Zinc supplementation and psychosocial stimulation: effects on the development of undernourished Jamaican children 1 3

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1 Zinc supplementation and psychosocial stimulation: effects on the development of undernourished Jamaican children 1 3 Julie M Meeks Gardner, Christine A Powell, Helen Baker-Henningham, Susan P Walker, Tim J Cole, and Sally M Grantham-McGregor ABSTRACT Background: Undernourished children have poor levels of development that benefit from stimulation. Zinc deficiency is prevalent in undernourished children and may contribute to their poor development. Objective: We assessed the effects of zinc supplementation and psychosocial stimulation given together or separately on the psychomotor development of undernourished children. Design: This was a randomized controlled trial with 4 groups: stimulation alone, zinc supplementation alone, both interventions, and control (routine care only). Subjects were 114 children aged 9 30 mo and below 1.5 z scores of the National Center for Health Statistics weight-for-age references who were recruited from 18 health clinics. Clinics were randomly assigned to receive stimulation or not; individual children were randomly assigned to receive zinc or placebo. The stimulation program comprised weekly home visits during which play was demonstrated and maternal-child interactions were encouraged. The supplementation was 10 mg Zn as sulfate daily or placebo. Development (assessed by use of the Griffiths Mental Development Scales), length, and weight were measured at baseline and 6 mo later. Weekly morbidity histories were taken. Results: Significant interactions were found between zinc supplementation and stimulation. Zinc benefited the developmental quotient only in children who received stimulation, and benefits from zinc to hand and eye coordination were greater in stimulated children. Zinc supplementation alone improved hand and eye coordination, and stimulation alone benefited the developmental quotient, hearing and speech, and performance. Zinc supplementation also reduced diarrheal morbidity but did not significantly improve growth. Conclusion: Zinc supplementation benefits development in undernourished children, and the benefits are enhanced if stimulation is also provided. Am J Clin Nutr 2005;82: KEY WORDS Zinc, deficiency, supplementation, child development, psychosocial stimulation, play programs, infants, young children, undernutrition, malnutrition, Jamaica INTRODUCTION Childhood undernutrition affects 180 million children under the age of 5 y (1). Undernourished children are at high risk not only of increased mortality and morbidity (2) but also of poor cognitive development and subsequent school failure (3). The mechanism linking undernutrition to poor development is not well established. One hypothesis (functional isolation) is that undernourished children s low levels of activity and exploration restrict their ability to acquire skills (4). This altered behavior induces less stimulating behavior from their caretakers toward them, thus further reducing the amount of interaction the child has with his or her environment (4). Zinc deficiency is thought to be highly prevalent in undernourished children and has also been linked to reduced activity and play (5, 6) and may exacerbate undernourished children s poor development. Zinc deficiency is associated with growth retardation (7) and increased rates of diarrhea and pneumonia in children (8); however, evidence of links with psychomotor development in young children is inconsistent (9). At least 7 trials (10 16) have examined the effects of zinc supplementation on young children s psychomotor development. In one (10), zinc and copper were given to very-low-birthweight children and their motor development benefited. Four of the trials showed no benefit to developmental levels (11 14), but 2 of these found improvement in behavior (11) or motor quality (12), whereas in one (14), children with the lowest birth weights were more irritable when given zinc. One Bangladeshi study found no benefit to mental or motor development from iron or zinc given alone but improved motor development when iron and zinc were combined (15). In contrast, in a further study (16), Bangladeshi infants supplemented with zinc had slightly lower developmental scores, possibly because of micronutrient imbalance. Zinc supplementation in older children has also had inconsistent benefits on cognition (17 20). It is clear that the role of zinc deficiency in children s development needs to be clarified. Zinc status is difficult to measure, 1 From the Epidemiology Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, Kingston, Jamaica (JMMG, CAP, and SPW), and the Centres for International Child Health (HBH and SMG-M) and Paediatric Epidemiology and Biostatistics (TJC), Institute of Child Health, University College London, London, United Kingdom. 2 The stimulation trial was funded by The Thrasher Research Fund; the zinc supplementation trial was funded by the Nestle Foundation. The Grace, Kennedy Foundation (Jamaica); Dr Jeffrey Meeks; and the Matalon and Melhado families provided further financial assistance. The zinc supplement and the vitamin preparation were donated by Federated Pharmaceuticals Limited. 3 Address reprint requests to JM Meeks Gardner, Caribbean Child Development Centre, School of Continuing Studies, University of the West Indies, Mona, Kingston 7, Jamaica. julie.meeksgardner@uwimona.edu.jm. Received June 18, Accepted for publication April 11, Am J Clin Nutr 2005;82: Printed in USA American Society for Clinical Nutrition 399

