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Effect of micronutrient supplement on health and nutritional status ofschoolchildren: biochemical status

Battiprolu Sivakumar, Ph.D.a,*, Krishnapillai Madhavan Nair, Ph.D.a,Dande Sreeramulu, Ph.D.b, Palla Suryanarayana, Ph.D.b, Punjal Ravinder, Ph.D.a,

Veena Shatrugna, M.D.c, Prattipati Ajey Kumar, M.Sc.c, Manchala Raghunath, Ph.D.b,Varaganti Vikas Rao, M.Sc.a, Nagalla Balakrishna, Ph.D.d, Putcha Uday Kumar, M.D.e, and

Namala Raghuramulu, Ph.D.ba Division of Biophysics, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, India

b Division of Endocrinology and Metabolism, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, Indiac Division of Maternal and Child Health, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, India

d Division of Field Studies, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, Indiae Division of Pathology, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, India

Manuscript received April 6, 2004; accepted July 23, 2005.

bstract Objective: We assessed the effect of a daily intake of a micronutrient-fortified beverage for 14 moon indicators of biochemical status of important micronutrients in schoolchildren.Methods: A double-blind, placebo-controlled, matched-pair, cluster, randomization study design wasused. Biochemical indicators of micronutrient status were evaluated at baseline and at the end of 14mo on a subsample in nine matched pairs. Prevalence (percentage) of subclinical deficiency, mean,and mean increments of each indicator were compared between supplemented and placebo groups.Results: Extent of inadequacy at baseline was more or less 100% for folic acid, 65% for vitaminsB2 and B6, and 55% for vitamins C and A. Prevalence of anemia among subjects was 55%, withinadequacy of vitamin B12 being 40% and that of vitamin D being 30%. No subject had inadequacyof iodine based on urinary iodine. Supplementation of a micronutrient-enriched beverage for 14 mosignificantly improved the status of many of the nutrients. The effect was significant with respect tovitamins A, B2, and B12, folic acid, vitamin D, parathyroid hormone, and thyroid-stimulatinghormone in children who received the supplement compared with those who received only placebo.Hemoglobin status improved only in children who had anemia in the supplemented group.Conclusions: Prevalence of multiple subclinical micronutrient deficiencies are high in middle-income Indian school children. Daily consumption of a micronutrient-enriched beverage hadpositive effects that were confined to those nutrients that were inadequate at baseline. © 2006Elsevier Inc. All rights reserved.

eywords: Micronutrients; Biochemical status; Nutritional supplementation; Children; Vitamins; Minerals; Subclinical

Nutrition 22 (2006) S15–S25www.elsevier.com/locate/nut

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Protein, energy, and micronutrient deficiencies affecthysical work capacity, body fitness, and mental function

This study was supported by M/S GlaxoSmithKline Consumer Health-are, Ltd., India.

* Corresponding author. Tel.: �91-40-2701-8083.
tE-mail address: [email protected] (B. Sivakumar).
899-9007/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.nut.2005.07.012

1–3]. In particular, deficiency of micronutrients such asron, vitamin A, zinc, iodine, and B-complex vitamins haveeen shown to affect growth, maximal work capacity [3],ental function [2,3], visual acuity [4], and psychomotor

unction [5]. Supplementation of malnourished childrenith iron and B-complex vitamins has been reported to

mprove these functions [4–6]. Supplementation with min-rals and vitamins has been associated with improved men-
al function [7] and growth and development of children

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8–11]. It has been reported that the benefit of micronutrientupplementation is optimal only when multiple micronutri-nts are provided [10,12–14] and the effect is pronounced ifhere is a basal micronutrient deficiency [15–17].

