Low-dose weekly supplementation of iron and/or zinc does not affect growth among Bangladeshi infants

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1 (2009) 63, & 2009 Macmillan Publishers Limited All rights reserved /09 $ ORIGINAL ARTICLE Low-dose weekly supplementation of iron and/or zinc does not affect growth among Bangladeshi infants CL Fischer Walker 1, AH Baqui 1,2, S Ahmed 3, K Zaman 2, S El Arifeen 2, N Begum 2, M Yunus 2, RE Black 1 and LE Caulfield 1 1 Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 2 ICDDR,B: Centre for Health and Population Research, Dhaka, Bangladesh and 3 Johns Hopkins Bloomberg School of Public Health, Department of Population and Family Health, Baltimore, MD, USA Objectives: To determine the effect of low-dose weekly supplementation with iron, zinc or both on growth of infants from 6 to 12 months of age. Subjects/Methods: A total of 645 breastfed infants age 6 months who were not severely anemic (HbX90 g l 1 ) or severely malnourished (weight-for-age X60% median) were randomized to receive 20 mg iron and 1 mg riboflavin; 20 mg zinc and 1 mg riboflavin; 20 mg iron, 20 mg zinc and 1 mg riboflavin; or riboflavin alone (control) weekly for 6 months. Results: Baseline characteristics were similar among the four supplementation groups. Weight, length and mid-upper arm circumference were assessed at baseline, 8, 10 and 12 months of age. There was no interaction of iron and zinc when given in a combined supplement on either weight or length (P40.05). There were no effects of either iron or zinc on the rate of length or weight gain for all infants or when stratified by baseline Hb concentration. Conclusions: Weekly supplementation of 20 mg Fe, 20 mg Zn, or both does not benefit growth among infants 6 12 months of age in rural Bangladesh, a region with high rates of anemia and zinc deficiency. (2009) 63, 87 92; doi: /sj.ejcn ; published onnline 19 September 2007 Keywords: supplementation; iron; zinc; growth Introduction Correspondence: Dr CL Fischer Walker, Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe St. Rm E5543, Baltimore, MD 21205, USA. cfischer@jhsph.edu Contributors: AHB and REB designed the study and wrote the initial protocol. AHB, KZ, SEA, NB and MY contributed to the final study design, implemented the study in Bangladesh and ensured the quality of the data. CLFW, AHB, SA, LEC and REB designed the analysis plan, carried out the analysis and wrote the manuscript. All authors reviewed the manuscript and contributed to the final version. Received 21 February 2007; revised 4 August 2007; accepted 9 August 2007; published onnline 19 September 2007 Micronutrient malnutrition is a widespread problem in lowincome populations and deficiency in one or more nutrients may be a growth-limiting factor for young children in developing countries (Allen, 1994). For infants o6 months of age, exclusive breastfeeding provides an adequate daily intake of essential micronutrients for growth and development (Kramer and Kakuma, 2002). Complementary foods introduced at 6 months of age are often low in micronutrient quality and this leads to nutritional deficiencies, especially during the period of rapid growth from 6 to 11 months of age (Brown et al., 1998). Iron deficiency is the most commonly reported micronutrient deficiency worldwide and may lead to developmental delays and decreased cognitive performance (Stoltzfus, 2001). Providing additional iron via daily or weekly supplementation to iron-deficient children under 5 years may have some positive effects on developmental indicators, especially among children who are anemic or iron deficient at baseline (Iannotti et al., 2006). The effects of iron supplementation on growth have been mixed. While some trials have demonstrated a positive effect of iron supplementation on growth (Angeles et al., 1993; Lind et al., 2004), meta-analyses of all trials did not demonstrate a benefit (Ramakrishnan et al., 2004). Zinc is an essential micronutrient for growth and deficiency can lead to severe

2 88 growth retardation (Prasad et al., 1963). Daily zinc supplementation appears to have an overall positive effect on both height and weight among all children under 5 years with a more pronounced positive effect among children who are undernourished at baseline (Brown et al., 2002). Each of the two trials that provided large doses of zinc weekly observed a positive effect of zinc on height (Smith et al., 1999; Brooks et al., 2005). The best dietary sources for iron and zinc are animalsource foods, especially meat; thus, in populations that typically eat few animal-source foods, it is likely that iron and zinc deficiencies coexist. Although both iron and zinc are essential minerals the effect of combined supplementation on growth has not been widely studied. Two recently published trials