2 400 MEEKS GARDNER ET AL and response to supplementation is often used as an indicator of deficiency (9). Possible explanations for the lack of response in development in some studies are that the children were not zinc deficient initially or that additional zinc produced imbalances in other micronutrients, such as iron. A further possibility is that even if children become more exploring and active with zinc supplements, this may not lead to better developmental levels if their environment is unstimulating. Additional stimulation has been shown to improve the development of stunted children who received food supplementation (21). Thus, zinc-deficient children living in unstimulating environments may need improved stimulation as well as zinc to improve in development. To test the latter hypothesis, we conducted a randomized double-blind trial to determine the effect of zinc supplementation with or without psychosocial stimulation on young children s psychomotor development. We also examined the effect of zinc on growth and morbidity, because an improvement with supplementation would confirm that the children were initially zinc deficient. SUBJECTS AND METHODS Sample The project was conducted in the parishes of Kingston, St Andrew, and St Catherine, Jamaica. Children attending government health centers who are underweight are referred to special nutrition clinics at the centers, where their growth is monitored and their caregivers are counseled about child feeding. All children aged 9 30 mo who were attending 18 nutrition clinics were identified. Those with current weight-for-age z scores below 1.5 SDs of the National Center for Health Statistics references (22) and who had weight-for-age below 2 SDs in the previous 3 mo were enrolled into the study. Twins or children with physical or mental impairments that could affect development were excluded. It was not considered feasible to have both the stimulated and the nonstimulated groups of children at the same clinic; therefore, the 18 clinics were randomly assigned to stimulation or control. Within each clinic, the children were stratified into 2 age groups (9 18 and mo) and were then randomly assigned to receive the zinc supplement or the placebo. To detect a difference of 0.5 SD in developmental levels at P 0.05 with 80% power, 64 children were required in each arm of the study (supplemented and placebo). Ninety-nine children were identified and enrolled over a period of 5 mo. For logistic reasons, we could not extend the stimulation program. To achieve sufficient power to detect an effect of zinc, we continued enrolling children for a further 2 mo to the zinc trial only. A further 27 children were enrolled from all the clinics in this time period. As shown in Figure 1, the 4 groups were as follows: stimulation only group (n 23), zinc only group (n 35), combined treatment group (n 26), and a control group (n 42). Therefore, 61 children received zinc and 65 received placebo. Informed consent was obtained from parents or guardians, who were unaware of the children s assignment to zinc or placebo. Ethical approval was obtained from the Ethics Committee of the University of the West Indies and the Jamaican Ministry of Health. FIGURE 1. Assignment to the zinc supplementation and psychosocial stimulation groups. Interventions Zinc and placebo supplementation Zinc supplementation consisted of 10 mg elemental zinc (the recommended dietary allowance for children aged 12 mo) as sulfate in a flavored syrup or a placebo (syrup only) given daily for 6 mo. The supplement or placebo was delivered by a community health worker to the homes weekly in 7 vials, each containing one dose. At the end of each week, the community health worker returned with another set of supplement or placebo vials and collected the vials from the previous week. A record was kept of the number of empty vials. All children received a proprietary brand of micronutrients containing iron and vitamins, and caregivers were instructed to give them 0.5 ml daily (Table 1). Psychosocial stimulation The main focus of the psychosocial stimulation program was to improve maternal-child interactions. The children and their mothers were visited weekly for half an hour by a specially trained community health worker who showed the mother ways to play with her child. We used a detailed curriculum based on Piagetian concepts for children aged 24 mo and concepts of shape, size, position, and color for children aged 24 mo. In addition, activities to facilitate language development, fine motor skills, and problem solving were included. The curriculum was culturally appropriate and was used successfully with Jamaican mothers and children in previous studies (23). The community health worker also left simple homemade toys with the TABLE 1 Contents of vitamin-iron drops provided to all children 1 Value Vitamin A, retinyl palmitate (IU) 1500 Vitamin D, calciferol (IU) 400 Vitamin B-1, thiamine HCl (mg) 0.5 Vitamin B-2, riboflavin (mg) 0.8 Nicotinamide (mg) 7.0 Vitamin B-6, pyridoxine HCl (mg) 1.0 Vitamin C, ascorbic acid (mg) 30.0 Iron, as polysaccharide (mg) 8.0 Folic acid (mg) 1.0 Vitamin B-12 ( g) Per 0.5 ml.

