Original Article
Reduced Mortality among Children in Southern India Receiving a Small Weekly Dose of Vitamin A
N Engl J Med 1990; 323:929-935October 4, 1990
- Abstract
- Abstract
Background.
Clinical vitamin A deficiency affects millions of children worldwide, and subclinical deficiency is even more common. Supplemental vitamin A has been reported to reduce mortality among these children, but the results have been questioned.
Methods.
We conducted a randomized, controlled, masked clinical trial for one year in southern India involving 15,419 preschool-age children who received either 8.7 μmol (8333 IU) of vitamin A and 46 μmol (20 mg) of vitamin E (the treated group) or vitamin E alone (the control group). Vitamin supplements were delivered weekly by community health volunteers who also recorded mortality and morbidity. Weekly contact was made with at least 88 percent of the children in both study groups. The base-line characteristics of the children were similar and documented a high prevalence of vitamin A deficiency and undernutrition.
Results.
One hundred twenty-five deaths occurred, of which 117 were not accidental. The risk of death in the group treated with vitamin A was less than half that in the control group (relative risk, 0.46; 95 percent confidence interval, 0.30 to 0.71). The risk was most reduced among children under 3 years of age (6 to 11 months — relative risk, 0.28; 95 percent confidence interval, 0.09 to 0.85; 12 to 35 months — relative risk, 0.46; 95 percent confidence interval, 0.26 to 0.81) and among those who were chronically undernourished, as manifested by stunting (relative risk, 0.11; 95 percent confidence interval, 0.03 to 0.36). The symptom-specific risk of mortality was significantly associated with diarrhea, convulsions, and other infection-related symptoms.
Conclusions.
The regular provision of a supplement of vitamin A to children, at a level potentially obtainable from foods, in an area where vitamin A deficiency and under-nutrition are documented public health problems contributed substantially to children's survival; mortality was reduced on average by 54 percent. (N Engl J Med 1990; 323:929–35.)
Media in This Article
Figure 1
Cumulative Deaths Monitored Weekly, According to Study Group.Table 1
Doses Missed and Minimal Amount of Vitamin A Received during 52 Weeks of Intervention.Article Activity
- Article
TWENTY to 40 million children worldwide are estimated to have at least mild vitamin A deficiency, and nearly half are said to reside in India.1 Controlled field trials in an area of endemic vitamin A deficiency in Indonesia revealed a reduction of 34 percent in mortality among infants and young children given high-dose vitamin A supplements,2 and a reduction of up to an estimated 75 percent3 after periodic mass treatment with large-dose (209 μmol [200,000 IU]) vitamin A. Reductions in mortality of 11 to 45 percent were reported after the normal marketing of vitamin A—fortified monosodium glutamate.4 The results of these studies and an earlier observational trial in Indonesia5 have been questioned because of aspects of the study designs6 and because the mortality data provided no cause-specific information and were obtained retrospectively, assuming compliance.4
Clarifying the role of vitamin A deficiency in child health and survival and defining successful, sustainable control measures have broad public health, public policy, and programmatic importance. For this reason, we conducted a randomized, placebo-controlled, masked clinical trial among 15,419 preschool-age children using a small, weekly dose of vitamin A (8.7 μmol [8333 IU]) given directly to the children by community health volunteers. We monitored morbidity and mortality weekly for one year. The dose of vitamin A was meant to simulate the amount that could be obtained from food, if food consumption was near the level recommended by international groups (approximately 1 to 1.4 μmol [300 to 400 μg] of vitamin A daily7 , 8).
Methods
The study was carried out in three drought-prone, economically and environmentally deprived panchayat unions (local-government areas) in the Trichy district of Tamil Nadu in southern India. The people of the area had been underserved by child-care programs, including the national program of administering a large-dose (209 μmol) supplement of vitamin A every six months. A survey of all children under 60 months of age in the study area revealed that only 1 percent had participated in this program.
