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* Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
Center for Micronutrient Research, Annamalai University, Tamil Nadu, India
Ranbaxy Research Laboratories, Gurgaon, Haryana, India
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods. A randomized, double-blind, controlled trial with 2-by-2 factorial design enrolled 1154 full-term small for gestational age infants to receive in syrup 1 of the following: riboflavin; riboflavin and zinc (5 mg as sulfate); riboflavin, calcium, phosphorus, folate, and iron; or riboflavin, zinc, calcium, phosphorus, folate, and iron. A fixed dosage of 5 mL per child was given daily from 30 to 284 days of age. Household visits were made 6 days per week to provide the syrup and conduct surveillance for illness and death. When a child’s death was reported, parental reports and medical records were used to ascertain the cause. The effects of zinc and of the combination of iron, folate, calcium, and phosphorus were analyzed by intent to treat. The mortality analysis was performed using a survival analytic approach that models time until death as the dependent variable; all models had 2 terms as independent variables: 1 for the zinc effect and 1 for the vitamin and mineral (calcium and phosphorus, folate and iron) effect.
Results. Zinc supplementation was associated with significantly lower mortality, with a rate ratio of 0.32 (95% confidence interval: 0.12–0.89). Calcium, phosphorus, folate, and iron supplementation was not associated with a mortality reduction, although a statistically nonsignificant trend toward reduction was observed with a rate ratio of 0.88 (95% confidence interval: 0.36–2.15).
Conclusion. Zinc supplementation in small for gestational age infants can result in a substantial reduction in infectious disease mortality.
Key Words: zinc • micronutrients • mortality • randomized trial
Abbreviations: LBW, low birth weight • SGA, small for gestational age • WHO, World Health Organization • PI, Ponderal index • RR, rate ratio • CI, confidence interval • RDA, recommended daily allowance
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Evidence of the importance of zinc deficiency in child health has come from recent randomized, controlled trials of zinc supplementation.3,4 A pooled analysis of data from 7 trials evaluating preventive effects of zinc supplementation on diarrhea and pneumonia found an overall 18% lower diarrhea incidence and a 41% lower pneumonia incidence in zinc-supplemented preschool children.3 The significant effects on diarrhea and pneumonia, which are the major causes of death in this age group, lead to the question of whether there is an effect on mortality as well.
Developing countries account for 90% of the 20 million annual low birth weight (LBW) deliveries worldwide; 75% of these are in India, Pakistan, and Bangladesh.5,6 Birth weight is the single most important determinant of infant survival in developing countries,7,8,9 estimated to be an underlying risk factor in >70% of perinatal deaths, 90% of neonatal deaths, and 50% of infant deaths.10 Unlike in developed countries, where preterm birth is the main cause of LBW, in developing countries most LBW infants are small for gestational age (SGA).6,10 Nutrient deficiencies during fetal development can cause this intrauterine growth retardation and may also compromise immune function after birth.12 Low zinc concentrations in the cord blood of LBW newborns have been noted in a number of settings, and birth weight has been shown to be highly correlated with cord zinc concentration in India.13,14,15,16 Because of impaired immunocompetence and other factors, SGA infants have higher rates of respiratory infections7,8 and diarrhea.7,9 Therefore, zinc supplementation in SGA infants may reduce infectious disease morbidity and mortality.
We conducted a randomized, double-blind, controlled trial with a 2-by-2 factorial design to assess the effects of zinc or vitamin and mineral (calcium, phosphorus, folate, and iron) supplements on development, growth, morbidity, and mortality in 1- to 9-month-old SGA infants. The effects on mortality are reported here.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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A census and baseline survey covered 2066 households with a population of 10 003. Current pregnancies were recorded, and this register was updated by surveys every 3 months. Pregnant women were offered free antenatal services, and those who attended the clinic were given tetanus toxoid and iron supplements according to current World Health Organization (WHO) and Government of India policy. Pregnant women were followed monthly until 36 weeks of gestation, then weekly for 2 weeks, and finally daily until delivery. They were advised to inform the field clinic of a delivery, at which time a physician, nutritionist, and field assistant visited the home. A birth assessment form was completed, and birth weight, length, and head circumference were recorded. Weight was measured to 10 g with an electronic scale (SECA Corporation, Columbia, MD) by 2 independent observers. Gestational age was assessed according to Capurro et al.17 Only children with gestational age >37 weeks were considered for the study. The newborn was designated SGA if the birth weight was less than the 10th percentile for that gestational age compared with the reference population.18 Parents of the newborns who were SGA were invited to participate in the study. All mothers were advised to exclusively breastfeed and to bring the infant for immunizations.
