Risk of Zinc, Iodine and Other Micronutrient Deficiencies Among School Children in North East Thailand

Home , Iodine deficiency, Retinol, Vitamin A, Vitamin A deficiency

ORIGINAL ARTICLE Risk of zinc, iodine and other micronutrient deficiencies among school children in North East Thailand

RA Thurlow2, P Winichagoon1, T Pongcharoen1, S Gowachirapant1, A Boonpraderm1, MS Manger2, KB Bailey2, E Wasantwisut1 and RS Gibson2

1Institute of Nutrition, Mahidol University, Salaya, Thailand and 2Department of Human Nutrition, University of Otago, New Zealand

Introduction: Micronutrient deficiencies during childhood can contribute to impairments in growth, immune competence, and mental and physical development, and the coexistence of several such deficiencies can adversely affect the efficacy of single micronutrient interventions. Objective: To assess the prevalence of zinc and iodine deficiency and their interrelationships with vitamin A deficiency and anemia and associations with socio-economic status, hemoglobin type, and anthropometry in a cross-sectional study. Setting: A total of 10 primary schools in North East Thailand. Methods: Non-fasting venipuncture blood samples and casual urine samples were collected from 567 children aged 6–13 years. Anthropometric measures and serum zinc, albumin, C-reactive protein and urinary iodine, are reported here and integrated with published data on vitamin A, anemia, and socio-economic status. Results: Of the children, 57% had low serum zinc and 83% had urinary iodine levels below the 100 mg/l cutoff. Suboptimal serum zinc and urinary iodine concentrations may result from low intakes of zinc and iodized salt. Significant risk factors for low serum zinc were serum retinol o1.05 mmol/l and being male. Those for urinary iodine o100 mg/l were height-for-age score4median and being female. For serum retinol o1.05 mmol/l, risk factors were low hemoglobin, low serum zinc, and o9 years, and for low hemoglobin indicative of anemia risk factors were o9 years, AE hemoglobinopathy, and serum retinol o1.05 mmol/l. Of the children, 60% were at risk of two or more coexisting micronutrient deficiencies, most commonly suboptimal urinary iodine and low serum zinc. Conclusion: The findings emphasize the need for multimicronutrient interventions in North East Thailand. European Journal of Clinical Nutrition (2006) 60, 623–632. doi:10.1038/sj.ejcn.1602361; published online 14 December 2005