During the past 25 y, a large database has been accumu-ated on the diet and nutritional status of the rural populationf different states of India [18]. These surveys indicate thathe diets of the rural population are inadequate and deficientn most nutrients. However, there have been no studieshowing the effect of micronutrient supplementation in chil-ren with adequate dietary intake and no apparent clinicaleficiency of macronutrients. It is worthwhile to examineuch a situation because inadequate concentrations of mi-ronutrients in the body may be responsible for suboptimalrowth and development. To test this hypothesis, we carriedut a double-blind, placebo-controlled, cluster, randomized,atched-pair study in residential schoolchildren and com-

ared their micronutrient status before and after supplemen-ation.

aterials and methods

The details of the study design, composition, and admin-stration of the micronutrient-enriched beverage and otherritical issues related to the methodology of the study arerovided in a separate report [19]. Briefly, we have adopteddouble-blind, placebo-controlled, matched-pair, cluster,

andomization design. The children were 6 to 18 y of agend in grades 1 to 10 from a middle-income residentialchool near Hyderabad, India. Effect on biochemical statusas assessed in a randomly selected subsample of a mini-um of 4 to a maximum of 19 from each pair. There were

ine matched pairs available for biochemical status assess-ent at the end of 14 mo of supplementation.Various biochemical parameters such as hemoglobin,

erritin, calcium, phosphorus, parathyroid hormone (PTH),rinary iodine, triiodothyronine (T3), thyroid-stimulatingormone (TSH), albumin, zinc, vitamins A, C, D, B1, B2,6, and B12, and folic acid were measured at baseline andfter 14 mo.

Blood samples after an overnight fast or random urineamples were used for estimation. Hemoglobin was esti-ated by the cyanmethemoglobin method [20]; plasma lev-

ls of ferritin by enzyme-linked immunosorbent assay [21];itamin A by high-performance liquid chromatography22]; folic acid, vitamin B12 and PTH (Diagnostic Productsorporation, Los Angeles, CA, USA), and T3 (BRIT, Mum-ai, India) by radioimmunoassay kits; TSH by immunora-iometric assay (BRIT, Mumbai, India); vitamin C [23],rinary iodine [24], and phosphorus by colorimetry [25];lasma calcium [26] and zinc [27] by atomic absorptionpectrometry; vitamin D by protein binding assay [28];erum albumin by dye binding [29]; vitamins B1, B2, and6 by enzyme activation coefficient assays in erythrocyte

ysate [30]; and urinary riboflavin (B2) concentration was s

easured fluorometrically [31]. Because analysis of vitamincould not be performed immediately, the sample at base-

ine was smaller but was more than adequate for all otherarameters. For vitamin B6 the number was smaller ataseline due to some technical problems.

For convenience in comparison, different biochemicalndicators were broadly categorized according to their func-ional association with an important nutrient:

1. Measurements related to hemopoiesis (hemoglobin,ferritin, vitamin C, folic acid, vitamin B12, and vita-min A)

2. Measurements related to bone health (calcium, phos-phorus, vitamin D, PTH, zinc, and albumin)

3. Measurements related to iodine status (T3, TSH, andurinary iodine)

4. Measurements related to status of psychomotor vita-mins (vitamins B1, B2, and B6)

tatistical analysis

The percentage of inadequacy of micronutrient status ataseline in these schoolchildren was computed from cutoffalues derived from the literature [32–36]. The effect ofupplementation on indicators of micronutrient status wasvaluated in cohort samples from the differences betweennal and baseline values. Whenever baseline differencesetween groups differed (vitamin D), these differences wereorrected by a regression model before testing the finaleans between the supplement and placebo groups. Anal-

sis was also done to test whether the supplement had anyffect in improving hemoglobin in children who were ini-ially anemic by t test. SPSS 11.5 (SPSS, Inc., Chicago, IL,SA) was used for computation and statistical analysis.

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Subclinical deficiency or the proportion of children withnadequate micronutrient status is presented in Table 1. Ataseline, there were no significant differences in subclinicaleficiency in any biochemical indicator between the supple-ented and placebo groups; except for vitamin D. All chil-

ren in both groups had inadequate red blood cell (RBC)olate status. More than 50% of children had anemia andere deficient in vitamin C at the beginning. About 40% of

hildren had vitamin A and B12 inadequacies at baseline.The proportion of children who had poor calcium and PTH

tatus at baseline was low (�7%) except for vitamin D, whichas high and values were significantly different between the

upplement (30.3%) and placebo (21.6%) groups. The propor-ion with inadequacy of plasma zinc (�30 �mol/L) was very
mall and those with inadequate vitamin B2 and B6 were