The study was reviewed and approved by the human-subjects internal review boards of the Indian Council of Medical Research and the Aravind Eye Hospital. Informed consent was obtained from the leaders of the panchayat unions and then from the individual families at the time of the base-line survey.
Survey Personnel and Procedures
All the communities within the areas selected for study were mapped by locally recruited enumerators. A house-by-house demographic and socioeconomic survey was carried out by specially trained local workers, who also obtained from each mother a five-year history of mortality among her preschool-age children. Households with children under 60 months of age were identified and assigned a census number.
Two medical-examination teams were formed, consisting of a medical officer, nurses, and child-care and social workers. The child-care and social workers were trained to undertake ocular examinations, anthropometric measurements, and a morbidity history. The ocular examination was checked by the medical officer who conducted the medical examination and verified the morbidity history. The ocular examination was repeated by the same trained fieldworkers after six months of intervention, and all the indexes measured at base line were reassessed by the medical teams at the end of the study.
A finger-prick blood sample and a dietary history detailing the frequency of intake of locally available foods containing vitamin A9 were obtained from a randomly selected 2 percent of the children by specially trained community workers.
At the base-line medical examination, all the children with symptoms of xerophthalmia, including night blindness, were treated with a large-dose combination of vitamin A (209 μmol) and vitamin E (46 μmol), and they continued to be followed as part of the study. The data were analyzed both including and excluding them. Children with symptoms of xerophthalmia at the six-month and final ocular examinations were treated in a similar manner. All the children were given the large-dose supplement during their final medical examination at the end of the study.
The children's height (or length for those under 24 months) was measured to the nearest centimeter with a calibrated board. Weight was determined to the nearest 0.1 kg with a hanging Salter scale.
The ocular examination was performed with the classification criteria of the World Health Organization.10 A history of night blindness was obtained by interviewing the mother about the incidence in her children of malai ken, a term used in Tamil Nadu to describe the commonly recognized symptom of "evening eyes," the inability to see well in dim light. The same term was subsequently used by the community health volunteers to monitor the occurrence of night blindness on a weekly basis.
Fieldworkers were aware that they were involved in a study to determine the effect on morbidity of giving vitamins, but they were not told that the study was specifically one of vitamin A or that mortality was an outcome variable.
Randomization
Because of the varied population density in the panchayat unions, we used a cluster-sampling design. From the 15,419 children identified and examined at base line, 206 clusters were formed on the basis of the minimal and maximal workloads that could be expected from the community health volunteers. The majority of clusters consisted of 50 to 100 children 6 to 60 months of age. The clusters were arranged according to population size; after a random start, they were assigned alternately to the treated or control groups. The adequacy of randomization in achieving matching according to base-line data was checked for the following characteristics: age and sex distribution, one-month history of diarrhea and respiratory disease, anthropometric indexes of nutritional status, xerophthalmia status, five-year retrospective history of mortality of children under five, household economic and hygienic status, and serum retinol levels. Matching was satisfactory at base line for all the variables examined.
Implementation and Management
Community health volunteers were trained to dispense the supplement, collect morbidity data, and record mortality according to a standard procedure. The volunteers visited each home assigned to them every week for 52 weeks. During the visits they recorded illnesses according to symptoms and duration and checked for any deaths. They dispensed the appropriate liquid supplement directly into the mouth of the study child from a calibrated, color-coded amber bottle. Community health volunteers knew that they were responsible for dispensing from one color-coded bottle, but they were unaware of what it contained other than vitamins.
Trained supervisors were each assigned to oversee seven or eight community health volunteers. The supervisors were responsible for weekly meetings with the volunteers to verify the completeness of the morbidity-data forms for the previous week and to review their proper use. The supervisors also collected the dispensers each week and distributed refilled bottles. In addition, they checked the accuracy of the data gathered from a random 5 percent of the households weekly.
A block officer met every week with the supervisors to review the forms and procedures, discuss problems, and provide refilled bottles for delivery to the community health volunteers. The supervisors were informed weekly of the performance — in terms of rates of contact and accuracy in data recording — of the community health volunteers for whom they were responsible. Evidence of problems was sought and the difficulties were remedied within a two-week period. Unannounced spot checks on households were conducted by block officers and headquarters staff.