of daily supplementation did not show a benefit of combined iron and zinc supplementation on growth in Indonesian infants (Dijkhuizen et al., 2001; Lind et al., 2004), but these results have not yet been confirmed in other populations. We previously reported the effects of 6 months of supplementation with iron, zinc, both or a multiple micronutrient mix on the morbidity, biochemical status and development outcomes in a sample of Bangladeshi infants (Baqui et al., 2003, 2005; Black et al., 2004). In this paper, we report the results of iron and/or zinc supplementation on rates of growth during 6 months of supplementation. Subjects and methods The study was conducted as a randomized, controlled trial in the rural Matlab field research area of the International Center for Diarrhoeal Disease Research, Bangladesh (ICDDR,B). The study design, population, trial profile and methods have been published previously (Baqui et al., 2003). To summarize, we enrolled breastfed infants, 5 6 months of age, who were permanent residents of the selected villages. Any infant was excluded if he/she was low weight-for-age (o60% of the National Center for Health Statistics reference median), severely anemic (hemoglobin o90g l 1 ) or showed any signs of neurological disorder, physical handicap, or chronic illness affecting feeding, activity or cognitive development. Prior to enrollment all study procedures were explained to the caregiver and a statement of parental permission was signed. Infants were stratified at baseline by length-for-age Z score (LAZ) using 2 Z as the cutoff. Block randomization was done within strata to ensure equivalent enrollment from both o 2 LAZ and X 2 LAZ. We enrolled 799 infants and randomized each to one of five study groups: (1) iron alone (20 mg elemental iron and 1 mg riboflavin); (2) zinc alone (20 mg elemental zinc and 1 mg riboflavin); (3) iron and zinc (20 mg elemental iron, 20 mg elemental zinc and 1 mg riboflavin); (4) multiple micronutrients or (5) control (1 mg riboflavin). All supplements were directly fed by a trained community health worker (CHW) weekly at a home visit. In addition, all infants received IU of vitamin A at the start of the study as part of a national program. For this analysis we excluded the multiple micronutrient group because the dropout rate was much higher (41%) compared to 9 17% in the other four groups (Baqui et al., 2003). Presented here are results of the iron alone, zinc alone, iron and zinc and riboflavin groups (n ¼ 654). Growth was assessed by trained health assistants and CHWs using standard anthropometric protocols as per the World Health Organization (WHO) guidelines (WHO, 1983). Measurements were taken at enrollment and every 2 months thereafter, that is, at approximately 6, 8, 10 and 12 months of age by two trained anthropometrists who were blinded to the supplementation allocation. Each anthropometrist was assigned an equal number of infants from all supplementation groups. The infant s naked weight was measured using a Salter scale (Model 235 6S, England) which was standardized with a 1-kg weight prior to each measurement. Weight was recorded to the nearest 50 g. Recumbent length was measured using a locally constructed length board with a footplate and head bar. Length was recorded to the nearest 0.1 cm. The mid-upper arm circumference (MUAC) was measured with TALC insertion tapes (TALC, Herts, UK); the mean (to the nearest mm) of two consecutive measurements was recorded as the observed value. About 5% of the anthropometric measurements were re-measured by a trained supervisor; there was an overall 95% observed agreement between original and re-measured values. All anthropometric measures were compared to the WHO reference population for breastfed infants and corresponding Z scores were generated (WHO Multicenter Growth Reference Study Group, 2006). All study procedures and data collection forms including parental permission forms were approved by the Ethical Review Committee of the ICDDR,B. Statistical methods All questionnaires and forms were reviewed by the investigators and study supervisors for accuracy, consistency and completeness. A 5% sample of children were re-interviewed and re-measured within 2 days of the original interview and measurement to assess data quality. If necessary, the CHWs made field visits to clarify inconsistencies and to collect missing information. The data were entered into an online custom-designed data entry program with built in range and logic checks. Data were periodically checked with frequency and cross-tabulation reports. The sample size, 140 infants per treatment arm, was calculated to demonstrate a difference of 0.4, we assumed that the s.d. of the Z scores in each group was 0.8. All statistical differences were assessed with at least 80% power and a 95% significance level. All calculations assumed a 10% loss to follow-up. Sociodemographic indicators and infant baseline characteristics were assessed by supplementation group. Means and proportions were compared using analysis of variance and