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idespread because more than 65% of children in both groupsere deficient at the start of the study. However, the subclinicaleficiency of B1 was lower (�12%).

able 1icronutrient status of children at baseline

Micronutrient %Inadequate

Pooled Supplement Placebo

BC folate (�550 nmol/L) 99.0 98.0 100.0itamin B6 (�1.80 AAT-AC) 66.9 65.2 68.6itamin B2 (�1.40 GR-AC) 66.4 66.0 65.9itamin C (�30 �mol/L) 59.6 57.1 62.5emoglobin (�120 g/L) 55.7 54.8 56.6itamin A (�0.7 �mol/L) 43.9 54.7 33.1itamin B12 (�150 pmol/L) 43.8 39.3 48.4itamin D (�25 nmol/L) 25.9 30.3* 21.6itamin B1 (�1.25 TK-AC) 11.7 12.2 11.3alcium (�2.2 mmol/L) 6.1 5.8 6.4TH (�12 ng/L) 2.6 1.4 3.8inc (�10.7 �mol/L) 0.7 1.3 0hosphorus (�0.87 mmol/L) 0 0 0

3 (�1.08 nmol/L) 2.6 1.4 3.7SH (�0.17 mlU/L) 0.3 0.7 0rinary Iodine (�20 �g/L) 0 0 0

AAT-AC, aspartate aminotransferase activation coefficient; GR-AC,lutathione reductase activation coefficient; PTH, parathyroid hormone;BC, red blood cell; T3, triiodothyronine; TK-AC, transketolase activationoefficient; TSH, thyroid-stimulating hormone

* P � 0.01 by Wilcoxon’s sign-rank test.

ig. 1. Initial and final levels of hemoglobin, plasma ferritin, vitamin B1upplement (white bars) and placebo (black bars) groups at the beginning an
rom placebo group by paired t test, P � 0.001. RBC, red blood cell.
There was a very low prevalence of iodine deficiency asssessed with standard indicators of iodine deficiency (uri-ary iodine excretion level � 20 �g/L, T3 level � 1.08mol/L, and TSH � 0.17 mIU/L) in these schoolchildren.

ffect of daily intake of micronutrients

Results for various biochemical parameters at baselinend after supplementation are presented in Figs. 1 to 11.

Among the hematopoietic micronutrients tested, a sig-ificant net change was observed only with respect to folatend vitamin A (Figs. 1, 2, 7, and 8). Supplementation had noignificant effect in improving mean hemoglobin in theupplement or placebo group (Figs. 1 and 7). Althoughean serum ferritin levels in both groups were comparable

t baseline, concentrations decreased in both groups at thend of the treatment period. However, this decrease was notronounced in children who received the supplement andnal levels were significantly higher compared with those in

he placebo group. When pooled data from each group ofhildren who were anemic at baseline were considered, finalean hemoglobin concentration was significantly higher in

he supplement group than in the placebo group (Fig. 3).Daily intake of a micronutrient-enriched beverage regis-

ered significant increases in RBC folate status (Fig. 1) andlasma vitamin A and C levels (Fig. 2). Increments in RBC

BC folate. Bars represent the pooled mean � standard deviation of thef 14 mo of supplementation. ***Supplement group is significantly different

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olate status (Fig. 7) and vitamin A (Fig. 8) were signifi-antly higher in the supplement group than in the placeboroup and were uniform across grades 1 to 10. Althoughlasma vitamin B12 status (Fig. 1) was higher in the sup-lement group, it did not significantly differ from that in thelacebo group. The increment seen in vitamin C and B12evels over the study period was not confined to the treat-

ig. 2. Initial and final levels of plasma vitamin A and vitamin C. Bars replacebo (black bars) groups at the beginning and end of 14 mo of suppleaired t test, P � 0.001.

ig. 3. Mean hemoglobin levels in children with anemia (�120 g/L) and thean � standard deviation of supplement (white bars) and placebo (black b

ad anemia and received supplement were significantly different from those who

ent group because the placebo group also registered im-rovement (Fig. 7).