Data were verified and then recorded on diskettes with use of portable computers in the field offices. The diskettes were sent weekly to the headquarters office, where they were again checked for completeness and accuracy. The procedures for personnel and data management allowed close surveillance and a two-week feedback to the field staff regarding their performance, thus giving them time to correct any possible errors.
Supplements
Liquid supplements (kindly provided by Hoffmann—LaRoche, Basel, Switzerland) were provided in color-coded aluminum cans containing approximately 1 liter each. The appearance and taste of the solutions were identical. The solution containing vitamin A was prepared to contain approximately the following: 8.7 μmol (8333 IU or 2500 μg) of vitamin A palmitate and 46 μmol (20 mg) of vitamin E per milliliter dissolved in peanut oil. The placebo solution contained approximately 46 μmol (20 mg) of vitamin E per milliliter dissolved in peanut oil.
The stability of the solutions was checked by Hoffmann—LaRoche initially and after 1, 3, 6, and 12 months of storage, at room temperature, 35°C, and 45°C, in both the dispenser bottles and the aluminum flasks. In the flasks there was no loss of vitamin A and about a 10 percent loss of vitamin E, and in the bottles there was a loss of less than 5 percent of vitamin A after one year or less at room temperature and at 35°C. Stability was also checked by randomly withdrawing dispensers from the study areas halfway through and at the end of the study. The field-laboratory analyses, done approximately 18 to 24 months after the supply had been received in India and used under the conditions of storage prevailing in the field, revealed a vitamin A loss of approximately 25 percent.
Data Monitoring
Six months after the weekly distribution began, a data-monitoring committee reviewed the data, summarized according to dose color code only. No one associated with the study was aware of the color code, which was held by Hoffmann—LaRoche until the study ended. Although differences were evident in the mortality trends of the study groups after six months, they could not be associated unambiguously with the incidence, severity, or duration of morbidity. The committee concluded that the study should continue.
Statistical Analysis
Randomization according to cluster rather than according to child introduced a moderate increase (about 30 percent) in the variance of the estimators of the relative risk of death in the treated group as compared with the control group. Relative risks, significance, and confidence intervals were therefore calculated according to the cluster design.11 The risk of death among the controls was used as the reference value for relative risk of death: a relative risk of 0.5 means that the risk in the treated group was half that among the controls, or conversely, that the risk among the controls was twice that in the treated group. All ages were adjusted to reflect age at the start of the intervention, which began on the same date for all the children.
nutritional status was assessed with use of the CASP anthropometric software package (version 3.0) provided by the U.S. Centers for Disease Control. Values more than 2 SD below the reference value were considered abnormal.
Results
Mortality data and associated morbidity are reported here. An analysis of morbidity in the 15,419 children is currently under way.
Contact with the Children
During each of the 52 weeks of the study, at least 88 percent of the children were contacted. There was no difference in rates of contact between the treated and control groups. The reasons for lack of contact (of which some children had more than one) included moving from the study area (10 percent), temporary absence (13 percent), refusal to participate (28 percent), sickness (29 percent), and other reasons (30 percent). Table 1Table 1
Doses Missed and Minimal Amount of Vitamin A Received during 52 Weeks of Intervention. summarizes the study contact and compliance in terms of the number of weeks the dose was missed. Nearly 42 percent of the children received all the doses. For those in the treated group, this was equivalent to more than 453 μmol (433,000 IU) of vitamin A, or approximately the amount available in the commonly used large-dose supplement (209 μmol every six months). More than 90 percent of the children received at least 322 μmol (307,000 IU), which is equivalent to more than 70 percent of what they would have received in a large-dose supplement.Base-Line Characteristics
Sex, age, xerophthalmia status, serum retinol level, and nutritional status at base line are shown in Table 2Table 2
Base-Line Characteristics of the Study Population.. There were no substantial differences in these indexes between the control and treated groups. Although the study was meant to include only children from 6 to 60 months of age, birth records were unavailable, and our recall records include a small number of younger (1.8 percent) and older (5.4 percent) children.The base-line prevalence of xerophthalmia was 11 percent. The risk of xerophthalmia did not differ according to sex, except for a slight predominance among boys after three years of age. Thirty-seven percent of the serum retinol values from the randomly sampled subgroup (n = 280) were ≤0.70 μmol per liter, and 21 percent were ≤0.35 μmol per liter. The prevalence of vitamin A deficiency in each of the clinical and biochemical categories thus exceeded the World Health Organization's criteria for a public health problem.10 Seven cases of active corneal involvement (category X2, X3A, or X3B) were seen (four in the control group and three in the treated group). Night blindness accounted for about one third and Bitôt's spots for about two thirds of the milder cases of xerophthalmia.