3 w 2, respectively to assess differences for each characteristic among supplementation groups. Mean length, weight and MUAC were compared among supplementation groups at baseline and after 6 months of follow-up using analysis of covariance. Final length, weight and MUAC were first compared controlling only for sex and mean baseline value for the selected anthropometric indicator. A similar analysis of covariance was then constructed, which also controlled for the prevalence of diarrhea and acute lower respiratory tract infection (ALRI) during the 6-month of follow-up (measured in days with reported illness). We then assessed the rate of growth for both length and weight using a latent growth mixed model controlling for sex and age (STATA Corporation, 2005). Models were first fit as a two-factor analysis to determine the presence of interaction between iron and zinc. Where the interaction term was found to be significant (Po0.05), all four groups were included in the final analysis. If no interaction was found, the model was reduced to estimate the main effects of iron and zinc. Analyses were also conducted for all infants controlling for prevalence of diarrhea and ALRI, and then stratified by baseline hemoglobin (Hb) status (o105 vs X105 g l 1 ) and LAZ (o 2 vs X 2) to assess possible differences in response to supplementation by baseline iron or anthropometric status. All analyses were conducted using STATA 9.0 statistical software (STATA Corporation, 2005). Results There were no differences among groups for any sociodemographic characteristic, sex or age at baseline (Table 1). Because withdrawal rates were different among supplementation groups (iron alone 9.1%; zinc alone 12.4%; iron and zinc 16.7%; control 10.8%; Baqui et al., 2003), we compared baseline characteristics among supplementation groups only for infants who completed the study and observed no differences (data not presented). Compliance was high throughout all groups with infants receiving on average 80 90% of the supplements (Baqui et al., 2003). There were no differences for length, weight or MUAC among supplementation groups at baseline or after 6 months of supplementation controlling for sex and no differences when controlling for the prevalence of diarrhea and ALRI during follow-up (Table 2). At baseline (B6 months of age) the mean (7s.d.) LAZ was and declined to after 6 months of supplementation. WAZ was at enrollment and declined to at the end of the study. Average WLZ also declined from to after supplementation. There were no interaction effects of combined iron and zinc supplementation for either length or weight for all infants, or when stratified by either baseline LAZ or Hb status. Table 3 presents the main effects of iron and zinc on length and weight for all children. The intercept represents the mean length or weight at 6 months of age (that is, enrollment) where all other variables are zero. The latent growth analyses compare the rate of growth between infants receiving any zinc (zinc age) with those not receiving zinc and infants receiving any iron (iron age) with those not receiving iron. These analyses utilize the baseline, 8-, 10- and final 12-month anthropometric values. In essence, the variables zinc age and iron age describe the shape of the growth curve rather than a more traditional regression analysis, which may account for only the baseline and final end points. Any b coefficient in the negative direction is indicative of greater gains in length and weight for the comparison group, that is, for any iron the b coefficient is 0.16 suggesting that infants, who received no iron grow longer than infants, who received any iron. Neither zinc nor iron had a statistically significant effect on the rates of weight or length gain as observed in the zinc age and iron age variables. There were no statistically significant differences when prevalence of diarrhea and ALRI were added to the latent growth analyses or when stratified by baseline Hb or LAZ score (data not presented). Discussion We assessed the effect of weekly low-dose iron, zinc or combined iron and zinc supplementation on growth among Bangladeshi infants 6 12 months of age. In this randomizedcontrolled trial, growth among infants who received 20 mg of iron and/or zinc one time per week was compared to those who received riboflavin alone. To our knowledge this is the first study of low-dose weekly iron and/or zinc supplementation to assess growth outcomes. Six months of low-dose weekly supplementation with iron and/or zinc did not affect the final weight, length or MUAC of