Keywords: zinc; iodine; vitamin A; anemia; children; Thailand

Introduction impact on the efficacy of single micronutrient intervention programs (Zimmermann et al., 2000; Hurrell and Hess, 2004; Coexisting micronutrient deficiencies in developing countries Lo¨nnerdal, 2004). The etiology of coexisting micronutrient are gaining increasing recognition. They can have a negative deficiencies is multifactorial: inadequate intakes, and genetic, parasitic and/or infectious diseases may all play a role (Egger et al., 1990; Fishman et al., 2000; Stoltzfus, 2001). Such Correspondence: Dr RS Gibson, Department of Human Nutrition, University of Otago, PO Box 56, Union Street, Dunedin, New Zealand. deficiencies during childhood contribute to impairments in E-mail: [email protected] growth, immune competence, and mental and physical Guarantor: RS Gibson. development (Viteri and Gonzalez, 2002). Contributors: RAT and RSG wrote the manuscript, with input from other In developing countries, poor dietary quality is often a authors. PW and RSG developed the study hypothesis and secured the funding and TP was the project field co-ordinator. RAT, TP, MSM, SG, AB, PW and RSG major determinant of inadequate micronutrient intakes. participated in the collection, analyses, and/or interpretation of the data. KBB Diets of poor quality are predominantly plant based, and carried out the biochemical analyses undertaken in New Zealand, EW often contain very small amounts of expensive animal supervised the analysis and interpretation of the serum retinol values in source foods. The quality of children’s diets may be Thailand. Received 25 April 2005; revised 11 October 2005; accepted 20 October 2005; particularly poor in the North East region of Thailand where published online 14 December 2005 the per capita income and education level are among the Zinc and iodine deficiencies among children in NE Thailand RA Thurlow et al 624 lowest in the country (Department of Health, 1995). Dietary Ubon Ratchathani province, North East Thailand. Details of surveys have reported low intakes of iron, zinc, and vitamin the subjects, their socio-demographic and health status, the A during childhood (Bloem et al., 1989a; Udomkesmalee prevalence of hemoglobinopathies, and their hematology et al., 1990; Egger et al., 1991) but very few studies and biochemical iron and vitamin A status have been have examined the prevalence of coexisting biochemical described elsewhere (Thurlow et al., 2005). Permission was micronutrient deficiencies in this region (Udomkesmalee sought from local school boards and Thai health workers et al., 1990). following meetings in which the purpose and methods of Inadequate intakes of iodine, selenium, and zinc can also the study were clearly explained by one of the principal be exacerbated by environmental factors, because their investigators (PW). The Human Ethics Committees of concentrations in plant-based foods are dependent on soil Mahidol University (Thailand) and the University of Otago trace element levels. North East Thailand is a region with low (New Zealand) approved the survey protocol. soil iodine and zinc concentrations, sometimes exacerbated Children aged 6.0–12.9 years that attended the largest by leaching through flooding (Wanaratana, 1992; Alloway, school in each of the 10 selected rural subdistricts were 2004), so it is not surprising that deficiencies of iodine eligible to participate. Ages of the children were obtained and zinc have been observed among school-aged children from the school records. Within each school, the target in the region (Udomkesmalee et al., 1990; Wongtala et al., enrollment was 60 children. Eligible children, whose parents 2000). Hemoglobinopathies are also common in the popu- or guardians gave informed written consent, were stratified lation of North East Thailand, especially the hemoglobin within each school by age and gender, and equal numbers E variant, which results in hypochromic, microcytic anemia of children were randomly selected from each stratum. The (Na-Nakorn et al., 1956). total number of children recruited was based on the sample In certain regions of Thailand, parasitic infections (Koski size needed for the intervention trial. The intended sample and Scott, 2001) and infectious diseases (Filteau and size for the trial was 500 children, based on an assumed Tomkins, 1994) may be additional factors exacerbating anemia prevalence of 20% in NE Thai school children micronutrient deficiencies because they induce anorexia (Department of Health, 1995). Because of the better than as well as a variety of pathophysiological responses in the expected response rate for involvement in the trial, 567 gastrointestinal tract (i.e. vomiting, diarrhea, malabsorption) children (281 males and 286 females) participated in the which increase micronutrient losses. Moreover, because baseline survey, which was conducted during the rainy deficiencies of zinc, iron, and vitamin A all impair immune season of June and July 2002. This sample size also allows function (Filteau and Tomkins, 1994), children with these estimation of the prevalence of micronutrient deficiencies micronutrient deficiencies are likely to become more heavily to within 5 percentage points of the true value with 95% infected with parasites, and more susceptible to infectious confidence, assuming an anticipated population proportion diseases, further exacerbating micronutrient malnutrition. (P) ¼ 0.5. The latter was chosen because a figure of 0.5 In the past, most nutrition interventions in Thailand have provides the safest choice, when estimates of P are not focused on deficiencies of single micronutrients, notably available. Use of these stated parameters yields a sample size iron, vitamin A, zinc, or iodine (Bloem et al., 1989b; Hathirat of 380 children (Lwanga and Lemeshow, 1991). et al., 1992; Pongpaew et al., 1998). Increasingly, interventions in Thailand and other regions are including more than one micronutrient (Udomkesmalee et al., 1992; Suharno et al., 1993; Ahmed et al., 2001; Dijkhuizen et al., Anthropometry 2001), although not necessarily the micronutrients that are Prior to the anthropometric assessment, the precision of the the most limiting. anthropometric measurements was determined by calculat- The aim of this study was to investigate the importance of ing the technical error of each measurement on 20 children coexisting multimicronutrient deficiencies among children (Lohman et al., 1988). Measurements of weight, standing in North East Thailand by examining the prevalence and height, and mid-upper arm circumference were taken in interrelationships of deficiencies of zinc, iodine, vitamin triplicate using calibrated equipment and standardized A, and anemia among primary school children. Associations techniques, with children wearing light clothing and no with hemoglobin type, socio-demographic, and anthropo- shoes (Lohman et al., 1988). Each measurement was taken metric status were also examined. by the same trained anthropometrist to eliminate interex- aminer error. Z-scores for height-for-age (HAZ), weight-for- age (WAZ), and weight-for-height (WHZ) were calculated Subjects and methods from NCHS/CDC/WHO 1977 growth reference data using the EPiINFO program (version 6.0, USD Inc., Stone Subjects Mountain, GA, USA). Mid-upper-arm circumference-for-height Briefly, this cross-sectional study was part of the baseline (MUACH) Z-scores were also calculated from the MUAC-for data collection for an intervention trial conducted between height reference for international use compiled by Mei et al. June 2002 and March 2003 in 10 poor rural subdistricts of (1997).