The Ponderal index (PI = weight [g]/length [cm]3) for each child was calculated and compared with the 10th percentile of gestational age-specific values from Indian children.19 The values for gestational age 36–37, 38, 39, 40, 41, and 42 weeks were 2.23, 2.25, 2.26, 2.24, 2.20, and 2.14 g/cm3, respectively. A child below this value was considered to be wasted.
Eligible neonates were visited at home 2 weeks after birth. Each child was given an identification number in 1 of the 2 PI strata (wasted or not wasted); this number was used for random allocation of the child to 1 of the 4 treatment groups.
Before enrollment, a parent was given a full explanation of the study, and written informed consent was obtained. The study was approved by the human research review committees at the Center for Micronutrient Research, Annamalai University, Society for Essential Health Action and Training (a nongovernment organization in Delhi, India), the Johns Hopkins Bloomberg School of Public Health, and the WHO.
Experimental Maneuver
The supplements (prepared by Ranbaxy Research Laboratories, Gurgaon, India) were assigned 1 of 16 letter codes (4 codes for each study group). A statistician then made lists for each PI stratum, using permuted blocks of 10. The serial identification number given at enrollment was used to allocate a child to 1 of the 16 codes (and thus to 1 of the 4 treatment groups). A pharmacy assistant, using the list of assigned letter codes, labeled each bottle with a child’s name and identification. No one at the field site, including the investigators, had information about the assignment of the 16 letter codes or their corresponding micronutrient content. Because of the presence of calcium and phosphorus, the bottles of 2 groups (ie, bottles with 8 of the 16 letter codes) were more viscous, but the taste, color, and smell of the 2 pairs of zinc and nonzinc preparations were identical.
The randomization process allocated enrolled children to receive in 5 mL of syrup either riboflavin (0.5 mg/day); riboflavin and zinc (5 mg/day); riboflavin, calcium (180 mg/day), phosphorus (90 mg/day), folate (60 µmol/day), and iron (10 mg/day); and riboflavin, zinc, calcium, phosphorus, folate, and iron. Sulfate salts of zinc and iron were used.
When the neonate was 15 days old the mother was given a bottle of the supplement and advised to start giving the supplement beginning with 1 mL and increasing to 5 mL within 15 days. From 30 days of age, daily supplementation with 5 mL was given. Field assistants visited the family to feed the supplement to the child every day except Sundays and holidays, for which they left a measured dose in a separate vial for the mother to feed.
Baseline Assessment and Surveillance
At the first household visit soon after birth, weight, length, gestational age, and conditions of delivery were recorded. The additional baseline information was collected at the start of the illness surveillance at 30 days of age, including socioeconomic indicators and family characteristics. Each enrolled child was visited at home by a trained field worker every day, except Sundays or holidays, between 30 and 284 days of age. If the child was not available, an attempt was made to make a second visit later in the day, failing which the information was collected, if possible, on the next day. At each visit, information on the previous 24 hours, including the number and consistency of stools, the presence of fever or vomiting, and the pattern of feeding, were recorded, respiratory rate was counted, and compliance with supplement consumption was checked. During the study, compliance was 76.9% (76.7%, 77.7%, 76.3%, and 76.9% in groups 1 through 4), the mother gave the supplement two thirds of the time, and the field worker fed the supplement one third of the days it was taken. Treatment of diarrhea, dysentery, and pneumonia under WHO guidelines was provided free to the participating children throughout the study. When a death was reported, recall information and records available from the family and study physicians were used to describe the illness leading to the death. Two independent physicians blinded to study group allocation assigned a cause of death for each child.
Data Management
The data for each child visit were entered the day after the visit. By the end of that day the records were sent back to the field, along with a printout of the entered data and a list of range and logical errors. These were corrected by return household visit, if necessary. The printout was checked manually by the supervisor, who corrected entry errors. In addition, a second data entry was performed.
Study Profile
Of 1302 eligible SGA children, 52 died or moved before being randomized at 15 days of age (Fig 1). A total of 1250 children were randomized to the 4 groups, but 96 children dropped out before the surveillance began at 30 days of age (22, 23, 25, and 26 for groups 1 through 4, respectively). All 1154 children (292 control group, 292 zinc group, 281 vitamin and mineral group, and 289 zinc and vitamin and mineral group) on whom the surveillance was started were included in the analysis regardless of their compliance in taking the supplement. Of 290 364 days of potential surveillance, if each of the 1154 children had information for the complete 254 days or till the day of death if they died, we had information on 216 805 days, indicating that death, withdrawal, or temporary nonavailability accounted for 25.3% of days (this was similar in all 4 groups: 26.7%, 24.5%, 24.3%, 25.9%, respectively). Of 385 children who did not die and did not complete full 254 days of surveillance, 339 (88.1%) outmigrated and 46 (11.9%) withdrew consent to continue. Children not completing the study were included in the analysis using information available.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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2500 g), and 50% of infants were wasted.
