Impact of Zinc Supplementation on Diarrheal Morbidity and Growth Pattern of Low Birth Weight Infants in Kolkata, India: A Randomized, Double-Blind, Placebo-Controlled, Community-Based Study
From the Division of Epidemiology, National Institute of Cholera and Enteric Diseases, Kolkata, India
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective. To assess the impact of zinc supplementation on diarrheal morbidity and growth pattern of low birth weight (LBW) infants.
Methodology. In a randomized, double-blind, placebo-controlled, community-based study conducted in the Tiljala slum of eastern Kolkata, India, between 1999 and 2001, a birth cohort of 100 LBW infants was randomly allocated into either an intervention group receiving 1 mL daily dose of 5 mg of elemental zinc as zinc sulfate in vitamin B complex-based syrup or a placebo group receiving an identical placebo of 1 mL of vitamin-based syrup from birth up to 1 completed year of age. Active weekly surveillance was conducted for detection of diarrhea. Anthropometric measurements of each child were recorded once every month as close to the child’s birth date as possible. Data were analyzed by using statistical software packages SPSSPC+ 4.0 (SPSS, Inc, Chicago, IL) and Epi Info 6.0 (Centers for Disease Control and Prevention, Atlanta, GA).
Results. Among the zinc-supplemented group, diarrheal incidence of 1.36 episodes per child per year were observed, whereas it was 1.93 episodes per child per year among the placebo group, giving a relative risk of 1.4 (95% confidence interval: 1.02-2.00). Linear growth and weight for age showed significant differences between the supplemented and placebo groups only at the end of 1 year. Interestingly, the impact of zinc supplementation was masked to a large extent by the protective action of breastfeeding.
Conclusions. The study showed that zinc supplementation had a beneficial impact on the incidence of diarrhea and also weight gain among LBW infants.
Key Words: low birth weight • zinc supplementation • diarrhea • nutrition • breastfeeding
Abbreviations: LBW, low birth weight • RR, relative risk • CI, confidence interval • NCHS, National Center for Health Statistics
The role of zinc in human nutrition is being increasingly highlighted after recent advances in biomedical research. Zinc as a micronutrient contributes greatly to healthy growth and development, especially of children.1–3
Low birth weight (LBW) infants (ie, infants weighing <2500 g at birth irrespective of gestational age) have high rates of morbidity and mortality from infectious diseases because of impaired immunity and are at increased risk of growth failure. Studies have demonstrated low zinc status in LBW infants.4,5 Additionally, it has been shown that low maternal zinc concentration during pregnancy may be associated with an increased risk of LBW; also, zinc supplementation during pregnancy has resulted in reduction of health risks of the infants.6 These studies indicate a reduced level of zinc in LBW infants, which might well account for the increased morbidity and growth failure in such children. Because there are no reliable biochemical indices for marginal zinc status, particularly for young children, it is therefore convenient to use controlled supplementation, assessed by growth indices and morbidity reduction, as outcome variables.7
Because LBW is a major pediatric problem, accounting for 
30% of all live births in a developing country such as India,8 this study was undertaken to assess the impact of zinc supplementation on morbidity caused by diarrhea and growth pattern in these infants. Additionally, not many community-based longitudinal studies have been conducted with zinc supplementation to LBW infants from birth through 1 year of age. Studies of shorter duration and also with children of older age groups have been conducted with different objectives, and they have not expressed consistent results.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The study was a randomized, double-blind, placebo-controlled, community-based intervention trial conducted between December 1999 and November 2001 in the Tiljala slum of eastern Kolkata, India, with a population of
10 000. The project was funded by the Indian Council of Medical Research and approved by the Scientific Advisory and Ethical Committees of the National Institute of Cholera and Enteric Diseases.
Selection of LBW Infants
A birth cohort of 100 LBW infants were identified in the study area. Informed consent was obtained from the parents before including them in the study. The children were enrolled in the study as soon as possible after birth, and it took nearly 1 full year to reach the required sample size. The birth weights of the infants were confirmed from their birth records. Exclusion criteria included major birth defects or congenital deformities and unwillingness to participate. All the births were institutional deliveries except for 3 of the LBW infants who were delivered at home, and their birth weights were noted within 24 hours of delivery. An attempt was made to estimate the gestational ages of the newborn infants, but because none of the mothers were certain of their last menstrual period, it was felt by the investigators that it would be safe to maintain the definition of LBW as weighing <2500 g at birth irrespective of gestational age and not attempt to classify them any further.