Zinc supplementation at 15% of Codex in the beverageid not increase plasma zinc levels (Fig. 4). Functionalnzyme status representing vitamins B1, B2, and B6 wasomparable at baseline between the supplement and placeboroups (Figs. 5 and 9). After supplementation, vitamin B2

the pooled mean � standard deviation of the supplement (white bars) andon. ***Supplement group is significantly different from placebo group by

hout anemia (�120 g/L) before and after supplementation. Bars representoups at the beginning and end of 14 mo of supplementation. Children who

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nd B6 statuses improved dramatically as reflected by aecrease in enzyme activity coefficients in both groups.owever, improvement in vitamin B2 status was signifi-

antly greater in the supplement group than in the placeboroup. In contrast, vitamin B1 status remained similar inoth groups at the beginning and end of the study period.

ig. 4. Plasma zinc in supplemented and placebo groups. Bars representooled mean � standard deviation of the supplement (white bars) andlacebo (black bars) groups at the beginning and end of 14 mo of supple-entation.

ig. 5. Initial and final levels of vitamins B1, B2, and B6 in supplement (wheviation of the supplement and placebo groups at the beginning and endifferent from placebo group by paired t test. AAT-AC, aspartate aminotran
K-AC, transketolase activation coefficient.
There were no significant differences in values of serumalcium, phosphorous, and PTH at baseline. At the end ofhe study, plasma PTH was significantly lower in the sup-lement group. Supplementation significantly increasedlasma vitamin D levels in the supplement group at the endf the study despite lower mean levels at the start of thetudy compared with the placebo group (Fig. 6). The mag-itudes of improvement were in opposite directions withespect to plasma PTH and vitamin D, lower and higherith supplementation, respectively (Fig. 10).There was no inadequacy of iodine in these schoolchil-

ren. Mean concentrations of T3 and TSH did not differetween groups at baseline or after the study period. Excre-ion of iodine in urine was significantly lower in the placeboroup than in the supplement group at baseline. Both groupshowed adequate excretion of iodine (�50 �g/L of urine).he decrease in TSH values in the supplement group wasignificant compared with the placebo group (Fig. 11).

Mean urinary excretion of riboflavin at the end of thetudy was higher in the supplement group (0.47 � 0.26g/mL, n � 113) than in the placebo group (0.26 � 0.17g/mL, n � 131).

) and placebo (black bars) groups. Bars represent pooled mean � standardmo of supplementation. ***P � 0.001, supplement group is significantlyactivation coefficient; GR-AC, glutathione reductase activation coefficient;

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Over the past four to five decades, the prevalence ofrotein-energy malnutrition, beriberi, and scurvy has de-reased in India with improvement in overall health facili-ies [37]. However, micronutrient malnutrition, also referredo as “hidden hunger,” remains a widespread problem. Forxample, in the National Nutrition Policy, deficiencies ofron, iodine, and vitamin A were considered to be of graveublic health importance because they cause impaired phys-cal and mental development, particularly in young, grow-ng children [38]. There have also been sporadic reports ofeficiencies of other micronutrients such as riboflavin, pyr-doxine, and folic acid in pregnant women and children39]. Although the prevalence of clinical signs of iron anditamin deficiencies has decreased, iron deficiency anemiaontinues to be a major problem. Among the many strate-ies suggested to control the prevalence of micronutrienteficiency, fortification of food(s) with micronutrients is aery practical and effective strategy.

The present results show surprising facts about the prev-lence of subclinical micronutrient deficiency in otherwiseealthy Indian children who live in semi-urban areas ofndia with adequate food intake.