European Journal of Clinical Nutrition Zinc and iodine deficiencies among children in NE Thailand RA Thurlow et al 625 Laboratory and clinical assessment (s.d. 0.7) mmol/l (CV 5.5%, n ¼ 5) and 52 (s.d. 2) g/l (CV 2.8%, Urinary iodine was determined on morning casual urine n ¼ 34), respectively. Corresponding certified values were samples (15 ml) frozen at À201C prior to analysis. Measure- 13.6 (range 12.6–14.5) mmol/l for zinc and 51 (range ment of urinary iodine concentrations was performed at 44–59) g/l for albumin. Ramthibodi Hospital, Mahidol University, Thailand, using a spectrophotometric technique based on the method of Benotti et al. (1965). The coefficients of variation for low, Statistical analyses medium, and high urinary iodine controls were 20.9, 6.0, Statistical analyses were carried out using EPiINFo (version and 3.5%, respectively. A single trained Thai nurse (TP) using 3.2.2; CDC, Atlanta, GA, USA), SPSS (version 12.0.1; USD a standardized procedure for palpation also examined the Inc., Stone mountain, GA, USA), and Stata 5.0 (College presence of goiter on each child; thyroid size was graded Station, TX, USA). Data were checked for normality by using according to the WHO/UNICEF/ICCIDD (2001) criteria. the Komogorov–Smirnov test. Continuous data were pre- A non-fasting venipuncture blood sample was drawn in sented as medians and interquartile ranges (IQR). Differences the morning from each child in the recumbent position, into by age and gender were tested using the independent groups a trace element-free evacuated tube protected from the light t-test or the Kruskal-Wallace test, where appropriate for the (Becton Dickinson, Franklin Lakes, NJ, USA). Blood samples continuous variables, and the w2 test for categorical variables. were refrigerated immediately after collection, and the serum Correlations between anthropometric, socio-economic separated within one hour using appropriate trace-element- (i.e. annual income, education level of head of household, free techniques (Hotz and Brown, 2004) for the analyses of caregiver or mother, occupation of head of household), and serum zinc and albumin. Serum ferritin, transferrin receptor, biochemical indices were examined using Spearman’s Rank C-reactive protein (CRP), and retinol were also analyzed, as Correlations test. described earlier (Thurlow et al., 2005). An additional 7 ml Logistic regression analysis was used to examine the blood was drawn into an EDTA-treated evacuated tube for relationship between suboptimal micronutrient status and complete blood count and hemoglobinopathy analysis a number of variables that were known or suspected to have (Thurlow et al., 2005). biological importance for that particular micronutrient. Briefly, the analysis of serum ferritin was performed with Variables investigated included: sex, age, HAZ score, AE an IMx analyzer (Abbott Laboratories, Abbott Park. IL, USA) hemoglobinopathy, low serum zinc concentrations, low which uses Microparticle Enzyme Immunoassay (MEIA) hemoglobin concentrations, and low serum retinol concen- technology, serum transferrin receptor with an enzyme trations o1.05 mmol/l. immunoassay and commercial kits (Ramco Laboratories The following interpretive criteria were used to define Inc, Houston, TX, USA), CRP by using the Behring Turbiti- risk of coexisting micronutrient deficiencies: serum zinc mer System (Behring-werke AG Diagnostica, Germany), and o9.9 mmol/l (children o10 years); serum zinc o10.7 mmol/l retinol by the HPLC method of the International Vitamin A (males X10 years); serum zinc o10.15 mmol/l (females X10 Consultative Group (IVACG, 1982). A complete blood count years) (Hotz and Brown, 2004); urinary iodine o100 mg/l was obtained with an electronic Coulter Counter (Beckman, (WHO/UNICEF/ICCIDD, 2001); hemoglobin o115 g/l Fullerton, CA, USA), and hemoglobinopathy analyses were (children 6.0–11.99 years); hemoglobin o120 g/l (children performed by using the Variant b-Thalassemia Short Program X12 years) (Stoltzfus and Dreyfuss, 1998); serum retinol (Bio-Rad Laboratories Inc., Hercules, CA, USA). Details of the o1.05 mmol/l (Ballew et al., 2001). For CRP, serum concen- procedures used to check the precision and accuracy of these trations X10 mg/l were taken to indicate the presence of analytical methods are given in Thurlow et al. (2005). inflammation or infection as recommended by the manu- Serum zinc analysis was performed by flame atomic facturer, whereas for serum albumin, values below the 2.5th absorption spectrophotometry (Perkin Elmer 2690, Ebos percentile of the reference data of Ritchie et al. (1999) were Group Ltd, Auckland, New Zealand) using a standardized used to indicate low levels. Statistical significance was set at procedure (Smith et al., 1979). Serum albumin was deter- Po0.05. mined using an automated dye-binding method with bromocresol green (McPherson and Everard, 1972). Serial replicates of aliquots from a pooled serum sample and Results quality control sera were used to check the precision and accuracy of the zinc and albumin assays. The coefficients Anthropometric assessment of variation (CV) for zinc and albumin in a pooled serum Table 1 presents the median (1st–3rd quartile) growth sample were 6.1 % (n ¼ 26) and 3.2% (n ¼ 34), respec- measurements and HAZ, WAZ, WHZ, and MUACH Z-scores tively. Mean values for the quality control sera for zinc for the children by age and gender. For each age range, (Bovine Serum Reference Material no. 1598; National females had HAZ scores that were less negative than males, Institute of Standards and Technology, Gaithersburg, MD, and in the youngest and oldest age group this difference was USA) and albumin (N/T Protein Control SL/M, Dade Bhering significant. Median WAZ scores were similar for males and Marburg GmbH, D-35041, Marburg, Germany) were 13.1 females for all age groups, as were the median WHZ scores

European Journal of Clinical Nutrition Zinc and iodine deficiencies among children in NE Thailand RA Thurlow et al 626 Table 1 Selected anthropometric variables by age and gender a

Age (years) 6.00–7.99 years 8.00–9.99 years 10.00–12.99 years

Females n ¼ 89 n ¼ 91 n ¼ 106 Height (cm) 116.0 (113.6, 119.5) 126.4 (122.4, 130.7) 138.0 (133.7, 142.5) Weight (kg) 18.5 (17.3, 19.9) 22.7 (20.9, 25.2) 29.5 (26.6, 33.4) Height-for-age Z-scoresb À0.7 (À1.3, À0.3) À0.9 (À1.4, À0.3) À1.1 (À1.5, À0.4) Weight-for-age Z-scoresb À1.2 (À1.7, À0.8) À1.3 (À1.7, À0.8) À1.2 (À1.7, À0.5) Weight-for-height Z-scoresb,f À1.0 (À1.4, À0.6) À1.0 (À1.5, À0.4) (n ¼ 88) À0.7 (À1.2, 0.1) (n ¼ 47) MUAC-for-height Z-scoresc,d À1.3 (À1.8, À0.8) À1.1 (À1.8, À0.4) À0.9 (À1.6, À0.3) (n ¼ 91)