these infants. We previously reported a significant benefit of combined iron and zinc supplementation on incidence of severe diarrhea in this population but no effect of zinc or iron alone (Baqui et al., 2003). We also previously assessed development in these infants and reported a benefit of iron and/or zinc on orientation engagement and a benefit of combined supplementation on infant motor development (Black et al., 2004). Although we observed the benefits of supplementation on functional outcomes, we did not observe an effect of supplementation on Hb, serum ferritin or transferrin receptor in a smaller biochemical sub-study in this population (Baqui et al., 2005). While individual studies demonstrating an effect of iron supplementation on growth are mixed, published reviews of the evidence do not show an overall effect of iron on growth (Ramakrishnan et al., 2004). Because recent studies have suggested that the response to iron supplementation (with or without zinc; Sazawal et al., 2006) may be modified by baseline iron status, we also stratified the latent growth analyses by Hb status (o105 and X105g l 1 ) and did not observe an effect of iron on rate of growth in either stratum. 89

4 90 Table 1 Baseline characteristics by supplementation group a Iron (n ¼ 165) Zinc (n ¼ 161) Iron þ zinc (n ¼ 162) Control (n ¼ 157) Mother s education, years Father s education, years Income, taka b Household size Boys, % (95% CI) 43.3% (35.3, 51.4) 46.8% (38.4, 55.1) 46.7% (38.1, 55.2) 53.6% (45.2, 61.9) Age, months Birth order Baseline Hb, g l Abbreviations: ANOVA, analysis of variance; CI, confidence interval. a Values are reported as mean7s.d., unless otherwise noted. There were no differences among groups for any baseline characteristics using ANOVA to compare means (P40.05) and w 2 to compare proportions. b 1USD approximates 69 BDT. Table 2 Anthropometric status by supplementation groups at baseline and after 6 months of supplementation a n Iron alone n Zinc alone n Iron þ zinc n Control Length, cm Baseline month follow-up Weight, kg Baseline month follow-up MUAC, mm Baseline month follow-up Abbreviations: ALRI, acute lower respiratory tract infection; ANCOVA, analysis of covariance; MUAC, mid-upper arm circumference. a Values are reported as mean7s.d. In ANCOVA analyses, there were no differences among groups at baseline, no differences among groups after 6 months of supplementation after controlling for baseline values and sex, and no differences among groups after 6 months of supplementation after controlling for baseline values, sex and the prevalence of diarrhea and ALRI during follow-up (P40.05). Table 3 Results of latent growth analyses assessing the effect of 6-month weekly supplementation with iron and/or zinc on rates of growth Latent growth analysis Length (n ¼ 566) Weight (n ¼ 566) b 95% CI b 95% CI Intercept , , 7.27 Any iron , , 0.20 Any zinc , , 0.13 Any iron age , , 0.01 Any zinc age , , 0.01 Female infant , 0.90 a , 0.30 a Age in months b , 1.16 a , 0.23 a Abbreviation: CI, confidence interval. a Statistically significant effect on rate of growth (Po0.05). b Age was zeroed at 6 months. In a meta-analysis of published and unpublished studies in developing and developed countries, daily zinc supplementation has been shown to increase height and weight (Brown et al., 2002). In a previously published study of Bangladeshi infants, those receiving 70 mg zinc once per week from 60 days until 12 months of age had greater length gain (0.9 cm) and grew at a faster linear rate (Po0.05) than infants who received placebo, but remained similar in weight (Brooks et al., 2005). In our previously published sub-study (n ¼ 163) of these infants, we reported that 45% of infants were zincdeficient at baseline and serum zinc increased among infants who receive zinc alone and both zinc and iron (main effect of zinc; Po0.05; Baqui et al., 2005). It is possible that 20 mg zinc per week dose is an adequate dose to increase serum zinc but not to observe a benefit on anthropometric indicators. Several trials have supplemented infants 4 7 months of age with 10 mg per day iron and/or zinc compared to placebo for 6 months (Lind et al., 2004; Berger et al., 2006; Wasantwisut et al., 2006). In Thailand, a slight interaction (P ¼ 0.103) between iron and zinc was only observed for LAZ score (Wasantwisut et al., 2006). In two separate trials, a negative interaction of iron on the benefit of zinc on WAZ score was observed among Indonesian and Vietnamese infants (Lind et al., 2004; Berger et al., 2006). The interaction observed in these studies was primarily the reversal of the benefit of zinc on growth in the presence of iron. Because we did not observe a benefit of zinc on growth it is not surprising that we also did not observe an interaction effect of combined supplementation.