Seventy-two percent of the children were classified by anthropometry as undernourished (defined as more than 2 SD below the reference mean). Approximately one third of the children were stunted, 18 percent stunted and wasted, and 23 percent wasted (Table 2). Stunting thus affected a somewhat larger proportion of the children than wasting, indicating that prolonged malnutrition was more common than acute undernutrition among the study children.
The five-year history of mortality among children under five years of age taken at base line was not significantly different between families of control and families of treated children (data not shown).
Mortality Outcome
There were 125 deaths in the study population during the 52 weeks of surveillance, for an overall mortality rate of 8.1 per 1000. Eight of these deaths, however, involved accidents unrelated to symptoms that could have been associated with the intake of vitamin A: animal bite (two deaths), drowning (three), poisoning (one), and falling (two). Five of the accidental deaths were in the treated group and three in the control group.
Figure 1Figure 1
Cumulative Deaths Monitored Weekly, According to Study Group. shows the cumulative deaths according to study group. Regardless of treatment, girls were at somewhat higher risk of death than boys, but not significantly so (relative risk, 1.5 in the control group and 1.2 in the treated group). Vitamin A significantly reduced the risk of death for both sexes, the effect being somewhat larger for girls (relative risk, 0.41 for girls [P<0.01] and 0.52 for boys [P<0.05]).Table 3Table 3
Mortality, According to Age and Study Group. shows the mortality according to age and study group for the 117 nonaccidental deaths. The risk of death in the group receiving vitamin A was 46 percent of that in the control group. The relative risk was reduced most for infants (relative risk, 0.28; 95 percent confidence interval, 0.09 to 0.85) and those 12 to 35 months of age (relative risk, 0.46; 95 percent confidence interval, 0.26 to 0.81); it was less than 1.0 in all age groups. Excluding the children who had received the high-dose supplement at any time or who received it only at base line did not substantially change the age-specific relative risks shown in Table 3. In addition, these relative risks were not significantly changed by excluding those who did not receive the study supplements for more than seven consecutive weeks (n = 1863) or those who did not receive the supplements for more than four weeks on four occasions (n = 11). These exclusions were designed to minimize any possible confounding due to a differential participation effect or missing the supplements for a prolonged period.Among the nonaccidental deaths, 18 occurred among children with xerophthalmia at base line. All 18 occurred in children over 12 months of age (12 children in the control group and 6 in the treated group). The death rate among children with xerophthalmia was 10.6 per 1000, as compared with 7.2 per 1000 among the children without xerophthalmia.