Males n ¼ 86 n ¼ 89 n ¼ 106 Height (cm) 116.6 (113.9, 120.5) 125.9 (121.7, 131.0) 134.9 (129.8, 139.1) Weight (kg) 19.0 (18.1, 21.1) 23.4 (21.4, 26.1) 27.2 (24.7, 30.1) Height-for-age Z-scoresb À1.3 (À1.7, À0.7)e À1.0 (À1.7, À0.3) À1.2 (À1.9, À0.7)e Weight-for-age Z-scoresb À1.5 (À2.0, À0.9) À1.2 (À1.8, À0.6) À1.4 (À1.9, À0.9) Weight-for-height Z-scoresb À0.9 (À1.5, À0.5) À0.9 (À1.4, À0.2) À0.7 (À1.2, À0.1) (n ¼ 82) MUAC-for-height Z-scoresc,d À1.0 (À1.7, À0.6) À0.9 (À1.4, À0.3) À0.8 (À1.3, À0.1) (n ¼ 99)

aMedian and interquartile range. bNCHS reference data, WHO (1983). cMid-upper arm circumference-for-height Z-scores (children o145 cm only (Mei et al., 1997). dSignificantly different by age group (Po0.05). eSignificantly different from females (Po0.05). fWeight-for-height Z-scores (children o10 years and/or with height o145 cm).

for the two groups of children aged 6.00–7.99 and 8.00–9.99 Table 2 presents the median urinary iodine concentra- years. Median MUAC-for-height Z-scores were similar for tions by sex and age. Values were highest for the youngest males and females for all age groups, and increased male and female children (i.e. 6.00–7.99 years), although significantly with increasing age in both groups. this age-related trend was only significant for the males Overall, the prevalence of stunting (i.e. HAZ oÀ2 s.d.) was (Po0.01). The median urinary iodine concentration was 10% (n ¼ 58). Stunting was higher among males than females significantly higher in the males than the females (i.e. 62.2 (14 vs 7%; P ¼ 0.004). The prevalence of stunting increased vs 46.6 mg/l; Po0.001), and indicative of mild iodine significantly with increasing age among males (P ¼ 0.028) deficiency, whereas for the females, the median level but was independent of age in females. The prevalence of corresponded to moderate iodine deficiency (WHO/UNICEF/ underweight (i.e. WAZ oÀ2 s.d.) was 12% (n ¼ 65). Under- ICCIDD, 2001). Consequently, as shown in Table 2, fewer weight followed the same trend as stunting, with a higher males than females had urinary iodine concentrations prevalence among males than females (15 vs 8%; P ¼ 0.004), below the WHO/UNICEF/ICCIDD (2001) criteria indica- but was independent of age for both genders. Among the tive of iodine deficiency disorders (IDDs). Nevertheless, in 481 children for whom WHZ scores could be calculated total 44 and 8% of the children had urinary iodine (i.e. those o10 years and/or with height o145 cm), the concentrations indicative of moderate and severe iodine prevalence of wasting (i.e. WHZ oÀ2 s.d.) was 5% (n ¼ 23). deficiency, respectively. Mid-upper arm circumference-for-height Z-scores could only As expected, children with elevated serum CRP levels be calculated for 545 children (Mei et al., 1997). Overall, the indicative of inflammation and infection (n ¼ 12) had a prevalence of low MUACHZ (i.e. oÀ2 s.d.) was 11% (n ¼ 59), significantly lower median value for serum zinc (7.7 vs and tended to be higher among females than males (13 vs 9.8 mmol/l; Po0.001) than those without inflammation 8%; P ¼ 0.07). The prevalence of low MUACH Z-scores or infection. These subjects were excluded from any decreased significantly with increasing age among males further statistical analyses of the serum zinc and serum (Po0.004); a nonsignificant age-related trend was also found retinol data. Serum zinc concentrations were independent among females. of hemoglobin type and age, but males tended to have lower concentrations than females (Table 3). Accordingly, the prevalence of low serum zinc concentrations was Iodine, zinc, and albumin assessment significantly higher in the males than in the females (64 vs The prevalence of goiter was low (i.e. 3.4%). Only 19 51%; P ¼ 0.004), and higher in the older children compared children had palpable but non-visible goiter (i.e. grade 1 to their younger counterparts (P ¼ 0.04). Geographic goiter), of whom 18 were aged between 8–12 years, and 14 variation in serum zinc concentrations was observed and were females. No children had grade 2 goiter. There was no reflected in significant interschool differences in mean difference in median HAZ and WAZ scores of children with serum zinc concentrations (data not shown). Mean (s.d.) and without grade 1 goiter. serum albumin concentration for the males was significantly

European Journal of Clinical Nutrition Zinc and iodine deficiencies among children in NE Thailand RA Thurlow et al 627 Table 2 Urinary iodine levels (mg/l) (n ¼ 567) and percentage of children below cutoffsa for severe, moderate and mild iodine deficiency

