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,2
* Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205 and
ICDDR,B: Centre for Health and Population Research, Dhaka 1000, Bangladesh
2To whom correspondence should be addressed. E-mail: abaqui{at}jhsph.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • micronutrient interventions • infant morbidity • randomized controlled trial
Diets given to young children in most developing countries are often deficient in multiple micronutrients including zinc and iron. Zinc deficiency is highly prevalent (1–3), and zinc supplementation has been shown to prevent acute and persistent diarrhea, dysentery and acute lower respiratory infection (ALRI)2 (4–8). Many infants in developing countries also develop iron deficiency by 6 mo of age (9–11), which can cause anemia and impair the child’s physical and mental development (12,13). Iron supplementation reduces anemia and improves development, but its effects on infectious morbidity are conflicting (14–17). Deficiencies of other vitamins and minerals are also common and may limit the benefits of supplemental zinc and iron. There is some evidence that supplementation with a micronutrient mix (MM) may be more beneficial than supplementation with a single nutrient for some outcomes, e.g., linear growth (18), but there are no data for morbidity.
Despite controversies, the balance of the evidence suggests that increased consumption of iron and zinc should be beneficial for infants, particularly those born small-for-gestational age (SGA), those who are raised in deprived communities or both. In settings in which it is difficult to prevent zinc and iron deficiencies through dietary approaches, it is important to define the feasibility and effects of zinc and iron supplementation of infants after 6 mo of age. Most of the earlier studies assessed the effects of iron or zinc separately. Because many of the micronutrients have synergistic (e.g., vitamin C enhances nonheme iron absorption) and antagonistic effects (e.g., iron interferes with zinc absorption, zinc interferes with copper absorption, calcium interferes with iron absorption), we examined the effect of supplementation of zinc only, iron only, iron + zinc and a MM on diarrhea and ALRI morbidity in 6- to 12-mo-old Bangladeshi infants, in whom SGA is frequent, infectious diseases are highly prevalent, and dietary insufficiencies of multiple micronutrients, including zinc and iron, are common.
With large-scale supplementation programs, factors such as cost, availability, distribution of supplements and compliance with prescribed supplement intake often reduce the program’s effectiveness (19). Therefore, alternative supplementation strategies must be investigated to improve effectiveness. Supplementation on a weekly rather than a daily basis is less expensive and may be easier to manage. In a recent study by Thu et al. (20), daily and weekly supplementations of iron or zinc had similar effects on hematological parameters in preschool children. In this study, we evaluated the efficacy of weekly supplementation on diarrhea and ALRI morbidity in Bangladeshi infants.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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This community-based, prospective, randomized, controlled trial was conducted in the Matlab field research area of ICDDR,B: Centre for Health and Population Research in Bangladesh. Matlab is a rural subdistrict of Bangladesh in which health and demographic research has been conducted since 1963. A Health and Demographic Surveillance System (HDSS) is currently operational in 142 villages with 210,000 people. HDSS gathers data on diarrhea and ALRI morbidity and vital event information on births, deaths and migrations on a regular basis through home visits. In this population, ALRI and diarrhea are important causes of morbidity and death (21).
Intervention.
We evaluated the efficacy of weekly supplementation of iron, zinc, both iron and zinc and a MM for 6 mo in infants beginning at 6 mo of age on iron and zinc status, diarrhea and ALRI morbidity, physical growth, and mental and motor development. Infants were assigned to one of the following five groups: 1) iron with riboflavin, 2) zinc with riboflavin, 3) both iron and zinc with riboflavin, 4) a MM and 5) riboflavin only. The iron group received 20 mg of elemental iron as ferrous sulfate and 1 mg of riboflavin; the zinc group received 20 mg of elemental zinc as zinc acetate and 1 mg of riboflavin every week. The iron + zinc group received 20 mg iron, 20 mg zinc and 1 mg of riboflavin every week. The MM3 group received approximately twice the WHO recommended daily intakes (22) of vitamins and minerals in addition to 20 mg of iron, 20 mg of zinc and 1 mg of riboflavin, every week. The riboflavin group received 1 mg of riboflavin weekly and was considered the control group. Because vitamin A supplementation is a national program in Bangladesh, infants in all groups received 100,000 IU of vitamin A [3.3 IU = 1 retinol activity equivalent (µg)] at the beginning of the study. This allowed us to evaluate the efficacy of various micronutrient formulations independently of any effects of vitamin A. We report here the effects of various micronutrient formulations on iron and zinc status and on diarrhea and ALRI morbidity. The effects on other outcomes will be reported elsewhere.
