamin D synthesis isnegligible [5] and so also during early morning and late eve-ning. Therefore, sensible sunshine exposure between the hoursof 10:00-15:00 is important for vitamin D synthesis. The neg-ative effect of pollution was elegantly demonstrated in a studyon Delhi children by Agarwal et al. who showed that childrenfrom a more polluted area of Delhi had significantly lowermean 25 OHD (12.4±7 ng/mL) compared to those from a lesspolluted area (24.7±7 ng/mL) [6]. Particulate matter absorbsUVB radiation and the high atmospheric pollution over most ofIndia’s cities would be playing an important role in diminishingthe amount of UVB radiation reaching earth. Currently, thereare web based calculators which take into account the latitude,

skin pigmentation, atmospheric and surface conditions andevaluate the amount of UVB exposure required for specifiedamount of cutaneous vitamin D synthesis [7].

Dietary Sources

Most dietary products are poor sources of vitamin D. Naturalsources of vitamin D include oily fish such as salmon, mack-erel, sardines, tuna, hilsa and cod fish, cod liver oil, liver andorgan meats. All these fish are available and eaten in India. Incountries like USA, many dietary products like milk andjuices are fortified with vitamin D. Breast milk is a poor sourceof vitamin D, containing about 20–60 IU/L. However whenlactating mothers are supplemented with generous amount ofvitamin D (6,400 IU/d), the 25 OHD of their infants is com-parable to that in babies receiving daily supplements of 400 IU[8].

The role of calcium in bone andmineral metabolism cannotbe ignored. Dietary calcium deficiency has been implicated asan important cause of rickets in India and other tropicalcountries [9].

Definitions of Vitamin D Deficiency

25OHD is the main circulating form of vitamin D and its levelis used to determine vitamin D status. There is debate centeredupon what constitutes normal levels of 25 OHD. Functionalcorrelates include the level at which (a) PTH remains in thenormal range (b) bone resorption is minimal and (c) calciumabsorption is maximally enhanced. Many authors have foundthis level to be 20 ng/mL (50 nmol/L) whereas others define itas 30 ng/mL (75 nmol/L) in adults [10, 11]. Viljakainen et al.demonstrated that 25 OHD >50 nmol/L is sufficient to pro-mote bone acquisition and increase BMD at lumbar spine inadolescent girls [12]. Cashman et al. found that 12 and 15 yold girls with 25 OHD > 46.3 nmol/L have higher BMD,lower PTH and lower bone resorption markers than those withlower levels [13].

Till more data are available in the pediatric age group,experts have argued for a conservative cut off of 25 OHD< 20 ng/mL (<50 nmol/L) to define deficiency in children, withlevels < 5–10 ng/mL (<12.5 to < 25 nmol/L) being indicative ofsevere deficiency [14 – 17].

Demography of Vitamin D Deficiency in India

Vitamin D deficiency has been described in all age groups inIndia. Pregnant women and their newborns, infants, adoles-cents (especially girls) and adults have all been shown to havevitamin D deficiency [18–20]. Studies demonstrating this

Indian J Pediatr (January 2014) 81(1):84–89 85

have been published from the north [18, 19, 21, 22] andsouth of India [20, 23], in urban [18–20, 22] as well asrural [21] populations, and higher and lower socioeconom-ic strata [22]. The prevalence of deficiency (as defined by25 OHD <20 ng/mL in most of the studies) ranges from75 to 90 %. The age group relevant to pediatricians wherethere is no information on the prevalence of deficiency isthe mid childhood age group, where it might be expectedthat both urban and rural children might get sun exposurein relation to school and play.

Is Vitamin D Deficiency a Public Health Problem in India?

What are the functional correlates of vitamin D deficiency inour population of children and does it have serious implica-tions? There is evidence demonstrating vitamin D deficiencyto be the commonest cause of hypocalcemic seizures present-ing in infancy [20, 24]. Vitamin D deficiency in infancy hasbeen linked, albeit not unequivocally, to higher risk of lowerrespiratory tract infections, a major cause of mortality andmorbidity [25, 26]. Furthermore the adolescent girl of todayis the young mother of tomorrow and the post-menopausalwoman of the future. Thus, supplementing her will protect hernewborn from hypocalcemia as well as her from later osteo-porosis (an osteoporotic hip fracture has a high risk formortality).