Sample Size Calculation
The sample size was calculated for 80% power and 5% level of significance. From previous community-based studies conducted by our institute, it was observed that infants <1 year old suffer on average 2.3 episodes of diarrhea per year. With an expected 30% reduction in diarrheal incidence9 among the zinc-supplemented group, and assuming a 10% drop-out rate, a total of 50 children was required in each group.
Randomization
Each of the enrolled infants was randomly allocated into either of 2 groups: an intervention group or a placebo group. Randomization schedules were prepared through computerized programs of simple random numbers. The numbers were allotted to either of the 2 groups and then arranged serially. The children were assigned sequential serial numbers, and preparations were distributed accordingly.
Intervention and Blinding
The syrups administered to the study children in the 2 groups were prepared by Messrs. Greenco & Co Pvt. Ltd, a Kolkata-based drug-manufacturing company. The infants in the intervention group received a 1-mL dose of 5 mg of elemental zinc as zinc sulfate in vitamin (B complex)-based syrup, and those in the control group received an identical placebo (similar taste, color, and consistency) of 1 mL of vitamin-based syrup. The composition of the B complex syrup included thiamine, riboflavin, pyridoxine, cyanocobalamine, and flavoring agents. In the first 3 months of life, the zinc group received 3 mg of elemental zinc in a 1-mL dose. Children of both groups received daily doses (5 days a week) from the day of enrollment (usually within 7 days of birth) to the age of 1 completed year. The zinc dose schedule was adapted from the recommendations of the Pediatric Nutrition Handbook.10 The syrups were supplied to both the groups in identical bottles with scored droppers and serial numbers. The mother of each child was shown individually how to administer the syrup by using the dropper and advised to give her child the daily dose. Each bottle contained 10 mL of syrup and was replaced every 2 weeks. The codes of the 2 groups were kept confidential and sealed with a person not in any way related to the trial and opened only after analysis of the outcome variables of the groups had been completed.
Follow-Up Visits
Once a child was included in the study, a standardized predesigned questionnaire was used to obtain family details including basic demographic and socioepidemiologic data. Active surveillance (weekly) for the detection of diarrhea was conducted by 2 locally recruited, resident female health workers who were trained in home management of diarrhea and also acted as depot holders for oral rehydration solution. Each worker was responsible for 50 LBW infants, and, during their weekly domiciliary visits, they also supervised the administration of the zinc/placebo syrup by the mothers.
Regular field visits (5 days a week) for additional data collection and supervision of the health workers were made by an epidemiologic team. Their observations were noted in predesigned individual child health cards, which included information on infant feeding practice including breastfeeding habits and assessment of nutritional status by measurement of length and weight for age. The anthropometric measurements of each child were recorded once every month as close to the child’s birth date as possible. Length was measured by the infantometer to the nearest millimeter, and weight was measured by the standard weighing machine (beam balance-type) to the nearest 50 g. The team, headed by a physician, examined and treated all reported cases of diarrhea and noted details of each episode in predesigned surveillance proforma. The mothers of children with diarrhea were advised to continue breastfeeding if the child was still being breastfed, or, alternatively, give plenty of fluids and oral rehydration solution.
Definitions Used
LBW was defined as weighing <2500 g at birth irrespective of gestational age.
Diarrhea was defined as passage of 3 or more loose or watery stools in 24 hours. For exclusively breastfed infants, a change in consistency of stool with increased frequency that was of concern to the mother was regarded as diarrhea. When there were 3 diarrhea-free days between 2 episodes, they were considered as 2 separate episodes.
Proportion of days ill per child per year = (total number of days ill because of diarrhea in a group/total number of days of observation in that group) x 365.
Percentage reduction of diarrhea = ([incidence among control group – incidence among supplemented group]/incidence among control group) x 100.
Data Management
Before entering data into the computer, individual forms were scrutinized thoroughly for accuracy and consistency. Data were subsequently fed into a personal computer using the database software package dBase IV (Ashton-Tate Corp, Torrance, CA). The data were validated by logical and range check and analyzed with the help of a statistical software package (SPSS PC + 4.0). For calculation of P values, relative risk (RR), 95% confidence interval (CI), etc, the Epi Info 6.0 software package was used. The 
2 and t tests were applied for comparison of differences in proportions and means, respectively. The z scores of weight for age and percentage median were calculated by using the software package Epi-Nut (Centers for Disease Control and Prevention) with National Center for Health Statistics (NCHS) reference data.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Table 1 summarizes the sociodemographic profile of 50 families studied in each group. It would be evident that the 2 groups were comparable in all the parameters. Thirty-five (70%) mothers in the intervention group and 32 (64%) in the control group were literate. Most families in the intervention group (66%) and also in the control group (72%) belonged to grade IV socioeconomic status according to Kuppuswamy’s Index.11 A safe water supply was available to 62% of the families in the intervention group and 56% of the families in the control group. Indiscriminate disposal of childrens’ feces was practiced by 82% and 76% of families in the intervention and control groups, respectively. Very few mothers in both groups had practiced hand-washing with soap before preparation of food, after ablution of the child, and before feeding the child. However, 64% of the mothers in the intervention group and 72% of those in the control group practiced hand-washing with soap after defecation.