Age (years) n Median (IQR) Percentage (95% CI) Percentage (95% CI) Percentage (95% CI) o20 (mg/l) o50 (mg/l) o100 (mg/l)

Females 6.00–7.99 year 89 53.7 (30.6, 77.5) 9.0 (3.9, 16.9) 46.1 (35.4, 57.0) 84.3 (75.0, 91.1) 8.00–9.99 years 91 44.3 (28.8, 69.2) 13.2 (7.0, 21.9) 57.1(46.3, 67.4) 87.9 (79.3, 93.8) 10.00–12.99 years 106 47.1 (30.8, 74.3) 12.3 (6.7, 20.1) 51.9 (42.0, 61.7) 89.6 (82.2, 94.7)

Subtotal 286 46.6 (30.3, 73.9) 10.8 (7.4, 15.0) 51.7 (45.8, 57.7) 87.4 (83.0, 91.0)

Males 6.00–7.99 years 86 74.7 (56.6, 106.3) 3.5 (0.7, 9.9) 19.8 (12.0, 29.7) 72.1 (61.4, 81.2) 8.00–9.99 years 89 55.2 (39.5, 93.7)b 5.6 (1.8, 12.6) 42.7 (32.2, 53.6)b 83.1 (73.7, 90.2) 10.00–12.99 years 106 58.0 (40.8, 83.1)b 4.7 (1.6, 11.2) 41.5 (32.0, 51.5)b 80.2 (71.3, 87.3)

Subtotal 281 62.2 (43.2, 95.2)c 4.6 (2.5, 7.8)c 35.2 (29.7, 41.1)c 78.6 (73.4, 83.3)c

Total 567 55.2 (36.7, 82.2) 7.8 (5.7, 10.3) 43.6 (39.4, 47.8) 83.1 (79.7, 86.1)

IQR, Interquartile range. aWHO/UNICEF/ICCIDD (2001). bSignificantly different from males aged 6.00–7.99 years (Po0.01). cSignificantly different from females (Po0.01).

Table 3 Serum zinc levelsa (mmol/l) (n ¼ 484) and percentage of urinary iodine concentration below 100 mg/l in combination children with low serum zinc values with a low serum zinc, 122 (21.5%) had coexisting anemia Age (years) n Median Percentage (95% CI) of and a urinary iodine concentration below 100 mg/l, and 93 (IQR) children with low serum (16%) had a serum retinol concentration below 1.05 mmol/l zinc concentrationsb and urinary iodine below 100 mg/l. In all, 76 children (13%) had a suboptimal biochemical status for three or more Females coexisting micronutrients. 6.00–7.99 years 73 10.1 (8.5, 11.4) 47.9 (36.1, 60.0) 8.00–9.99 years 76 10.1 (8.7, 11.3) 46.1 (34.5, 57.9) The logistic regression analysis presented in Table 4 high- 10.00–12.99 years 96 9.7 (8.6, 11.1) 56.3 (45.7, 66.4) lights the strong interrelationship of low serum zinc, serum retinol o1.05 mmol/l, and low hemoglobin concentrations; Subtotal 245 10.0 (8.7, 11.2) 50.6 (44.2, 57.0) serum retinol concentrations o1.05 mmol/l (odds ratio of Males 1.65; P ¼ 0.028) are a predictor of low serum zinc, low 6.00–7.99 years 77 9.5 (8.4, 11.2) 58.4 (46.6, 69.6) hemoglobin and low serum zinc are both significant 8.00–9.99 years 75 9.2 (8.2, 11.0) 61.3 (49.4, 72.4) predictors for serum retinol o1.05 mmol/l, and serum retinol 10.00–12.99 years 87 9.3 (8.6, 11.0) 70.1 (59.4, 79.5) o1.05 mg/l is a predictor for low hemoglobin (odds ratio of Subtotal 239 9.3 (8.4, 10.9) 63.6 (57.2, 69.7)c 1.61; P ¼ 0.062). Being aged less than 9 years is a predictor for both serum retinol o1.05 mmol/l (odds ratio of 1.49; Total 484 9.6 (8.5, 11.1) 57.0 (52.4, 61.5) P ¼ 0.078), and low hemoglobin concentrations (odds ratio P IQR, Interquartile range. of 2.42; o0.001). aExcluding children with infection (C-reactive protein X10 mg/l). In contrast there was no association between suboptimal bSerum zinc o9.9 mmol/l (children o10 years); serum zinc o10.7 mmol/l urinary iodine concentrations and low serum zinc, serum X X (males 10 years); serum zinc o10.15 mmol/l (females 10 years) (Hotz and retinol o1.05 mmol/l, or hemoglobin, serum ferritin or Brown, 2004). cSignificantly different from females (P ¼ 0.004). transferrin receptor concentrations indicative of low iron status; sex ¼ female and an HAZ score4median were the significant predictors for urinary iodine o100 mg/l. Serum lower than for the females (4.64 70.37 vs 4.7670.40 g/l; zinc was positively correlated with serum albumin levels P ¼ 0.001). (n ¼ 457, r ¼ 0.140; P ¼ 0.003). No significant relationships could be demonstrated between serum zinc and growth or MUACH Z-scores for the Interrelationships among biochemical, anthropometric, and prepubertal children (aged o9 years). However, males had an socioeconomic variables almost two-fold greater risk of being zinc deficient than In this study 60% (n ¼ 289) of the NE Thai school children females (Table 4). Similarly, there were no relationships had evidence for suboptimal biochemical status for two or observed between any of the biochemical indices and the more micronutrients. Of the children, 241 (42.5%) had a measured socioeconomic variables.