Pooled baseline results using standard cutoffs suggesthat the prevalence of anemia (hemoglobin level � 120 g/L)

ig. 6. Initial and final levels of indicators of bone health in supplement (wheviation of the supplement and placebo groups at the beginning and endifferent from placebo group by paired t test (Final) and t test (Initial). PT

as as high as 54% in conjunction with widespread defi- p

iencies of folic acid (98%), vitamins B2 and B6 (65%),itamin A (44%), vitamin B12 (40%), and vitamin D (22%).his finding is in agreement with previous reports from this

egion and elsewhere in India for deficiencies of someicronutrients [5,14].Micronutrient supplementation did not increase hemo-

lobin levels and substantially improve storage iron (plasmaerritin), even though 100% of the Codex recommendedietary allowances (RDAs) for vitamin B12, folic acid, anditamin C and 50% of the Codex RDA for vitamin Aimportant micronutrients that assist in iron absorption)ere given in addition to iron.Plasma ferritin concentrations decreased in both groups

ver the course of the study. This effect is paradoxicalecause a decrease did occur in supplement group, evenhough the decrease was less. Increased serum ferritin con-entrations at baseline may have been due to infections.owever, the contribution of this factor is unlikely because

he decrease in ferritin was seen progressively over thentire study period (14 mo) and such a prolonged effectannot be attributed to infection. In addition, the childrenere apparently normal and did not have obvious undernu-

rition. However, they had severe micronutrient deficiencyt baseline. Anttila and Siimes [40] suggested that a de-rease in ferritin is an adaptive response reflecting increasedron utilization for tissue growth, and this process may be

) and placebo (black bars) groups. Bars represent pooled mean � standardmo of supplementation. ***P � 0.001, supplement group is significantlyathyroid hormone.

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articularly important during adolescence in boys and girls.

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oreover, an Indonesian study [10] associated a lack ofemoglobin response to supplementation with iron withong-term undernutrition and multiple micronutrient defi-iencies.

ig. 7. Changes in levels of hematopoietic micronutrients (final minus inilacebo (black bars) groups. ***P � 0.001, supplement group is significanlood cell.

ig. 8. Changes in levels of vitamin A (final minus initial). Bars representooled mean difference of the supplement (white bars) and placebo (blackars) groups. ***P � 0.001, supplement group is significantly different

orom placebo group by paired t test. 1 to 9, grades 1 to 9.

The effect of supplementation on RBC folate and plasmaitamin B12 level was very positive. However, this did notesult in improved hemoglobin to any significant extent,uggesting that the cause for anemia in these children wasainly due to lack of iron. The question of compliance to

everage intake during a vacation was verified by measur-ng urinary riboflavin. The supplement group had higherxcretion levels, suggesting that the children had consumedhe supplement. The chances of possible worm infestationeading to anemia were negligible in the present studyecause all subjects were dewormed before initiation anduring the supplementation period. The other possibility ishat the milk protein present in the drink could have che-ated some of the non-heme iron in the drinks and thusnfluenced its absorption. It may also be that the amount ofron (14 mg) provided through the supplement was insuffi-ient to meet the children’s requirements, which is higherhan the amount in the Codex RDA. The Indian RDA forron for children 6 to 16 y of age is 19 to 41 mg/d [41].owever, when the same data were stratified according to

hose who had anemia at baseline, a statistically significantmprovement in hemoglobin was seen after supplementationn comparison with placebo. Thus, improvement occurred

ars represent pooled mean difference of the supplement (white bars) anderent from placebo group by paired t test. 1 to 9, grades 1 to 9; RBC, red

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nly when there was a pre-existing deficiency of micronu-

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rients and this has been well established with iron defi-iency anemia.

No direct changes in plasma calcium were expectedespite 50% of the Codex RDA (400 mg) being supple-ented daily. However, there was a significant decrease inTH levels of the supplement group compared with thelacebo group, which can be considered an effect of sup-lementary calcium. As expected, 25OH D3 levels repre-enting vitamin D status also improved significantly in theupplement group; all of these promote increased calciumetention. It is not clear whether this was a reflection of thehanges taking place in the body (drawing more mineralnto the bone) because total bone area and muscle massere increased in the supplemented children [42].There was no difference in incremental values of urinary

odine or associated hormones except suppression in thenal TSH level in the supplement group. The adequate levelf excretion of iodine is in tune with the lower goiterrevalence noted in these children [43]. The change in TSHevel may be a reflection of the improved iodine status,

ig. 9. Changes in levels of B vitamins (final minus initial). Bars representroups. ***P � 0.001, supplement group is significantly different fromminotransferase activation coefficient; GR-AC, glutathione reductase act