Pharmacokinetics of Vitamin D

Knowledge of the pharmacokinetics of vitamin D is importantas it can help determine the dose, frequency and the route ofadministration. Traditionally, vitamin D3 (cholecalciferol,from animal sources) and vitamin D2 (ergocalciferol, fromplant sources) have been administered in small daily dosesorally, or in intermittent larger doses orally or intramuscularly(“stoss therapy”, stoss in German means push or bump up).The pattern of serum 25 OHD after oral administration ofdaily doses is highlighted in the study by Heaney et al. [27].Cholecalciferol (1,000 IU, 5,000 IU and 10,000 IU given dailyorally for 20 wk) resulted in a slow rise of serum 25 OHD inall groups, peaking 80 d into the study, with a plateau there-after. This is in contrast to the brisk rise seen in all studiesemploying single large doses. Ilahi et al. found that after asingle large oral dose of cholecalciferol (100,000 IU), serum25 OHD peaked on day 8 and declined thereafter to fall below32 ng/mL after 70 d. They concluded that a 2 monthly dosinginterval of D3 is appropriate for maintaining serum 25 OHD[28]. The intramuscular route leads to a slow, sustained rise inserum 25 OHD unlike the oral route. Romagnoli et al. com-pared the effect of a single large dose of 300,000 IU chole-calciferol given orally vs. intramuscularly. They showed thatwith the i.m. route a gradual rise in serum 25 OHD was seen

and sufficiency levels were reached only by day 60, whereaswith the oral route serum 25 OHD showed a brisk rise reachingsufficiency levels by 3 d with peak levels at 30 d, which weresignificantly higher than serum 25 OHD of the i.m. group [29].

Therefore to conclude, administration of cholecalciferol bythe oral route leads to faster and higher peak 25 OHD whichfall to baseline by 2 mo, whereas the parenteral route gives amore slow and sustained rise.

Pharmacological Vitamin D Supplementation

The American Academy of Pediatrics (AAP) and The Instituteof Medicine of the National Institutes of Health (IOM), USA,have now recommended a higher daily intake of 400 IU ofvitamin D for all newborns and infants who are not onsupplemented formula feeds, a change from their previousrecommendation of 200 IU/d [14, 15]. The Australasian Pediat-ric Endocrine Group (APEG) and the Endocrine Society (USA)also endorse the same recommendation [16, 30] (Table 1). TheIndian Council for Medical Research (ICMR) and NationalInstitute of Nutrition (NIN) in their recently revised guidelinesdo not mention routine use of vitamin D in their RDA,explaining that there is a need to improve education and aware-ness regarding adequate sunshine exposure [31]. Instead, theyleave it to the discretion of the pediatrican or physician, toprescribe 400 IU daily in “situations of minimal exposure tosunlight”. Daily supplementation of 400 IU in infants has beenfound to be safe and efficacious in raising 25 OHD levels tosufficiency status [8, 32]. Atas et al. from Turkey comparedsupplementation of 200 IU vs . 400 IU daily and found that allthe infants in the 400 IU group had 25 OHD levels >30 ng/mL.The authors therefore recommend supplementation of 400 IUdaily. However, it must be noted from the study that even dailysupplements of 200 IU of vitaminDwere enough tomaintain 25OHD levels >20 ng/mL (current definition of deficiency) in97 % of the cohort of children [33].

For older children and adolescents, the IOM and the En-docrine Society (USA) recommend a daily vitamin D intake

Table 1 Recommendations of expert groups regarding daily intake andmaintenance doses of vitamin D in childhood

Age AAP APEG IOM (NIH) Endocrine Society (USA)

< 1 y 400 IU 400 IU 400 IU a 400 – 1,000 IU

1 - 18 y 400 IU 400 IU 400 IU b 600 – 1,000 IU

AAP American Academy of Pediatrics; APEG Australasian PediatricEndocrine Group; IOM Institute of Medicinea Adequate Intake (AI): Used when an EAR/RDA cannot be developed;average intake level based on observed or experimental intakesb EAR- Estimated average requirement; corresponding to the medianintake needs of the population

86 Indian J Pediatr (January 2014) 81(1):84–89

of 400–600 IU [15, 30]. These doses may be translated intoapproximately half a sachet of 60,000 IU every 2 mo forinfants and a whole sachet 2 monthly for anyone older formore economical dosing than daily supplementation. It mustbe stated that studies are not available on the use of large dosesin children below 6 mo and care must be exercised withpreventive regimens in this age group.