Table 4Table 4
Symptom- and Disease-Specific Mortality, According to Treatment Group. shows the symptom- and disease-specific relative risk of death in the treated and control groups. According to the "verbal autopsy," there were too few deaths specifically associated with the symptoms of respiratory disease and malnutrition to provide a reliable relative risk. Excluding these two categories of symptoms, the relative risk was consistently lower for the treated group — and significantly so, except for deaths associated with measles. More than 40 percent of the deaths were associated with diarrhea, 16 percent with measles, and the remainder with symptoms suggesting other infections.Table 5Table 5
Mortality, According to nutritional Status.* shows the mortality according to treatment group and base-line nutritional status. Data on nutritional status were missing for 469 children (3 percent), among whom 7 died (6 in the control group and 1 in the treated group). Among the children not treated with vitamin A (the control group), the death rate of those who were both stunted and wasted was 1.5 to 2 times higher than the death rate of those who were either stunted or wasted, and it was 2.7 times higher than the rate of normal children. Thus, the risk of death was increased by acute undernutrition superimposed on chronic malnutrition. But the effect of treatment with vitamin A was pronounced (relative risk, 0.11; P = 0.01; 95 percent confidence interval, 0.03 to 0.36) among stunted children, whereas it was not significant among wasted, stunted and wasted, or normal children.A hierarchical log-linear model was used to assess the multivariate relation among death, treatment, age, sex, and nutritional status. The significant association between treatment and death persisted when adjusted simultaneously for age, sex, and nutritional status.
Discussion
The results of this community-based, masked controlled field trial clearly indicate that in an area where clinical vitamin A deficiency and chronic undernutrition are common, ensuring a constant consumption of vitamin A at least equivalent to the recommended dietary allowance enhanced children's survival. In Indonesia, somewhat similar effects among preschool—age children (a 45 percent reduction in mortality) were reported with vitamin A—fortified monosodium glutamate when it was a consistent part of the food supply.4
For the one-year follow-up period the overall mortality rate among children 6 to 60 months of age was 8.1 per 1000 in our study, comparable to the 7.8 per 1000 for the 12- to 71-month age group reported by the Aceh, Indonesia, study.2 It was higher, however, than the 5 per 1000 reported from an area near Hyderabad, India, where a placebo-controlled, blinded trial with a high-dose supplement has also been performed.12 These rates are considerably below the 20 per 1000 reported as the national average for India.12 We monitored infant mortality in the study area for a one-year period in 1988 and 1989 and obtained a rate of 64 per 1000, a figure somewhat lower than the 83 per 1000 reported for Tamil Nadu in 198213 and the 98 per 1000 for India generally.14 The mortality rate among infants less than 6 months old was 42 per 1000 live births, and among those 6 to 11 months old it was 22 per 1000. We were unable to find any reliable information on mortality rates among one-to-five-year-olds in Tamil Nadu. The lower mortality figures we report undoubtedly reflect in part the well-recognized effect of the frequent contact of households with trained fieldworkers.12 , 15 Nonetheless, because the contact was comparable in our two study groups, the efficacy of vitamin A supplementation at the level of the recommended dietary allowance in reducing mortality by 54 percent remains evident; mortality rates were 10.5 per 1000 in the control group as compared with 4.8 per 1000 in the treated group.
We found an insignificant sex-related difference in the risk of death without regard to treatment. Treatment with vitamin A reduced the risk of mortality in both sexes, but the reduction was somewhat greater among girls. This finding contrasts with that reported from Indonesia, in which a significant treatment effect of large-dose supplementation was found only in boys, among whom the prevalence of xerophthalmia was also higher.2 In our study, the prevalence of xerophthalmia at base line was not significantly different between the sexes until after three years of age, whereas the effect on mortality of treatment with vitamin A was pronounced among the younger groups.
The efficacy of our low-dose supplementation was considerably higher than the 34 percent reduction in mortality reported after high-dose supplementation in Indonesia as determined by intention-to-treat analysis,2 but lower than the estimated 75 percent reduction reported with an analysis based on actual receipt of the capsules.3 The estimate based on receipt of the capsules was derived from a total of only 18 deaths over a four-month follow-up period. As the authors noted, its validity awaits verification by a study that ensures consistent, periodic verification of compliance in taking the large-dose supplement, which has not been a feature of most large-scale programs to date.16
Vitamin A was most efficacious in children under three years of age, most prominently in infants. This finding contrasts with reports from Indonesia. In the Aceh study the effect of treatment was most marked among those 60 to 71 months old,2 and in the study involving vitamin A—fortified monosodium glutamate, mortality was reduced by 11 percent among infants and 45 percent among preschoolers.4 In the monosodium glutamate study the infants probably received a considerable portion of their food as breast milk, and the effect of the program would therefore be expected to be less. The reasons for the discrepancy between our results and those of the Aceh study are less clear but may be related to the relative level of underlying malnutrition in the two study populations. Our base-line prevalence of xerophthalmia was 11 percent, as compared with about 1 to 2 percent in Indonesia, and only 25 percent of the Indian children had normal anthropometric features, whereas at least 40 to 69 percent of the Indonesian children were classified within 10 percent of the median standards of the U.S. National Center for Health Statistics.