Infants aged 6 mo from selected Matlab villages were enrolled in the study over a 6-mo period. Sample sizes were calculated assuming that the incidence of diarrhea and ALRI were 5 and 3 episodes per child per year and that the supplementation would reduce the incidences by 30%. To detect 30% reduction of diarrhea and ALRI incidences between the control group and the treatment groups with 80% power and 95% significance level, 28 and 38 child years of observations, respectively were required in each study arm. We multiplied the calculated sample size by a factor of 2 to allow for stratified analysis and provided allowance for a 10% drop out. Because the plan was to follow each study infant for 6 mo, to ensure adequate sample size, we enrolled 160 infants in each study arm.
Each week, lists of potentially eligible infants were obtained from the HDSS database. After obtaining informed consent from the parents, the infants were screened for eligibility. A trained paramedic assessed socioeconomic and demographic conditions, 1 wk of retrospective morbidity, weight, length and hemoglobin concentration of study infants. Weight was measured to 0.1 kg using a Salter scale, length to 0.1 cm using a length board, and hemoglobin concentration using HemoCue B (HemoCue AB, Angelholm, Sweden). Infants fed infant formula, with severe malnutrition [mid-upper arm circumference (MUAC) < 110 mm], severe anemia (hemoglobin concentration < 90 g/L), with obvious neurological disorders, physical disability and chronic illness that might affect feeding, activity and cognitive development were excluded. Eligible infants were randomly allocated to one of the five study groups. Each study infant received a weekly dose of the assigned supplement, which was presented in the same type of capsules and labeled in such a way that the various types of supplements could not be differentiated. The supplements were fed to infants after mixing the contents of the capsules with flavored syrup. The capsules and the syrup were prepared by ACME laboratories (Dhaka, Bangladesh). Before the beginning of the study, the feasibility of mixing the supplement with syrup and the acceptability of the supplements was tested in 20 infants. Trained Community Health Workers (CHW) fed the supplements to study infants during weekly home visits using a special medicine spoon. If an infant was absent on a scheduled visit day, the infant was revisited within 2–3 d. Each week, the worker recorded the infants supplement intake as full or partial or no dose. Intake was considered partial if the CHW was unable to feed the full dose or if the infant vomited immediately after feeding the supplement.
Outcome definitions and follow-up.
Diarrhea was defined as 
3 loose stools in a 24-h period or 1 loose stool containing blood. A diarrheal episode was considered new if the episode was preceded by 3 diarrhea-free days (23). Oral rehydration solution (ORS) packets were readily available in the study villages free of charge and mothers were expected to use ORS in all episodes. However, mothers made the decision to use ORS on the basis of their knowledge and perception of the severity of the diarrhea; in this study, only 
38% of episodes were treated with ORS. These episodes were considered to be severe. ALRI was diagnosed if the child had reported symptoms of cough or difficulty in breathing with rapid breathing with or without chest in-drawing; episodes with chest in-drawing were categorized as severe ALRI (23). The CHW collected information on the occurrence, type and severity of diarrhea and ALRI morbidity by interviewing mothers during the weekly home visits. To ensure data quality, the study supervisors and investigators made random spot checks. In addition, a 5% sample of study children was reinterviewed and remeasured within 2 d of the original interviews/measurements. The reinterview data were compared with the original interview data and were used primarily as a management tool to identify workers requiring support and retraining. Overall, there was 95% agreement between the interview and reinterview findings. Blood samples were obtained from a random sample of infants at 6 and 12 mo of age to measure serum ferritin, hemoglobin and zinc levels.
Data quality assurance, management and analysis.
All questionnaires and data forms were reviewed by one of the investigators for accuracy, consistency and completeness. Whenever necessary, the CHW made additional field visits to clarify inconsistencies or collect missing information. After editing, the data were entered in databases using on-line custom-designed data entry programs. Necessary range and consistency checks were built in. Data were periodically checked by running and reviewing frequency distributions and cross-tabulations.
Baseline characteristics of the different treatment groups and the control group were examined for group comparability. The group means were compared using ANOVA with the Bonferroni correction and the group proportions were compared using the 
2 statistic. Significant baseline differences were controlled for during data analysis. The effects of iron, zinc, iron + zinc and MM supplementation on hemoglobin, serum ferritin and serum zinc were evaluated by comparison with the 12 mo group levels after adjusting for age and 6 mo levels using linear regression methods. The effect on the incidence of diarrhea and ALRI morbidity were evaluated by calculating incidence rate ratios (IRR) and 95% CI using the Poisson regression model. Because infants’ age, sex, mothers’ education, fathers’ education and family income were significantly associated with both diarrhea and ALRI morbidity, the analysis was repeated to adjust for the distribution of these variables in the study infants. The analysis was extended to assess the effects of supplements on severe diarrhea and severe ALRI in all infants and in less well-nourished infants with weight-for-age Z-score below -1.