For pregnant women, though the IOM recommends a dailyintake of 600 IU, this has been shown in a large number ofstudies to be inadequate in maintaining vitamin D sufficiency.Dawodu et al. compared the response to supplementation with400 IU, 2,000 IU or 4,000 IU daily from the second trimesteronwards, in pregnant women in the UAE, the baseline25 OHD of this population being low as in Indian women.They showed mean maternal serum 25 OHD at term tobe > 20 ng/mL only in the 2 larger dose groups, and cord 25OHD to be > 20 ng/mL only in the 4,000 IU (and close to20 ng/mL in the 2,000 IU) group [34].

Who Should Get Routine PharmacologicalSupplementation for Prevention of Vitamin D Deficiencyin India?

Until awareness regarding the importance of sun exposurebecomes a part of the public health discourse, vulnerablegroups like newborns and infants, adolescent girls, pregnantwomen, and the elderly, perhaps deserve routine pharmaco-logical supplementation. Vitamin D deficiency is ubiquitousand the estimation of serum 25 OHD is too prohibitivelycostly to be recommended as a necessity before preventivesupplementation in India. Based on the above literature, thedoses in infancy may be 400 IU daily or half of a 60,000 unitsachet once in 2 mo (though sufficient literature has not beengenerated on oral stoss doses in infants, this dose would beexpected to be safe, while being far less expensive than thedaily dose); and in adolescents at least 600 IU daily (in this agegroup, it would be safe enough to administer a full sachet of60,000 IU once in 2 mo). Other vulnerable groups are listed inTable 2. Some of these groups may require higher doses for

effective maintenance. A complete discussion on this aspect isbeyond the scope of this article.

Treatment of Rickets

Who Needs Treatment?

1. Emergency indication: Infancy and adolescence are twoage groups when severe vitamin D deficiency can presentas hypocalcemic seizures, due to increased demands ofthe growing skeleton. These children require treatmentwith calcium, initially IVand then oral along with vitaminD. Active vitamin D (calcitriol) can be given for the initialcouple of days to enable rapid correction of hypocalcemiaand reduce the need for IV calcium. However, endoge-nous calcitriol formation is brisk once cholecalciferol hasbeen administered and therefore, calcitriol as a medicationhas no role in long term treatment of hypovitaminosis D.

2. Any child presenting with clinical/biochemical features ofrickets or detected to have vitamin D deficiency onscreening.

Treatment Protocol

Various regimens for treatment have been described in theliterature. Therapy can be given in smaller daily doses or

Table 2 Indications for prophylactic vitamin D supplementation

1. Neonates and infants who are not formula fed

2. Adolescent girls and pregnant women

3. Children with evidence of malabsorption - celiac disease, inflammatorybowel disease, cystic fibrosis

4. Chronic liver or kidney disease

5. Medications which cause hypovitaminosis D or decrease calciumabsorption - anticonvulsants, rifampicin, antifungals, glucocorticoidsetc.

6. Limited sunshine exposure due to disability, illness or religious/culturalreasons.

Table 3 The APEG daily dose protocol for treatment of ricketsa [16]

Age Treatment: daily dose Treatment: stoss dose

<1 y 1,000 IU/d×3 mo 50, 000 IU stat and review after

1 mo (consider repeating dose)b

1–18 y 3,000–4,000 IU/d×3mo

150,000 IU stat and repeat 6 wk later

aAPEG Australasian Pediatric Endocrine Groupb Stoss regimen not recommended in children <3 mo

Table 4 Available vitamin D3 supplements

Formulation Strength Cost

Cholecalciferol granules 60,000 Units/sachet Rs 15–30

Cholecalciferol + Calciumcombinations

125 IU + 250 mgelemental Ca

Rs 1.5 – 2

250 IU + 500 mg Ca Rs 2.5 - 3.5Syr 125 IU +250 mg Ca/5 mL

Rs 32 (150 mL) i.e.,Rs 1/5 mL

Cholecalciferol capsules 1,000 IU Rs 5.9

Drops 400 IU/mL Rs 20 – 25

Injectable 600,000 IU Rs 15 – 25

(Sunshine) (Unlimited) (Free)