5 There are several limitations to our study. In this placebocontrolled randomized trial, supplements were delivered by community health workers to increase compliance which remained high, but was not 100%. Because children were receiving supplements weekly, missing a dose resulted in 2 weeks without the added zinc and/or iron which may have affected efficacy. However, because weekly compliance for all supplementation groups was between 80 and 90%, infants rarely missed more than one dose so this cannot entirely explain the lack of effect. In this study, we excluded infants who were severely anemic. Because these are likely signs of more depleted iron and zinc stores compared to infants who have higher Hb, it is possible that these infants may have been more likely to benefit from the low-dose weekly supplements than infants who were included in this trial. We did stratify by baseline Hb status to look for remaining confounding of the effect of iron by Hb status, yet no differences were observed. Given that, we previously reported no benefit of iron supplementation (with our without zinc) on any iron status indicators in a small sample of these infants when stratified by baseline Hb status, the iron results were not surprising (Baqui et al., 2005). Iron and zinc deficiencies are widespread among children in the developing world and often coexist. Low-dose weekly supplementation of 20 mg zinc and/or 20 mg iron was not sufficient to affect growth rates in this population. Infants became progressively more stunted, wasted and underweighted during the supplementation period, suggesting that the diets of these infants may have been deficient in more than iron and zinc. This is not surprising given that this is the period when complementary foods of substandard nutritional quality are commonly introduced. One limitation of this study is that we did not collect information with regard to the daily diet of these babies to be able to determine the relative extent of micro- or macronutrient deficiencies among these infants. A strength of this study is that we also collected morbidity data throughout the supplementation period (Baqui et al., 2003). Because combined iron and zinc supplementation has decreased incidence in severe diarrhea and severe ALRI in our prior analysis, it is possible that such differences could be affecting our interpretation of the growth data. However, when we adjusted for the prevalence of diarrhea of ALRI, this did not change the lack of a detected effect of zinc on growth. Supplementation with both iron and zinc may be one way to combat these individual micronutrient deficiencies, but additional research is needed to identify the safest and most effective dose and the best delivery mechanism. While lowdose weekly supplementation with iron and zinc resulted in minimal benefits on severe diarrhea (Baqui et al., 2003), the overall lack of effect on growth suggests that 20 mg zinc provided once a week is not an adequate dose for infants 6 12 months of age. Weekly supplementation with a higher dose needs to be studied more widely to determine if the benefits of daily supplementation on functional indicators, including growth can be replicated in a weekly supplement. High-dose supplementation with more than one micronutrient has not yet been studied. Additional research is needed to evaluate the risk of potential interaction between iron and zinc when given together in a high-dose supplement and to evaluate the benefit of combined supplementation on functional indicators such as morbidity and growth. Randomization groups Iron (Fe) Zinc (Zn) Iron and zinc 20 mg iron plus 1 mg riboflavin; 20 mg zinc plus 1 mg riboflavin; 20 mg iron 20 mg zinc plus 1 mg riboflavin; Multiple Micronutrients (not presented here) Control Acknowledgements 20 mg iron, 20 mg zinc, 1 mg riboflavin plus 2 times the RDA of iodine, copper, manganese, selenium, vitamin C, vitamin D, vitamin E, thiamin, niacin, pyridoxine, folic acid, cyanocobalamin and pantothenic acid; 1 mg riboflavin. This study was possible because of the many