The study procedures were approved by the research and ethical review committees of ICDDR,B. Written informed consent was obtained from parents of study infants.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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50% of the time. With all other supplements, study infants received the full dose 80% of the time (Fig. 2). There was no sex differential in compliance.
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38% were treated with ORS; these episodes were considered severe. When the analysis was restricted to severe diarrheal episodes, the iron + zinc group had a 19% lower rate of diarrhea in all infants (P < 0.05) and a 30% lower rate in less well-nourished infants (P < 0.01) (Table 3). MM supplementation was not associated with increased risk of severe diarrhea. To investigate whether the MM group was more diarrhea prone to begin with, we calculated the diarrhea rates of infants in the five treatment groups before study (0–6 mo) using routine data from the Matlab HDSS. There was no differential in diarrhea morbidity between the groups. Because MM was poorly tolerated, we extended the analyses to adjust for dose but that did not change the results. To further examine whether infants who completed 6 mo of supplementation with MM and those who did not started with differential morbidity experience, we calculated the diarrhea and ALRI rates of infants in these two groups in their first 6 mo of life (the period before enrollment in the trial) using routine data collected by the ICDDR,B HDSS; the diarrhea and ALRI rates in the first 6 mo of life were not different (data not shown).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Iron deficiency is the commonest micronutrient deficiency in the world, especially in the developing world (24). To address the high prevalence of iron deficiency, programs of presumptive therapy, mass supplementation, dietary diversification and food fortification have been introduced in many countries. At the same time, concerns have long existed about the interaction between iron supplementation and certain infections (25–27). Because studies confirm that iron is important for bacterial virulence and growth and either a lack or excess of iron may impair immune function, a link between iron and infection is plausible. However, the literature concerning the relationship between iron and clinical infections is not consistent (25). Although earlier prospective studies of iron supplementation in infants among deprived Western populations demonstrated a reduction in respiratory infection rates (26), several later reports from developing countries indicated an increased risk of diarrhea, malaria and respiratory infections (27). In contrast, a number of trials showed no effects on malaria morbidity (28–30). Part of the explanation for this inconsistency lies in the uncontrolled nature of many of the studies and the erroneous use of serum ferritin level as a marker of iron overload. Inflammation and infection can elevate serum ferritin level independently of iron status (31). A number of recent reviews concluded that studies that more carefully separated the contribution of iron to infection, controlling for potentially confounding variables, showed no role of iron in increasing the risk of infection (24,25). Our findings of no effect of iron supplementation on diarrhea and ALRI morbidity are consistent with these recent reviews but our findings relate only to a 20-mg weekly dose of iron, a lower dose than in most previous studies.
Zinc supplementation was shown to reduce the incidence of diarrhea and ALRI morbidity in a zinc-deficient population (4,5,8). We observed a nonsignificant 13% lower incidence of diarrhea and severe ALRI in less well-nourished, zinc-supplemented infants. It seems that a weekly dose of 20 mg elemental zinc alone was not sufficient to effectively reduce diarrhea and ALRI morbidity. It is also possible that the benefits of zinc supplements on morbidity are smaller in infants than older children as suggested for diarrhea outcomes in a pooled analysis of seven trials (8).
Because iron may interfere with zinc absorption and vice versa (20), information on interactions between iron and zinc when supplemented together is of particular importance. The only published study we are aware of that evaluated the effect of simultaneous supplementation of iron and zinc on morbidity was conducted by Rosado et al. (32). In that study, Mexican preschoolers were supplemented daily with 20 mg iron, 20 mg zinc, 20 mg iron + 20 mg zinc or a placebo. Children in both zinc-supplemented groups had fewer episodes of disease including diarrhea. In contrast to the findings of Rosado et al. (32), we observed a significant reduction of severe diarrhea and severe ALRI morbidity only with simultaneous supplementation of iron and zinc, and the reduction of ALRI was restricted to less well-nourished infants. Because simultaneous iron + zinc supplementation was associated with improved iron and zinc status, the effect on diarrhea and ALRI morbidity seems plausible. It is important to note that there were differences between our study and the study by Rosado et al. (32) in age of study population (infants 6–11 mo vs. children 18 and 36 mo) and in the frequency of supplementation (weekly vs. daily). Because iron and zinc deficiencies are likely to coexist in populations whose diets are low in animal products and high in phytate and because simultaneous supplementation of iron and zinc had the greatest effect on diarrhea and ALRI morbidity, if these results are confirmed, it would be logical to provide iron + zinc supplementation for infants in these populations.