Indian J Pediatr (January 2014) 81(1):84–89 87

intermittent bolus doses. Gordon et al. showed thathypovitaminosis D can be effectively treated with daily dosesof 2,000 IU as well as weekly 50,000 IU D2 given for 6 wk[35]. However, this weekly dose was not without risk oftoxicity in some babies (see below under “Toxicity”). Cesuret al. used three different oral stoss doses of vitamin D3 to treatrickets in children aged 3–36 mo and found that a single doseof 150,000 IU was safe and effective whereas 300,000 IU and600,000 IU doses were associated with the risk of hypercal-cemia when the babies were followed up 30 d after adminis-tration of therapy [36]. Therefore they concluded that thelower dose was sufficient to treat rickets, with higher dosescarrying an unacceptable risk of vitamin D toxicity. Zhegoudet al. treated newborns with single stoss oral D3 doses of600,000, 200,000 and 100,000 IU and found that a significantproportion of children treated with 600,000 IU developedprolonged 25 OHD overload with significant rise in calcium.Those children treated with 100,000 IU and 200,000 IU de-veloped more modest rise in 25 OHD with no evidence ofhypercalcemia though even with these lower doses someinfants had transient rise of 25 OHD to toxic range [37].

Soliman et al. studied the effect of intramuscular adminis-tration of high dose D3, 10,000 IU/kg in infants and adoles-cents, and found it to be effective in normalizing 25 OHD at3 mo, without any evidence of toxicity [38, 39].

A reasonable approach as follows is recommended by theAustralasian Pediatric Endocrine group [16] :- for children< 1 y, 1,000 IU daily for 3 mo and then maintenance with400 IU daily. In terms of the stoss dose preparations, infantsand younger children may be given 50,000 units stat whichmay be repeated if required. However stoss therapy in notrecommended in children younger than 3 mo. For children> 1 y,: 3,000–4,000 IU daily may be given for 3 mo followedby maintenance, stoss therapy may be given with 150,000 IUD3 stat and may be repeated 6 wk later (Table 3). In developingcountries like India the cost of treatment must be an importantconcern. The cost of daily therapy is significantly higher thanthat of intermittent bolus therapy (Table 4). Pending morestudies on stoss dosing in children, intermittent dosing maybe a more feasible and cost effective option for our country.

Toxicity

Vitamin D toxicity is defined as serum 25 OHD exceeding150 ng/mL and hypervitaminosis D as 25 OHD > 100 ng/mL.As more knowledge about the benefits of vitamin D is be-coming available, its use has become indiscriminate, leadingto many reports of overtreatment. A recent report highlighted3 infants and toddlers developing hypervitaminosis D andhypercalcemia on doses which are considered acceptable[40]. The above mentioned study by Gordon et al. showedserum 25 OHD of some children treated with 50,000 IU D2

weekly for 6 wk to reach > 100 ng/mL. Caution needs to beexercised when treating young children as the administrationof dosages to infants that are often used in older children andadults has toxic potential. Hypervitaminosis D can presentwith serious consequences like hypercalcemia, hypercalciuria,concentration defects, renal calculi and even acute renal shut-down. Therefore, emphasis should be laid on using minimumtreatment doses of vitamin D which can produce adequatetherapeutic response.

Conclusions

& Vitamin D deficiency is present in a significant proportionof children across all age groups from India.

& Since hypovitaminosis D can have serious consequencesin the pediatric population, prevention of deficiency mustbe the goal.

& Most dietary sources are poor in vitamin D, thereforecutaneous production is the main source. Fifteen to20 min of daily sunshine exposure of about 25 % of theskin surface from 10:00-15:00 h should suffice for syn-thesis of about 1,000 IU of vitamin D daily.

& Infants not receiving formula must be supplemented with400 IU of vitamin D daily. Older children and adolescentsat risk for deficiency may require daily intake of 600 IU.

& Vitamin D deficiency must be treated with minimal effec-tive doses keeping in mind the cost of treatment as well astoxicity associated with overdose.

Conflict of Interest None.

Role of Funding Source V. Bhatia has been funded by Department ofBiotechnology, Government of India, and SGPGIMS, Lucknow, for thestudies on vitamin D and calcium nutrition.

References

1. HolickMF. Sunlight and vitamin D for bone health and prevention ofautoimmune diseases, cancers, and cardiovascular disease. Am J ClinNutr. 2004;80:1678S–88S.

2. Holick MF, Mac Laughlin JA, Dobbelt SH. Regulation of cutaneousprevitamin D3 photosynthesis in man: Skin pigment is not an essen-tial regulator. Science. 1981;211:590–3.

3. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative ofvitamin D sufficiency: Implications for establishing a new effectivedietary intake recommendation for vitamin D. J Nutr. 2005;135:317–22.

4. Goswami R, Gupta N, Goswami D, Marwaha RK, Tandon R,Kochupillai N. Prevalence and significance of low 25-hydroxyvitaminD concentrations in healthy subjects in Delhi. Am J Clin Nutr. 2000;72:472–5.

5. Holick MF. McCollum Award Lecture, 1994: Vitamin D: Newhorizons for the 21st century. Am J Clin Nutr. 1994;60:619–30.

88 Indian J Pediatr (January 2014) 81(1):84–89

6. Agarwal KS, Mughal MZ, Upadhyay P, Berry JL, Mawer EB,Puliyel JM. The impact of atmospheric pollution on vitamin Dstatus of infants and toddlers in Delhi, India. Arch Dis Child.2002;87:111–3.

7. Webb AR, Engelsen O. Calculated ultraviolet exposure levelsfor a healthy vitamin D status. Photochem Photobiol. 2006;82:1697–703.

8. Wagner CL, Hulsey TC, Fanning D, Ebeling M, Hollis BW. Highdose vitamin D3 supplementation in a cohort of breast- feedingmothers and their infants: A six-month follow-up pilot study.Breastfeed Med. 2006;1:59–70.

9. Thacher TD, Fischer PR, Pettifor JM, Lawson JO, Isichei CO, ChanGM. A comparison of calcium, vitamin D, or both for nutritionalrickets in Nigerian children. N Engl J Med. 1999;341:563–8.

10. Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D in-sufficiency. Lancet. 1998;351:805–6.

11. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ,Vieth R. Estimates of optimal vitamin D status. Osteoporos Int.2005;16:713–6.

12. Viljakainen HT, Natri AM, Kärkkäinen MM, Huttunen MM, PalssaA, Jakobsen J, et al. A positive dose–response effect of vitamin Dsupplementation on site specific bone mineral augmentation in ado-lescent girls: A double- blinded randomized placebo-controlled 1-year intervention. J Bone Miner Res. 2006;21:836–44.

13. Cashman KD, Hill TR, Cotter AA, Boreham CA, Dubitzky W,Murray L, et al. Low vitamin D status adversely affects bone healthparameters in adolescents. Am J Clin Nutr. 2008;87:1039–44.

14. Wagner CL, Greer FR; American Academy of Pediatrics Section onBreastfeeding; American Academy of Pediatrics Committee onNutrition. Prevention of rickets and vitamin D deficiency in infants,children, and adolescents. Pediatrics. 2008;122:1142–52.

15. IOM (Institute of Medicine). Dietary reference intakes for calciumand vitamin D. Committee to review Dietary Reference Intakes forcalcium and vitamin D .Washington DC: National Academies Press,Institute of Medicine; 2011.

16. Paxton GA, Teale GR, Nowson CA, Mason RS, McGrath JJ,Thompson MJ, et al; Australian and New Zealand Bone andMineral Society; Osteoporosis Australia. Vitamin D and health inpregnancy, infants, children and adolescents in Australia and NewZealand: A position statement. Med J Aust. 2013;198:142–3.

17. Braegger C, Campoy C, Colomb V, Decsi T, Domellof M, FewtrellM, et al. Vitamin D in the healthy European paediatric population. JPediatr Gastroenterol Nutr. 2013;56:692–701.

18. Sachan A, Gupta R, Das V, Agarwal A, Awasthi PK, Bhatia V. Highprevalence of vitamin D deficiency among pregnant women and theirnewborns in northern India. Am J Clin Nutr. 2005;81:1060–4.

19. Seth A, Marwaha RK, Singla B, Aneja S, Mehrotra P, Sastry A, et al.Vitamin D nutritional status of exclusively breast fed infants and theirmothers. J Pediatr Endocrinol Metab. 2009;22:241–6.

20. Balasubramanian S, Shivbalan S, Kumar PS. Hypocalcemia due tovitamin D deficiency in exclusively breast fed infants. Indian Pediatr.2006;43:247–51.

21. Sahu M, Bhatia V, Aggarwal A, Rawat V, Saxena P, Pandey A, et al.Vitamin D deficiency in rural girls and pregnant women despiteabundant sunshine in northern India. Clin Endocrinol. 2008;70:680–4.