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The 2 groups of children were observed for a total of 4907 weeks (94%) of a possible 5200 weeks (2514 weeks for zinc-supplemented and 2393 weeks for the control groups). A total of 155 diarrheal episodes were detected among the 2 groups of children during this period of follow-up. The infants in the supplemented group suffered from 66 diarrheal episodes giving an incidence of 1.36 episodes per child per year of observation, whereas in the control group 89 episodes were detected with an incidence of 1.93 episodes per child per year of observation. The difference was statistically significant (P < .03; RR: 1.4; 95% CI: 1.02–2.00), showing a percentage reduction of 29%.
All the infants were exclusively breastfed from birth, which continued up to 4 months of age in 75% of children, after which the rate fell substantially with initiation of weaning. It was observed that the median age of weaning was similar in both groups. Analysis of proportion of days ill with diarrhea per child per year revealed a difference in diarrheal incidence with increasing age, which could also be correlated with the breastfeeding status of the children. As shown in Table 2, during the exclusive breastfeeding period, both groups of infants had experienced a comparable incidence of diarrhea, which was less than that of the postbreastfeeding period. It was interesting to note that there was no significant difference in the proportion of days ill (3.7 vs 4.0 days) as well as diarrheal incidence (0.9 vs 1.0 episode per child per year) among the exclusively breastfed infants in supplemented and placebo groups, respectively. However, once the infants were taken off the breast, the proportion of days ill because of diarrhea was 6.6 vs 10.2 days, and the diarrheal incidence was 1.67 vs 2.65 episodes per child per year in the supplemented and placebo groups, respectively, and the differences were statistically significant (P < .001).
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Mean birth weight (2284 ± 160 g for the supplemented group and 2315 ± 168 g for the placebo group) and length (46.4 ± 1.6 and 46.4 ± 1.5 cm, respectively) was similar for the 2 groups of children. From the growth curve (with error bars) showing mean weight for age at each month of the 2 groups (Fig 1), it is apparent that they had a similar growth pattern as long as they were exclusively breastfed. In fact, the relative improvement in the mean weight for age in the supplemented group over the placebo group was noted only from
5 months of age, when most of the infants were weaned. However, only at the end of 1 year was the difference statistically significant (P < .001). It was observed further that the mean weight gain (difference between final weight and birth weight) in the supplemented group was 6084 vs 5280 g in the placebo group, and this difference was also statistically significant (P < .001).
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The linear growth pattern of the 2 groups of infants was comparable until 10 months of age (Fig 2), after which the supplemented group started showing a better performance. The difference, however, showed statistical significance only at the end of 1 year (P < .001). In fact, the gain in length of the supplemented group (difference between final length and birth length) was 23.7 cm, whereas it was 21.4 cm for the placebo group with a statistically significant difference (P < .001).
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The z scores of weight for age also showed a similar trend. The z scores are calculated by using reference data from the NCHS and represent the distance of a value above or below the mean weight of full-term infants of each age as expressed in standard deviation units. A z score below –2 is considered a low value and below –3 as very low. Negative values of z scores were observed throughout the study as shown in Table 3. However, the difference between the supplemented and placebo groups (–1.45 ± 0.95 vs –2.17 ± 0.90) was statistically significant at the end of 1 year (P < .001).