3 ZINC AND CHILD DEVELOPMENT 401 mother each week, which were exchanged at the next visit for other toys in an attempt to keep the intervention low cost. Measurements Developmental levels and anthropometric variables were measured at enrollment and after the 6-mo trial period. Developmental levels These were measured by using 4 subscales of the Griffiths Mental Development Scales (24): locomotor (large muscle activities such as walking or jumping), hand and eye coordination, hearing and speech, and performance (shape recognition, block construction, and block patterns). The Griffiths scales have been used in several studies in Jamaica and have been shown to have good test-retest reliability and to predict long-term development (25). All tests were carried out by a single tester, who was unaware of the children s group assignment. Reliability between the tester and the trainer was high before the study started (intraclass correlation: r 0.98; n 10 children) and in ongoing quality-control assessments (r 0.99; n 16). Anthropometry Weights and lengths or heights were measured by using standard techniques (26) by 2 research assistants. Their interobserver reliabilities with the trainer were 0.98 for all measurements (intraclass correlations; n 10). Many of the children (n 79) had both length and stature measured on one occasion. The linear regression of these lengths on stature was used to convert stature to estimated length wherever stature only had been measured [estimated length (cm) stature]. The lengthstature regression indicated a close correspondence between the 2 measurements (r 0.98). All analyses were then carried out with the measured or estimated length. Social background The children s caregivers were interviewed at enrollment to assess their home backgrounds. The level of stimulation in the home was assessed by questionnaire and observations by using the Bettye Caldwell HOME inventory (27), which was previously modified for Jamaica. Examples of the modifications made include removing questions that were considered inappropriate or ambiguous for the culture, rescaling questions to obtain variation, and changing the scoring to include the frequency of some of the activities the mother did with her child. The final instrument comprised 46 items. Two interviewers carried out these measurements. Interobserver reliabilities were 0.9 before the start of the study and continued at this level in 10% of all interviews throughout the study. The caregiver s height and verbal IQ on the Peabody Picture Vocabulary Test (28) were also measured. Morbidity Throughout the 6 mo of the zinc supplementation trial, weekly visits were made to the children s homes by the community health worker to take the children s morbidity history for the previous 7 d from the parents. Clinic visits for illness (not routine visits) and hospitalizations were also recorded. Any symptoms that occurred during the previous 7 d, and the day they were present, were recorded. Ten symptoms were specifically asked about: apathy, anorexia, fever, coughing, nasal discharge, diarrhea (loose or frequent stools identified by the mother as running belly ), vomiting, rapid or difficult breathing, pain or discharge from the ear, and skin conditions including any rashes or sores. Other symptoms were recorded as miscellaneous and were described. The mother s judgement was accepted for all symptoms and no attempt was made to reach a diagnosis. Further details of the instrument are reported elsewhere (29). The community health workers were trained in giving the questionnaire and achieved a minimum of 90% concordance with the trainer in 10 consecutive interviews before beginning the study. In addition, each month the supervisor observed 5 interviews to ensure quality control, and a high concordance was maintained. Statistics We compared the children s baseline characteristics by using analysis of variance (ANOVA) or chi-square tests. Correlational analyses were conducted to determine which variables were related to the final developmental scores. The effects of the interventions on developmental levels were examined by using multilevel analyses because of the hierarchical structure of the study. The random variables were clinic and child. Analyses were conducted with SPSS for WINDOWS version 11.5 (SPSS Inc, Chicago, IL) and MLwiN version 1.1 (Institute of Education, London, United Kingdom) for multilevel modeling. We did not hypothesize that the stimulation intervention would affect growth or morbidity, so these variables were compared by zinc supplement status only. The effect of the zinc supplement on the children s growth was examined by multiple regression of final anthropometry status. The independent variables were status at enrollment, age, sex, and supplementation status (zinc supplemented or placebo). To describe the children s morbidity, the number of episodes and the total duration of each symptom was recorded. These were corrected for the actual number of days when morbidity was recorded, because some information was unavailable because of the child or mother being away from home. An episode was defined as ended after 3 d without the symptom. The mean duration of each episode was calculated for each symptom. The data could not be normalized and were analyzed by using nonparametric statistics (Mann-Whitney U tests). RESULTS Twelve children (9%) did not complete the