European Journal of Clinical Nutrition Zinc and iodine deficiencies among children in NE Thailand RA Thurlow et al 628 Table 4 Risk factors for suboptimal levels of biochemical indices of micronutrient status

Dependent variable Independent variables Odds ratio 95% CI for odds ratio P-value for odds ratio

Low serum zinc concentrationa (n ¼ 474) Sex ¼ male 1.73 1.20À2.50 0.004 Serum retinol o1.05 mmol/l 1.65 1.05À2.57 0.029 Age, low Hb, HAZ 4median 40.1

Urinary iodine o100 mg/l (n ¼ 558) Sex ¼ female 1.83 1.15À2.89 0.010 HAZ score 4median 1.66 1.05À2.64 0.031 Age, low Hb, low serum retinol 40.1

Serum retinol o1.05 mmol/l (n ¼ 473) Low Hb concentrationb 1.69 1.07À2.66 0.025 Low serum zinc concentrationa 1.66 1.06À2.60 0.026 Age o9.0 years 1.49 0.96À2.31 0.078 Sex, HAZ 4median 40.1

Low hemoglobin (Hb) concentrationb,c (n ¼ 453) Age o9.0 years 2.42 1.56À3.77 o0.001 AE hemoglobinopathy present 2.17 1.40À3.38 0.001 Serum retinol o1.05 mmol/l 1.61 0.98À2.64 0.062 Sex, HAZ 4median, low serum zinc 40.1

Five independent variables were initially entered into each logistic regression equation. Variables with a P-value for the odds ratio of 40.1 were eliminated from the model. These variables are shown in each case as 40.1. The reported odds ratios are adjusted for the independent variables remaining in the equation. aSerum zinc o9.9 mmol/l (children o10 years); serum zinc o10.7 mmol/l (males X10 years); serum zinc o10.15 mmol/l (females X10 years) (Hotz and Brown, 2004). bHemoglobin o115 g/l, 6–11.99 years; o120 g/l, X12 years (Stoltzfus and Dreyfuss, 1998). cChildren with hemoglobinopathy type EE were excluded.

Discussion et al., 2001; Skeaff et al., 2002; Sebotsa et al., 2003) studies of school-aged children. Reasons for these sex-related The most striking finding of this study was the high differences are unclear. It is unlikely to be associated with prevalence of both suboptimal iodine and zinc status differences in the time of the urine sample collections among the children (Tables 2 and 3), concomitant with the because all the samples were collected in the morning (Frey relatively high levels of anemia (i.e. 31%) and marginal et al., 1973). It is possible that more of the older girls than vitamin A deficiency (i.e. 20%), reported earlier (Thurlow boys were experiencing their pubertal growth spurt, and et al., 2005). thus had higher iodine requirements for growth than their male counterparts. Whether these sex-related differences in median urinary iodine concentration had any adverse functional health consequences among the girls is unknown. Iodine status A survey of a random subsample of the children’s house- Our results emphasize that mild iodine deficiency disorders holds suggested that only about 15% used iodized salt. This (IDDs) are still a major public health problem in this region finding is disappointing in view of the extensive range of (WHO/UNICEF/ICCIDD, 2001) (Table 2), despite the intro- IDD control measures implemented in Thailand by the duction by the government of Thailand of several strategies government since 1993, when the goiter rate exceeded 5% to combat iodine deficiency (Wanaratana, 1992; Department (Wanaratana, 1992; Department of Health, 1998). However, of Health, 1998). Nevertheless, few of the children (i.e. 8%) it is possible that more attention was directed to the area had levels indicative of severe iodine deficiency (Table 2), along the northern mountain ranges where goiter rates were and the prevalence of goiter was low (3.4%), and below that higher than in the North East region. Lack of knowledge of indicative of IDD as a significant public health problem (i.e. the importance of iodized salt for optimal health, inadequate 45%) (WHO/UNICEF/ICCIDD, 2001). Indeed the goiter availability of quality iodized salt (Zimmermann et al., 2004), rate was similar to that reported for children in North or financial constraints may also be implicated (Dunn, 2000) East Thailand by the 1995 Thai National Nutrition Survey in the moderate IDD remaining. A sustained effort must be (Department of Health, 1995). However, even mild to made to eradicate mild and moderate iodine deficiency in moderate iodine deficiency can have detrimental effects in this North East region of Thailand. children, causing impairments in both neuropsychological and physical development (van den Briel et al., 2000; WHO/ UNICEF/ICCIDD, 2001). In this study, girls appeared to be more at risk to IDD than Zinc status boys (Tables 2 and 4). This trend is in accordance with The high prevalence of low serum zinc concentrations findings of some (Hollowell et al., 1998) but not all (Hess indicative of zinc deficiency noted here (Table 3) is nearly