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A frequently applied index to assess growth of children in developing countries is percent of median. Infants are considered to have normal growth if their weight for age is >80% of the median of NCHS standards. Weights between 70% and 80% of the median are considered as grade I malnutrition, 60% and 70% as grade II, 50% and 60% as grade III, and <50% as grade IV. By using this index for analysis it was observed that, of the 50 children in each group who were in various grades of malnutrition at birth, 33 (66%) children in the supplemented group reached normal status by 1 year of age, whereas only 23 (46%) in the placebo group reached normal status, and the difference was statistically significant (P < .04; RR: 1.43; 95% CI: 1.00–2.06).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Zinc deficiency is common in young children in the developing world and is associated with reduced immunocompetence and increased rates of serious infectious diseases. Several community-based studies conducted among children of different age groups have shown the beneficial impact of zinc supplementation in the form of reduced diarrheal episodes in children with zinc deficiency, because zinc supplementation leads to accelerated regeneration of mucosa, increased levels of brush border enzymes, enhanced cellular immunity, and higher levels of secretory antibodies.12 Zinc supplementation plays an important role in reducing childhood diarrheal incidence by up to 25% according to a systematic review of 10 randomized, controlled trials performed in developing countries.13 A pooled analysis conducted by the Child Health Research Project, a group of researchers from the Johns Hopkins School of Public Health and the World Health Organization, showed that zinc-supplemented children in 7 continuous trials had a pooled odds ratio for diarrheal incidence and prevalence of 0.82 (95% CI: 0.72–0.93) and 0.75 (95% CI: 0.65–0.88), respectively. The authors concluded, "The development of effective and feasible interventions to improve the zinc status of developing country populations is essential."14 LBW infants have higher postnatal requirements of zinc and, unless replenished, the newborns remain at increased risk of developing zinc deficiency.15 In fact, in a placebo-controlled, randomized trial in Bangladesh, where mothers were administered zinc supplementation during pregnancy, it was observed that there were larger reductions in frequency of acute diarrhea in LBW infants rather than normal birth weight infants.6 The present study also reiterates the fact that daily zinc supplementation is effective in reducing diarrheal incidence among LBW infants.
We further hypothesized that poor growth in LBW infants as has been documented already could be related in part to low body stores of zinc and inadequate zinc intake early in life.16 Zinc is required for production of enzymes involved in nucleic acid metabolism and protein synthesis, which are essential processes for growth.17 Because LBW infants exhibit prolonged growth deficit as compared with their normal birth weight counterparts, they probably suffer from suboptimal zinc intake, and, as such, supplementation may improve growth.
Studies on zinc supplementation to LBW infants from birth through 1 year of age are rarely conducted. However, studies of shorter duration on very LBW infants and also on children in older age groups have shown varying results. In a study conducted by Freil et al18 on very LBW infants who were supplemented with zinc up to 6 months of age, the supplemented group showed improved linear growth velocity but no significant change in weight gain over the placebo group. In yet another study on zinc supplementation to low-income preschool children conducted by Walravens et al,19 it was observed that zinc supplementation showed differences in linear growth but not in weight or weight-for-length velocity. A similar placebo-controlled study conducted by Shrivastava et al on malnourished children aged 8 to 24 months showed that children supplemented with zinc for 3 months had a significant weight gain (P < .001) compared with the placebo group.20 It was also highlighted in our study that LBW infants supplemented with zinc for 1 year show improvement in weight gain and linear growth compared with the control group.
The beneficial effect of breastfeeding on the incidence of diarrhea and weight gain especially in LBW infants has been amply demonstrated in the present study and previous studies as well.21 In fact, in the present study the impact of zinc supplementation was masked to a large extent by the protective action of breastfeeding on occurrence of diarrhea and nutritional status of children. The recommendations, however, will be to supplement zinc from birth because, although bioavailability of zinc in human milk is high, by 4 to 6 months of lactation even a well-nourished mother cannot supply the daily zinc requirement to her infant.22 In addition, zinc requirements of LBW infants are high because of their immature gastrointestinal tracts, which leads to both high endogenous losses and decreased absorption, an extended period of rapid growth, and low body stores of zinc.23,24 Thus, if zinc supplementation is started at birth in these infants, its sustained impact will continue in the weaning period when the introduction of supplements under unhygienic environmental conditions increases the risk of bacterial contamination and subsequent diarrheal diseases with resultant growth faltering.25 At the same time, low bioavailability of zinc in cereals and other common infant foods because of the presence of fibers and phytates increases the chances of zinc deficiency in such infants.26 This is endorsed by the fact that the control children in the present study had increased episodes of diarrhea, and their growth was affected adversely. The commonly used weaning foods in this part of the country include cereals, lentils, vegetables, and fruits.
It is evident from our study that zinc supplementation from birth to 1 year of age has been effective in reducing diarrheal incidence. The study also demonstrates improved weight gain and linear growth in LBW infants. These findings could have important implications for child health and survival programs in developing countries with high incidence of LBW, and operational feasibility studies of large-scale implementation of prolonged zinc supplementation, especially in this group of infants, need to be conducted in the future.
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FOOTNOTES |
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Received for publication Aug 29, 2002; Accepted Mar 7, 2003.
Address correspondence to Dipika Sur, MBBS, MD, Division of Epidemiology, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Rd, Scheme XM, Beliaghata, Kolkata 700010, India. E-mail: dipikasur{at}hotmail. com
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