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The 20 observed deaths were caused by diarrhea (1 in the zinc and 9 in the nonzinc group), pneumonia (3 in the zinc and 2 in the nonzinc group), septicemia (all 3 in the nonzinc group), and malnutrition (1 in the zinc and 1 in the nonzinc group). Although in the preceding analysis a single cause of death was indicated, 2 diarrheal deaths and 1 septicemia death also had underlying malnutrition.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The data from 10 trials evaluating the preventive effects of zinc supplementation3 have been subjected recently to pooled analyses, which indicated that there was a significant homogeneity in the results across the studies conducted in 9 developing countries. The substantial reduction in diarrhea and pneumonia rates in these trials and in the diarrhea rates in recently published studies from Ethiopia4 and Burkina Faso24 suggest that mortality could be affected as well. However, the magnitude of the effect on mortality found in this trial is more than can be expected given the previously demonstrated impact on morbidity, suggesting that there is an additional effect on the severity of episodes. We have previously documented effects of supplementation on the severity of diarrheal illness.25,26 Reductions in duration, stool volume, and treatment failure or death have also been found in therapeutic trials of zinc supplementation in acute and persistent diarrhea.27 Roy et al28 reported a reduction of mortality in hospitalized patients with persistent diarrhea and malnutrition given zinc supplements (relative risk 0.18, P = .06).
Although there is strong evidence of widespread zinc deficiency in children >1 year of age, the data on zinc deficiency in young breastfed children have been mixed. We did not estimate plasma zinc concentrations in this study but have previously documented that 36% of children in this population had a plasma zinc concentration <60 µg/dL and that the proportion of zinc-deficient children was similar in 6- to 11-month-olds and older children.29 Low concentrations of zinc in the cord blood of LBW infants have been noted in a number of settings and shown to be highly correlated with birth weight and gestational age at birth in India.13,14,15,16,30,31,32 Three studies reported lower zinc concentrations in SGA births,13,14,33 but 2 studies did not find this association.16,30
A possibility of zinc deficiency among exclusively breastfed LBW infants has been suggested based on the findings that after the first few months of lactation a large proportion of women may have breast milk zinc concentrations lower than that needed to provide the recommended daily allowance (RDA) of zinc to infants,34 and because the RDA is based on healthy infants, the need to provide for catch-up growth would make it a conservative estimate of the zinc need for SGA infants. Poor maternal nutritional status in these settings may also lead to lower breast milk production, so the breast milk zinc concentration needed to provide an RDA would be even higher.35 The infant’s zinc balance may also be affected by excess losses that can occur during diarrhea, resulting in the need for a zinc intake greater than that calculated for healthy children.36 There are reports of symptomatic zinc deficiency in breastfed infants in the literature.37,38,39,40,41 The beneficial effects of zinc supplements demonstrated in this study supports the finding that zinc deficiency can occur in breastfed SGA infants.
This study demonstrates that infants born with low PI (wasted) are at substantially greater risk of dying in the postneonatal period than nonwasted infants. SGA infants are born with impaired immune function, potentially an important factor leading to increased respiratory7 and diarrhea8 morbidity and mortality in infancy.12,41,42,43 Nutritional deficits, including micronutrient deficiencies, have been suggested to be responsible, at least in part.44 Our findings suggest that zinc deficiency occurs in SGA infants and that the lower mortality found with zinc supplementation results from reduced rates of severe diarrhea, possibly related to enhanced immunocompetence.
The potential of interventions to improve zinc status and reduce infant mortality has important implications for child survival in developing countries. The findings of this study must be confirmed in larger trials, preferably enrolling both small- and appropriate-for-gestational age infants.
Contribution of the Authors
Principal investigators S.S. and R.E.B. formulated the hypotheses, secured funding, developed the data collection instruments, coordinated the study implementation, conducted the analysis, and wrote the article; V.P.M. and P.D. supervised field work, contributed to development of forms and field procedures, and supervised field data collection and supplementation; L.E.C. provided input in design and development of gestational age assessment instruments; U.D. was responsible for programming, data management, quality control, and analysis; and A.B. was responsible for supplement design and development and quality control.
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ACKNOWLEDGMENTS |
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We thank the children and parents who participated in the study and the field team, including field workers, supervisors, physicians, nutritionists, data managers, and other support staff who assisted in the study. We thank Professor M. K. Bhan for his guidance and assistance in the early phases of this study. We gratefully acknowledge the assistance of Ranbaxy Research Laboratory in developing and providing the supplements. The efforts of V. K. Arora merit a special thanks.
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FOOTNOTES |
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Reprint requests to (R.E.B.) Department of International Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205. E-mail: rblack{at}jhsph.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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