families who allowed their children to participate and the dedication of the field and data management staff of the International Centre for Diarrhoeal Diseases Research, Bangladesh. This study was funded by the Nutricia Foundation and the US Agency for International Development (USAID). This paper does not necessarily reflect the views of USAID or the US government. References Allen LH (1994). Nutritional influences on linear growth: a general review. Eur J Clin Nutr 48, S75 S89. Angeles IT, Schultink WJ, Matulessi P, Gross R, Sastroamidjojo S (1993). Decreased rate of stunting among anemic Indonesian preschool children through iron supplementation. Am J Clin Nutr 58, Baqui AH, Walker CL, Zaman K, El Arifeen S, Chowdhury HR, Wahed MA et al. (2005). Weekly iron supplementation does not block increases in serum zinc due to weekly zinc supplementation in Bangladeshi infants. J Nutr 135, Baqui AH, Zaman K, Persson LA, El Arifeen S, Yunus M, Begum N et al. (2003). Simultaneous weekly supplementation of iron and zinc is associated with lower morbidity due to diarrhea and acute lower respiratory infection in Bangladeshi infants. J Nutr 133, Berger J, Ninh NX, Khan NC, Nhien NV, Lien DK, Trung NQ et al. (2006). Efficacy of combined iron and zinc supplementation on 91

6 92 micronutrient status and growth in Vietnamese infants. Eur J Clin Nutr 60, Black MM, Baqui AH, Zaman K, Ake Persson L, El Arifeen S, Le K et al. (2004). Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants. Am J Clin Nutr 80, Brooks WA, Santosham M, Naheed A, Goswami D, Wahed MA, Diener-West M et al. (2005). Effect of weekly zinc supplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban, low-income population in Bangladesh: randomised controlled trial. Lancet 366, Brown KH, Dewey KG, Allen LH (1998). Complementary feeding of young children in developing countries. In:World Health Organization: Geneva. Brown KH, Peerson JM, Rivera J, Allen LH (2002). Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a meta-analysis of randomized controlled trials. Am J Clin Nutr 75, Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal (2001). Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. J Nutr 131, Iannotti LL, Tielsch JM, Black MM, Black RE (2006). Iron supplementation in early childhood: health benefits and risks. Am J Clin Nutr 84, Kramer MS, Kakuma R (2002). The Optimal Duration of Exclusive Breastfeeding In: World Health Organization: Geneva. Lind T, Lonnerdal B, Stenlund H, Gamayanti IL, Ismail D, Seswandhana R et al. (2004). A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: effects of growth and development. Am J Clin Nutr 80, Prasad AS, Miale A, Farid Z, Sanstead HH, Schulert AR, Darby WJ (1963). Biochemical studies on dwarfism, hypogonadism and anemia. Arch Internal Med 111, Ramakrishnan U, Aburto N, McCabe G, Martorell R (2004). Multimicronutrient interventions but not vitamin a or iron interventions alone improve child growth: results of 3 meta-analyses. JNutr134, Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A et al. (2006). Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 367, Smith JC, Makdani D, Hegar A, Rao D, Douglass LW (1999). Vitamin A and zinc supplementation of preschool children. J Am Coll Nutr 18, STATA Corporation (2005). STATA 9.0 Reference Manual. STATA Corporation: College Station, TX. Stoltzfus R (2001). Defining iron-deficiency anemia in public health terms: a time for reflection. J Nutr 131, 565S 567S. Wasantwisut E, Winichagoon P, Chitchumroonchokchai C, Yamborisut U, Boonpraderm A, Pongcharoen T et al. (2006). Iron and zinc supplementation improved iron and zinc status, but not physical growth, of apparently healthy, breast-fed infants in rural communities of northeast Thailand. J Nutr 136, WHO (1983). Measuring Change in Nutritional Status In: World Health Organization: Geneva. WHO Multicenter Growth Reference Study Group (2006). WHO Child Growth Standards: Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height, and Body Mass Index-for-Age: Methods and Development In: World Health Organization: Geneva.