22. Marwaha RK, Tandon N, Reddy DR, Aggarwal R, Singh R,Sawhney RC, et al. Vitamin D and bone mineral density status ofhealthy schoolchildren in northern India. Am J Clin Nutr. 2005;82:477–82.

23. Harinarayan CV. Prevalence of vitamin D insufficiency in postmen-opausal south Indian women. Osteoporos Int. 2005;16:397–402.

24. Mehrotra P, Marwaha RK, Aneja S, Seth A, Singla BM, Ashraf G,et al. Hypovitaminosis D and hypocalcemic seizures in infancy.Indian Pediatr. 2010;47:581–6.

25. Muhe L, Lulseged S, Mason KE, Simoes EA. Case–control study ofthe role of nutritional rickets in the risk of developing pneumonia inEthiopian children. Lancet. 1997;349:1801–4.

26. Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin Dand respiratory tract infections: A systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013;8:e65835.

27. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ.Human serum 25-hydroxycholecalciferol response to extended oraldosing with cholecalciferol. Am J Clin Nutr. 2003;77:204–10.

28. Ilahi M, Armas LAG, Heaney RP. Pharmacokinetics of a single largedose of cholecalciferol. Am J Clin Nutr. 2008;87:688–91.

29. Romagnoli E, Mascia ML, Capriani C, Fassino V, Mazzei F,D’Erasmo E, et al. Short and long term variations in serumcalciotropic hormones after a single very large dose of ergocalciferol(vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J ClinEndocrinol Metab. 2008;93:3015–20.

30. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, HanleyDA, Heaney RP, et al; Endocrine Society. Evaluation, treatment,prevention of vitamin D deficiency: An Endocrine Society clinicalpractice guideline. J Clin Endocrinol Metab. 2011;96:1911–30.

31. National Institute of Nutrition. Nutrient requirements and recom-mended dietary allowances for Indians. A report of the IndianCouncil for Medical Research expert group 2010.

32. Mutlu GY, Kusdal Y, Ozsu E, Cizmecioglu FM, Hatun S. Preventionof vitamin D deficiency in infancy: Daily 400 IU vitamin D issufficient. Int J Pediatr Endocrinol. 2011;2011:4.

33. Atas E, Karademır F, Ersen A,Meral C, Aydınoz S, Suleymanoglu S,et al. Comparison between daily supplementation doses of 200 versus400 IU of vitamin D in infants. Eur J Pediatr. 2013;172:1039–42.

34. Dawodu A, Saadi HF, Bekdache G, Javed Y, Altaye M, Hollis BW.Randomized controlled trial (RCT) of vitamin D supplementation inpregnancy in a population with endemic vitamin D deficiency. J ClinEndocrinol Metab. 2013;98:2337–46.

35. Gordon CM,WilliamsAL, FeldmanHamay J, Sinclair L, Vasquez A,Cox JE. Treatment of hypovitaminosis in infants and toddlers. J ClinEndocrinol Metab. 2008;93:2716–21.

36. Cesur Y, Caksen H, Gundem A, Kirimi E, Odabas D. Comparison oflow and high doses of vitamin D treatment in nutritional vitamindeficiency rickets. J Pediatr Endocrinol Metab. 2003;16:1105–9.

37. Zeghoud F, Ben-Mekhbi H, Djeghri N, M G. Vitamin D prophylaxisduring infancy: Comparison of the long-term effects of three inter-mittent doses (15, 5, or 2.5 mg) on 25-hydroxyvitamin D concentra-tions. Am J Clin Nutr. 1994;60:393–6.

38. Soliman AT, El-Dabbagh M, Adel A, Al Ali M, Aziz Bedair EM,Elalaily RK. Clinical responses to a mega-dose of vitamin D3 ininfants and toddlers with vitamin D deficiency rickets. J Trop Pediatr.2010;56:19–26.

39. Soliman AT, Adel A, Wagdy M, Alali M, Aziz Bedair EM.Manifestations of severe vitamin D deficiency in adolescents:Effects of intramuscular injection of a megadose of cholecalciferol.J Trop Pediatr. 2011;57:303–6.

40. Vanstone MB, Oberfield SE, Shader L, Ardeshirpour L, CarpenterTO. Hypercalcemia in children receiving pharmacologic doses ofvitamin D. Pediatrics. 2012;129:e1060–3.

Indian J Pediatr (January 2014) 81(1):84–89 89