hich in turn would improve hormone synthesis. s

B-complex vitamins such as B1, B2, and B6 usually occurn food together and have parallel effects on psychomotorunction. The present results showed that there was a signifi-ant prevalence of vitamin B2 and B6 deficiencies at baseline.owever, supplementation had a differential effect on the

tatus of vitamins B2 and B6. Although levels of B2 improvedignificantly, B6 levels showed a variation over the studyeriod (from 65% to 12%), although supplementation for bothitamins was 100% of the Codex RDA. Such fluctuations initamin B6 levels may be due to seasonal changes in intake orequirements. However, vitamin B1 levels in both groups re-ained unchanged. Because supplementation of vitamin B1as at 50% of the Codex RDA, it can be argued that fortifi-

ation at 50% of the RDA (0.7 mg) is inadequate. However,he level of inadequacy at baseline did not support this notion.t is very important to provide adequate dietary intake of B1,2 and B6 vitamins in children because the inadequacy of

hese vitamins has been associated with decreased psychomo-or function in children [5,9]. When assessing the effect of

icronutrient supplementation on mental function, the present

mean difference of the supplement (white bars) and placebo (black bars)bo group by paired t test. 1 to 9, grades 1 to 9; AAT-AC, aspartatecoefficient; TK-AC, transketolase activation coefficient.

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nox Cube Test were higher in the supplement group than inhe placebo group [44].

There was no inadequacy of zinc as assessed by plasmainc concentration. This could be due to the poor sensitivityf plasma zinc concentration to reflect zinc status and theow level of zinc supplementation of 15% of the zinc CodexDI, which could not have made any difference to zinc

tatus. The reason for limiting the amount of zinc in theupplement to 15% of the Codex RDI was to conform to theocal regulatory requirement.

It is also worth mentioning that the present results wouldave been more amplified if the placebo had not been not ailk-based malted beverage because the milk and otheralted ingredients inherently contain micronutrients, whichould have conferred some beneficial effect to the placebo

ecipients, thereby decreasing the actual difference betweenhe supplement and placebo groups.

Many of the studies conducted previously in Indian chil-ren have shown that the state of health, particularly mi-ronutrient deficiency of schoolchildren, is far from satis-actory despite the fact that school health programs andther nutritional programs have been in operation for sev-

ig. 10. Changes in levels of indicators of bone health (final minus initial). Barars) groups. ***P � 0.001, supplement group is significantly different from

s represent pooled mean difference of the supplement (white bars) and placebo (black

ral decades [39–41]. However, most of these studies were s

ig. 11. Changes in levels of TSH (final minus initial). Bars representooled mean difference of the supplement (white bars) and placebo (blackars) groups. ***P � 0.001, supplement group is significantly differentrom placebo group by paired t test. 1 to 9, grades 1 to 9; TSH, thyroid-
timulating hormone.

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arried out in rural areas and in essentially malnourishedhildren with clinical signs and symptoms of micronutrienteficiency. In contrast, the present study evaluated subjectsho were apparently normal and healthy children with no

linical signs of deficiency. The diet provided, on average,0% of energy requirements. Intakes of protein, fat, cal-ium, folic acid, and vitamin C were adequate as per theDA for Indians [43]. The diet was limiting in some mi-ronutrients such as iron, thiamin, niacin, and vitamin A.he only difference between the placebo and supplementroups was the additional micronutrient provided in theupplement.

onclusion

Daily intake of a micronutrient-enriched beveragehowed a significant positive shift in the status of nutrientsuch as vitamins A, C, B2, and B12, folic acid, vitamin D,nd calcium across the age groups of 6 to 16 y, indicatinghe efficacy of this approach in correcting biochemical de-letion of multiple micronutrients. Thus, there is clearly areater need for micronutrient supplementation even in ap-arently normal healthy children.

cknowledgements

The authors are grateful for the expert advice of P.haskaram, M.D., A. Nadamuni Naidu, M.Sc., and B.esikeran, M.D., of the National Institute of Nutrition, Hy-erabad, India and of Sudhakara Rao, M.D., of the Henryord Hospital, Detroit, MI, USA.

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