study. Reasons for withdrawal given by the parents from the zinc-supplemented group were as follows: children became anorexic (n 2), child would vomit after the supplement (n 1), the fathers refused to allow participation after the mother had given consent (n 2), and family moved away (n 1). From the placebo group, parents reported illness (jaundice and liver problems; n 2), families moved away (n 2), the mother was unhappy with the doctors from the research unit (n 1), or the mother felt that giving the supplement daily was too onerous (n 1). The children who withdrew were not significantly different from those who completed the study in any of the enrollment characteristics shown in Table 2 or in baseline developmental quotients, weights, or lengths. Compliance with the supplementation was indicated by the number of vials returned at the end of the week still containing supplement or placebo. Of the 180 vials that were delivered to

4 402 MEEKS GARDNER ET AL TABLE 2 Characteristics of the children at enrollment by group 1 Stimulation and zinc group (n 11 M, 14 F) Stimulation only group (n 11 M, 10 F) Zinc only group (n 13 M, 17 F) Control group (n 9M,29F) Age (mo) Birth order Crowding Sanitation Possessions Mother s age (y) Maternal height (cm) a b a b Maternal PPVT HOME score All values are x SD. There were no significant differences in the numbers of males and females in each group by chi-square test. Means in a row with different superscript letters are significantly different, P 0.05 (2-factor ANOVA and Tukey s test). 2 Number of persons per habitable room. 3 Comprises a rating of water source and toilet facilities (range: 0 12). 4 Number of household possessions (range: 0 10). 5 Peabody Picture Vocabulary Test, raw score (28). 6 Based on the Bettye Caldwell Stimulation in the Home scale (27). Higher scores represent more stimulation. each child, the median return of full vials was 7.25 (quartiles: ), or 4.0%, for the children receiving zinc, and 9.25 (quartiles: ), or 5.1%, for those receiving placebo. The number of full vials returned was not significantly different between the groups (Mann-Whitney U test). The number of intended home visits for the stimulation intervention was not always attained. Sixty-two percent of the children received 3 or 4 visits per month, whereas the others were visited 1 2 times per month. Group characteristics at enrollment The characteristics of the groups at the time of enrollment are shown in Table 2. Differences among the groups were examined by 2-factor ANOVA, except for sex, which was compared by chi-square analysis. Maternal height was significantly different among the groups, with the mothers in the control and stimulation groups being taller than those in the both and the zinc only groups. The children s anthropometric variables at the time of enrollment are shown in Table 3. Children who received placebo were significantly taller than those who received zinc. The developmental quotient and subscale scores (Table 4) were not significantly different across the groups at the time of enrollment. The initial developmental quotient score was strongly negatively correlated with age (Pearson s r 0.75, P 0.001) and was significantly related to the Caldwell HOME score (r 0.26, P 0.01) but was not related to other measures of social background or other maternal characteristics. Treatment effects Development In all groups, there was an overall decline in developmental quotient and all subscale scores (Table 4). There were significant differences among the groups in the overall developmental quotient and in the hearing and speech subscale scores (Table 4). The intervention effects on development were evaluated by use of a multilevel modeling procedure. Separate analyses were carried out with the final developmental quotient or each subscale score as the dependent variable. Initial score and children s initial age were included as covariates for their fixed effects in all models and the random parameters were clinic and child. Intervention groups were entered as follows: for zinc supplementation, supplemented 1, not supplemented 0; and for stimulation, stimulated 1, not stimulated 0. A third term was included (in the stimulation trial) to control for any effect of being in the stimulation trial or not (Figure 1). An interaction term (supplementation status stimulation status) was also offered. The following possible confounding variables, ie, those that were significantly different between the groups or were correlated with the developmental quotient, were also considered: maternal height, initial length-for-age z score, HOME score, possessions, crowding, birth order, and mother s score on the Peabody Picture Vocabulary Test. None of these variables was significantly related to change in developmental quotient. TABLE 3 Anthropometric indexes of the children at enrollment and 6 mo later 1 Zinc-supplemented group (n 55) Placebo group (n 59) Weight (kg) Enrollment mo Length (cm) Enrollment mo Weight-for-age z score Enrollment mo Length-for-age z score Enrollment mo Weight-for-length z scores Enrollment mo All values are x SD. Values for z scores are from National Center for Health Statistics reference data. Growth was analyzed by multiple regression controlled for initial status, sex, and age. Group differences were not significant. 2 Significantly different from the zinc-supplemented group, P 0.05 (t test).