European Journal of Clinical Nutrition Zinc and iodine deficiencies among children in NE Thailand RA Thurlow et al 629 three times higher than the level set by IZiNCG as indicating inflammation noted here is well characterized, and attri- the need for a national intervention programme (Hotz and buted to the redistribution of zinc from plasma to the liver, Brown, 2004). Very few other studies in Thailand have induced by cytokines released during the acute-phase examined the zinc status of school children, with the response (Schroeder and Cousins, 1990). Reasons for the exception of a study in 1990 conducted in the same region, association between school and serum zinc concentrations in which 70% of the primary school children were reported to noted here are unclear. They are unlikely to be due to be zinc deficient (Udomkesmalee et al., 1990). By comparison, differences in the handling, separation, and analysis of the in the 2001 national survey of New Zealand school children blood samples because these factors were rigorously con- aged 5–14 years, only 16% had low serum zinc concentrations trolled in this study. (Parnell et al., 2003), based on the same collection, analysis Despite the biochemical evidence of a high risk for zinc and cutoff values (Hotz and Brown, 2004). deficiency, we did not detect any significant relationships Low intake of dietary zinc per se rather than poor between serum zinc and anthropometric status, even among bioavailability was probably the primary dietary factor the prepubertal children, after controlling for mid-parental responsible for the low biochemical zinc status of these height and serum retinol concentrations. The absence of any North East Thai children reported here. Certainly the anthropometric relationship may be associated with the median dietary zinc intake calculated from 24-h recalls age group studied and the confounding effects of puberty, based on a subsample of the children (n ¼ 229) was low (i.e. constraints on growth due to chronic infection (Filteau and 4.5 g/day (IQR, 3.5, 5.4 mg/day)) and consistent with the Tomkins, 1994), and/or the coexistence of other growth- earlier report (i.e. 4.3 mg/day) for North East Thai primary limiting micronutrient deficiencies such as iodine and school children (Udomkesmalee et al., 1992). Such low vitamin A, in addition to zinc. dietary zinc intakes are most likely to be associated with the low zinc content of glutinous rice, the major dietary staple in the region which is cultivated in low zinc soils Coexisting micronutrient deficiencies and implications (Alloway, 2004). The median phytate: Zn molar ratio of the for intervention programmes childrens’ diets was very low (W Krittaphol, pers. com), and Of concern in this study is that about two-thirds of the Thai below the ratio at which zinc absorption is likely to be school children were at risk of two or more coexisting severely compromised (Oberleas and Harland, 1981). micronutrient deficits. If such coexisting deficits were Two other nutritional factors are related to the bio- widespread, these findings explain why some interventions chemical zinc status of these Thai children. Serum retinol based on single micronutrients have had limited success was positively associated with serum zinc in this study. in developing country settings (Allen et al., 2000). This is Indeed, those children with serum retinol o1.05 mmol/l had especially of concern when the etiology for the primary an almost two-fold greater risk of being zinc deficient outcome (e.g. anemia, impaired linear growth) is not specific compared to those with serum retinol levels indicative of to a single micronutrient deficiency, and the micronutrient adequate vitamin A status (Table 4). Several other studies of supplied is not the first limiting micronutrient in the children in South East Asia have also shown a relationship population under study. between low serum zinc and reduced serum retinol concen- Obviously school children in North East Thailand need trations (Rahman et al., 2001, 2002). Serum albumin combinations of multimicronutrients. Such combinations concentrations also correlated positively with serum zinc are especially important because deficiency of one micro- concentrations. This relationship is not surprising as about nutrient may affect the absorption or metabolism of another 70% of zinc is transported in the serum bound to albumin. micronutrient (Lo¨nnerdal, 2004). For example, early studies As a result, conditions that alter serum albumin will, in turn, in animals (Smith et al., 1974; Baly et al., 1984), and more affect serum zinc concentrations. However, in this study recently in humans (Rahman et al., 2001, 2002), have none of the children had serum albumin levels indicative of emphasized that zinc deficiency may impair vitamin A hypoalbuminemia (Ritchie et al., 1999). metabolism, although the precise mechanism for this The non-nutritional factors associated with low serum zinc interaction is uncertain (Christian and West, 1998). Hence, concentrations were sex, infection, and school. Indeed, it is not surprising that a low serum zinc concentration was males had an almost two-fold greater risk of being zinc a significant predictor of low serum retinol concentrations deficient than females (Table 4), possibly a reflection of the in this study (Table 4). Indeed, in an earlier study of school higher zinc requirements of males than females because of children living in this same region of North East Thailand, their higher lean body mass and growth rate (Hotz and deficiency of zinc was shown to be more limiting than was Brown, 2004). A similar sex-related trend in serum zinc con- vitamin A for visual function in dim light (Udomkesmalee centrations has been documented among school children et al., 1992); supplementation with vitamin A resulted in a earlier by some (Smit Vanderkooy and Gibson, 1987; Cavan smaller improvement in visual function compared to those et al., 1993; Parnell et al., 2003), but not all (Pilch and Senti, children treated with zinc alone. Such an interrelationship 1984; Udomkesmalee et al., 1990) investigators. The reduc- has important implications for the health of North East Thai tion in serum zinc levels associated with infection and school children because the high prevalence of zinc