In accordance with many reports from developing countries where vitamin A deficiency is endemic, diarrhea was associated with the highest number of deaths, followed by measles and symptoms associated with other infections — convulsions, jaundice, and encephalitis, for example. The protective effect of vitamin A was significant for all these conditions except measles. This finding contrasts with hospital-based case–control reports from Africa, in which the protective effect of very large doses of vitamin A was exceptionally high in measles.17 , 18 Previous studies suggest that measles is a less severe disease in India than in Africa, and that factors other than vitamin A — the severity of concurrent malnutrition, for example — may be a more critical determinant of measles-associated morbidity and mortality.19 , 20 It may also be that a large dose of vitamin A is required to prevent a fatal outcome in severe measles complicated by vitamin A deficiency.
Prolonged undernutrition, as evidenced by stunting, characterized nearly one third of the children in our study at base line, and a continuous supply of vitamin A reduced the risk of dying to one-ninth that of the controls. The protective effect of vitamin A was unremarkable in children with wasting, an indicator of acute malnutrition, and in those with normal anthropometric features. Stunting reflects — in addition to an inadequate food supply — many characteristics of social deprivation that are frequently found in poor households. Our data suggest that these persistent ecological and physiologic insults undermine the ability of a child who is deficient in vitamin A to ward off a fatal outcome when confronted by an infection. The programmatic implication of this is that maximal reductions in mortality can be expected from vitamin A prophylaxis targeted to children who are chronically undernourished and to those with superimposed acute malnutrition.
Children with xerophthalmia are reported to be at 4 to 12 times the risk of death of neighboring children with normal eyes, and the risk increases with the increasing severity of symptoms.5 The mortality rate among children with xerophthalmia in our study was about 50 percent higher than among children without the condition (7.2 vs. 10.6 per 1000). When we adjusted for those who received a large dose of vitamin A because of xerophthalmia, the treatment effect of the continued small dose persisted — that is, half as many died among those who continued to receive the weekly supplement as among those who did not.
Sommer et al.2 noted that daily consumption of the recommended dietary allowance was the ideal approach to vitamin A prophylaxis, but considered it to be impractical from a programmatic point of view and chose distribution of the large-dose capsule every six months instead. Sommer et al. subsequently commented that the single most important limitation to achieving the maximal effect with large-dose capsules was inadequate contact and verification of compliance3; the large-dose approach requires careful monitoring of distribution channels to avoid possible overdosing. In contrast, our approach involving frequent low doses showed that when the supplement is provided at a safe dosage level in an easily dispensed form, community workers can be effective in attaining high rates of contact and verification if there is also an appropriate managerial and supervisory system. Importantly, the efficacy of supplementation at the level of the recommended dietary allowance suggests that a similar effect could be achieved by an equivalent supply of vitamin A from foodstuffs, an approach that would potentially address other nutritional deficiencies as well.
Supported by a grant from the Ford Foundation, New Delhi, India.
Source Information
From the Aravind Children's Hospital and Aravind Eye Hospital, Madurai, India (L.R., R.D.T., K.R., R.R, G.B.); the Office of International Programs (B.A.U.) and the Biometry and Epidemiology Program (R.C.M.), National Eye Institute, Bethesda, Md. Address reprint requests to Dr. Underwood at the National Eye Institute, Bldg. 31, Rm. 6A-17, 9000 Rockville Pike, Bethesda, MD 20892.
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