5 ZINC AND CHILD DEVELOPMENT 403 TABLE 4 Developmental scores at enrollment and 6 mo later 1 Stimulation and zinc group (n 25) Stimulation only group (n 21) Zinc only group (n 30) Control group (n 38) Developmental quotient Enrollment mo a a,b b a,b Locomotor Enrollment mo Hearing and speech Enrollment mo d d c c,d Hand and eyes Enrollment mo Performance Enrollment mo All values are x SD. Means in a row with different superscript letters are significantly different, P 0.01 (ANOVA and Tukey s test). The estimates and 95% CIs of these models are shown in Table 5. Where the interaction between stimulation and zinc supplementation entered the model, the stimulated coefficient is the difference between the stimulation alone group and the control group means, and the zinc coefficient is the difference between the zinc alone group and the control group means. There was a significant interaction between stimulation and zinc supplementation on developmental quotient, and children who received both treatments had the highest developmental quotients after the intervention. There was no main effect of zinc supplementation alone. There was a significant main effect of stimulation alone on developmental quotient. There was also a significant interaction between zinc and stimulation on the hand and eye subscale, which also indicated that children having both treatments had the highest scores. Zinc alone, however, also benefited the hand and eye subscale. There were significant main effects of stimulation alone on hearing and speech and performance. Neither intervention benefited locomotor development. Growth The initial and final anthropometric measurements are shown in Table 3. It was not hypothesized that the stimulation intervention would affect growth, so only the supplementation intervention was considered for the growth analyses. In multiple regression analyses, the effect of zinc supplementation on final status was determined, including as independent variables initial measurements, sex, and age. The following covariates were also offered stepwise: maternal height, crowding, sanitation, and possessions. Supplementation had no significant effect on any of the anthropometric indexes. Morbidity The median and range of the cumulative episodes, and the total days ill, are shown in Table 6 for the supplemented and placebo groups. The number of episodes of diarrhea (P 0.019) and the total days of diarrhea (P 0.033) were significantly fewer in the zinc-supplemented group. There were no significant differences between the groups in number of episodes or duration of any of the other symptoms. DISCUSSION Zinc supplementation benefited overall development (developmental quotients) in stimulated children but not in unstimulated children. All children who received zinc benefited in hand and eye coordination, but those who received both stimulation and zinc benefited the most. Zinc supplementation was randomly assigned, testers were unaware of the assignment to interventions, and there was little loss from the sample. The zincsupplemented children also had reduced diarrheal morbidity, TABLE 5 Multilevel analysis of the developmental quotient (DQ) and subscale scores showing the effects of the interventions 1 Fixed variables DQ Locomotor Hearing and speech Hand and eye Performance Initial score (0.56, 0.88) (0.39, 0.69) (0.27, 0.66) (0.41, 0.76) (0.32, 0.72) Child s age (0.11, 0.75) (0.23, 0.93) 0.24 ( 0.72, 0.24) 0.15 ( 0.19, 0.50) 0.07 ( 0.53, 0.39) Stimulated (0.05, 5.00) 1.94 ( 3.58, 7.46) (2.81, 11.73) 1.05 ( 2.64, 4.74) (1.58, 10.44) Zinc supplemented 1.82 ( 0.63, 4.26) 1.46 ( 1.90, 4.81) 2.44 ( 6.58, 1.71) (1.17, 7.69) 1.59 ( 2.54, 5.72) Stimulated zinc supplemented (0.34, 10.03) (3.71, 16.55) 1 95% CI in parentheses. n 114. Developmental scores were analyzed by multilevel analysis with clinic and child as random variables. Initial score, age, supplementation group, stimulation group, and whether the child was enrolled in the stimulation trial were entered and an interaction term (supplementation status stimulation status) was offered. 2 P 0.05.