European Journal of Clinical Nutrition Zinc and iodine deficiencies among children in NE Thailand RA Thurlow et al 630 deficiency in this age group may limit the efficacy of vitamin Grant. We thank all the school teachers, and the children A intervention programs. and their families who participated in this survey, It is of interest that in addition to low serum zinc, low Jane Campbell for her excellent laboratory expertise in hemoglobin concentrations were a risk factor for serum New Zealand and Arporn Sriphrapradang for the urinary retinol concentrations o1.05 mmol/l (Table 4). This relation- iodine analysis in Thailand, and all the dedicated ship has been discussed elsewhere (Thurlow et al., 2005), and research assistants. has been reported in other studies of school children in North East Thailand (Bloem et al., 1989b) and elsewhere in SE Asia (Ahmed et al., 1993). These relationships emphasize that in North East Thailand, interventions that supply at References least zinc, vitamin A, and iodine simultaneously are needed to achieve optimal status of the micronutrients (Suharno Ahmed F, Barua S, Mohiduzzaman M, Shaheen N, Bhuyan MA, et al., 1993; Bloem, 1995; Semba and Bloem, 2002). Margetts BM et al. (1993). Interactions between growth and Am J Coexisting suboptimal vitamin A status ( 1.05 mmol/l) can nutrient status in school-age children of urban Bangladesh. o Clin Nutr 58, 334–338. also exacerbate iodine deficiency. The mechanism proposed Ahmed F, Khan MR, Jackson AA (2001). Concomittent supplemental involves inhibition of thyroid-stimulating hormone TSH vitamin A enhances the response to weekly supplemental iron and secretion by the pituitary and thyroid hormone transport, folic acid in anemic teenagers in urban Bangladesh. Am J Clin Nutr 74, 108–115. mediated in part through retinol-binding protein and trans- Allen LH, Rosado JL, Casterline JE, Lopez P, Munoz E, Garcia OP et al. thyretin (Hurrell and Hess, 2004). Only 19% of the children (2000). Lack of hemoglobin response to iron supplementation studied here, however, had both suboptimal serum retinol in anemic Mexican preschoolers with multiple micronutrient and urinary iodine concentrations, and we observed no deficiencies. Am J Clin Nutr 71, 1485–1494. Alloway BJ (2004). Zinc in Soils and Crop Nutrition. International Zinc relationship between serum retinol and urinary iodine levels, Association: Brussels, Belgium. perhaps because of the low prevalence of visible goiters Ballew C, Bowman BA, Sowell AL, Gillespie C (2001). Serum retinol (3.4%). So far, this vitamin A–iodine interaction has only been distributions in residents of the United States: third National reported when the prevalence of visible goiters has been high Health and Nutrition Examination Survey, 1988–1994. Am J Clin Nutr 73, 586–593. (Wolde-Gebriel et al., 1993; Florentino et al., 1996). Baly DL, Golub MS, Gershwin ME, Hurley LS (1984). Studies of Iodine deficiency is also exacerbated by coexisting iron marginal zinc deprivation in rhesus monkeys. III. Effects on deficiency (Zimmermann et al., 2000). In subjects with iron vitamin A metabolism. Am J Clin Nutr 40, 199–207. deficiency anemia, levels of plasma thyroxine (T4) and Beard JL, Brigham DE, Kelley SK, Green MH (1998). Plasma thyroid hormone kinetics are altered in iron-deficient rats. J Nutr 128, triiodothyronine (T3) are lower, the conversion of T4–T3 is 1401–1408. slowed, and the concentrations of TSH are elevated (Beard Benotti J, Benotti N, Pino S, Gardyna H (1965). Determination et al., 1998). Unfortunately, in the study reported here of total iodine in urine, stool, diets, and tissue. Clin Chem 11, thyroid hormones were not measured. Moreover, very little 932–936. of the anemia (i.e. 15%) was associated with biochemical Bloem MW (1995). Interdependence of vitamin A and iron: an important association for programmes of anemia control. Proc iron deficiency (Thurlow et al., 2005), so it is not surprising Nutr Soc 54, 501–508. that no association was observed between urinary iodine Bloem MW, Wedel M, Egger RJ, Speek AJ, Chusilp K, Saowakontha S levels and biochemical iron indices. et al. (1989a). A prevalence study of vitamin A deficiency and xerophthalmia in northeastern Thailand. Am J Epidemiol 129, In conclusion, our findings highlight that 60% of these 1095–1103. North East Thai school children were at risk of two or more Bloem MW, Wedel M, Egger RJ, Speek AJ, Schrijver J, Saowakontha S coexisting micronutrient deficiencies, which could limit et al. (1989b). Iron metabolism and vitamin A deficiency in the effectiveness of programs to optimize status for some children in northeast Thailand. Am J Clin Nutr 50, 332–338. Cavan KR, Gibson RS, Grazioso CF, Isalgue AM, Ruz M, Solomons micronutrients. In North East Thailand, for example, efforts NW (1993). Growth and body composition of periurban Guate- to eradicate vitamin A deficiency may be compromised by malan children in relation to zinc status: a cross-sectional study. the coexistence of zinc deficiency, whereas a hematologic Am J Clin Nutr 57, 334–343. response to iron supplements may be limited by the Christian P, West Jr KP (1998). Interactions between zinc and vitamin A: an update. Am J Clin Nutr 68, 435S–441S. coexistence of suboptimal vitamin A status. Clearly, there Department of Health (Nutrition Division) (1995). The fourth national is an urgent need for coordinated multi-micronutrient nutrition survey of Thailand. 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