Many country programs and international agencies are considering starting supplementation of infants and children with a MM. Therefore, the higher risk of diarrhea morbidity in our study infants who were provided with a MM is of concern. Matlab HDSS data allowed us to determine whether any group was more prone to diarrhea before the study (0–6 mo). There was no difference in the number of registered episodes between the groups. Of the infants in the MM group, 41% dropped out. However, we did not observe any differentials in baseline characteristics between those who completed 6 mo of supplementation with MM and those who did not. Therefore, the higher diarrhea morbidity we observed in the MM group was probably real. A recently completed three-cell controlled trial in a cohort of 6- to 35-mo-old children with persistent diarrhea in Lima, Peru compared the protective efficacy of 6 mo of supplementation with zinc alone, zinc with a MM and a placebo on fever, cough and diarrhea morbidity. During the following 6 mo, children in the zinc group had fewer episodes of diarrhea, fever and cough, but only the reduction in cough was significant. The MM group had the highest incidence and prevalence of diarrhea, fever and cough but only the prevalence of dysentery was significantly increased (33). The investigators of this study concluded that they were unable to determine which component of their MM was responsible for the apparent detrimental effect but suspected that it could be due to iron. Our data suggest that supplementation with iron alone had no effect on diarrhea and ALRI morbidity and when supplemented simultaneously with zinc, it was actually beneficial. Because of public health significance of this finding, the efficacy of different micronutrient formulations must be investigated further before deciding which would be most beneficial. There is little evidence to date that supplementation with a MM provides any added benefit to iron + zinc, along with vitamin A.
Several possible limitations of our study and their implications for future research should be considered. Even with study workers feeding the supplements to study infants, the compliance was not 100%. Although the strategy of weekly supplementation we evaluated may have some advantages over daily supplementation (e.g., less expensive, easier to manage), a possible disadvantage is that a missed dose would lead to a long time without supplement. The MM preparation we used was poorly tolerated; improved formulation is required if it is to be used in future studies. Further studies are warranted to investigate the reasons for the apparent adverse effects of MM. It could be due to a particular vitamin or mineral or interaction among them or related to amounts of a single or sets of micronutrients.
Appropriate weekly doses of different micronutrient formulations are not known. Because there were indications of benefit with simultaneous supplementation with iron and zinc, it will be useful to determine whether higher doses would have a greater effect.
Although efforts must be targeted at improving dietary intakes of micronutrients in infants and children through improved breast-feeding and appropriate complementary feeding, these goals are difficult to achieve and are generally regarded as long-term strategies to improve micronutrient nutrition. There is a need for additional measures, e.g., supplementation to the general population or to high risk groups to increase the intake of certain micronutrients, particularly iron and zinc. We provided iron and zinc supplements to infants in a relatively small dose and only once each week. This strategy might have minimized the interference of zinc absorption by iron and maintained the iron and zinc level that enhanced immune responses by the host, but did not facilitate the availability of iron to microorganisms. This strategy of intermittent simultaneous iron + zinc supplementation seems promising and warrants further evaluation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ALRI, acute lower respiratory infection; CHW, community health worker; HDSS, Health and Demographic Surveillance; IRR, incidence rate ratio; MM, micronutrient mix; MUAC, mid-upper arm circumference; ORS, oral rehydration solution; SGA, small for gestational age.
4 Composition of the micronutrient mix: 20 mg iron, 20 mg zinc, 100 µg iodine, 1.2 mg copper, 1.6 mg manganese, 30 µg selenium, 70 mg vitamin C, 20 µg vitamin D, 8 mg vitamin E, 0.8 mg thiamin, 1.0 mg riboflavin, 12 mg niacin, 1.2 mg pyridoxine, 70 µg folic acid, 1.0 µg cyanocobalamin and 6 mg pantothenic acid.
Manuscript received 4 April 2003. Initial review completed 30 May 2003. Revision accepted 22 September 2003.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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30. Menendez, C., Kahigwa, E., Hirt, R., Vounatsou, P., Apontte, J. J., Font, F., Acosta, C. J., Schellenberg, D. M., Galindo, C. M., Kimario, J., Urassa, H., Brabin, B., Smith, T. A., Kitua, A. Y. & Tanner, M. (1997) Randomized placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for the prevention of severe anemia and malaria in Tanzanian infants. Lancet 350:844-850.[Medline]
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