6 404 MEEKS GARDNER ET AL TABLE 6 Number of episodes and duration of illness in the zinc-supplemented and placebo groups during the 6-mo trial 1 Number of episodes Duration Reported symptoms Zinc-supplemented group (n 55) Placebo group (n 59) Zinc-supplemented group (n 55) Placebo group (n 59) d Apathy 0.0 (0 2) 0.0 (0 3) 0.0 (0 7) 0.0 (0 8) Fever 2.0 (0 6) 1.0 (0 8) 3.8 (0 7) 2.2 (0 6) Anorexia 0.8 (0 4) 1.0 (0 6) 1.7 (0 9) 1.2 (0 22) Nasal discharge 3.0 (0 15) 3.0 (0 9) 15.0 (0 14) 17.0 (0 20) Cough 2.0 (0 8) 2.0 (0 9) 8.2 (0 16) 12.2 (0 21) Rapid or difficult breathing 0.0 (0 3) 0.0 (0 6) 0.0 (0 1) 0.0 (0 1) Diarrhea (0 3) 0.8 (0 9) 0.0 (0 6) 0.2 (0 10) Vomiting 0.0 (0 5) 0.0 (0 4) 0.0 (0 5) 0.0 (0 7) Ear infection 0.2 (0 5) 0.0 (0 2) 0.0 (0 28) 0.0 (0 15) Skin problems 0.0 (0 7) 0.0 (0 5) 0.0 (0 31) 0.0 (0 25) 1 All values are median; range in parentheses. Groups were compared by nonparametric statistics. 2 Episodes and duration of diarrhea were significantly less in the zinc-supplemented group, P 0.05 (Mann-Whitney U test). None of the other symptoms were significantly different between groups. which suggests that they were initially zinc deficient. Therefore, it is probable that zinc was responsible for the improvements. Some other studies of zinc supplementation failed to show a benefit to developmental levels (13 15). Possible reasons for finding benefits in the present study may be that the children were zinc deficient or that the children received small doses of iron, which may have reduced the chances of zinc affecting their iron status through competitive interactions (30). Unfortunately, we were unable to take blood from the children, so we have no measure of hemoglobin or iron status. However, the provision of additional stimulation appears to be the most important factor contributing to the positive effects on development. It is possible that encouraging the mothers to be more responsive to their children was particularly effective in those children who received zinc and were thus more active and exploring. Stimulation benefited developmental levels and language development and also interacted with zinc to produce further benefits to developmental quotient and hand and eye coordination. The preferred design would have been to randomly assign children to stimulation as well as zinc, but this was not feasible. We therefore assigned them to stimulation by clinic, and this was taken into account in the analyses. We have found benefits from stimulation interventions in several previous studies (21, 31), but the benefits were usually larger. The duration of the program was shorter than previous ones, which probably explains the smaller benefits. The global benefit of some 5 developmental quotient points is approximately equivalent to 0.4 of an SD score. Change in maternal behavior and other aspects of stimulation in the children s home may be one mechanism through which the stimulation intervention may have improved developmental outcomes. Unfortunately, we did not measure the levels of stimulation in the home after the intervention; however, similar interventions have shown improvements in the levels of home stimulation (32). This may be an important measure to include in future studies. All groups declined in developmental levels over the 6 mo of the study, but the group receiving both interventions declined the least. The children came from poor backgrounds, and declines in scores on developmental tests are common in disadvantaged populations at this age and have been shown before in Jamaica (21) and elsewhere (33). Jamaican children from middle socioeconomic backgrounds do not show declines in scores at this age (34). Although the Griffiths test is not standardized in Jamaica, the scores are reasonably stable over time, and the scores are predictive of later IQ and school achievement (25). The children receiving zinc had fewer episodes of diarrhea and fewer days ill with diarrhea. These findings add further to the consensus (8) that zinc deficiency plays an important role in diarrheal morbidity. There were no significant benefits of zinc supplementation on the children s growth. It may be that the zinc deficiency was only mild and that morbidity is more sensitive to this level of deficiency than is growth. Alternatively, it may be that zinc was not the growth-limiting nutrient in this population or that the study was too short to produce a growth response. We are unaware of other studies that have combined zinc supplementation with psychosocial stimulation. A possible mechanism underlying the interaction is that the children would be more alert and active with zinc supplementation and would be more able to benefit from stimulation. Unfortunately, we were not able to observe the children s behavior. The findings of interactions between zinc and stimulation have important implications for policy and indicate clearly that integrated programs of nutrition and child development activities are needed to support optimal child development in disadvantaged populations with nutrient deficiencies. We thank the Ministry of Health, Jamaica; Michael Ennis; Carla Redding; Joan Thomas; Pauline Alcott; and the community health workers for assistance. JMMG, CAP, and SMG-McG were responsible for the conceptualization and design of the study. JMMG was responsible for the implementation of the zinc trial and the writing of the manuscript, CAP had overall responsibility for the stimulation trial, HB-H was responsible for the stimulation intervention, SPW assisted with the data analysis, and TJC provided statistical advice. All authors contributed to the critical review of the manuscript and approved the final draft for publication. None of the authors had any financial or personal relation with any of the companies sponsoring the research. REFERENCES 1. UN ACC/SCN. 4 th Report on the world nutrition situation. Geneva, Switzerland: ACC/SCN in collaboration with IFPRI, 2000.

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