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The Journal of Nutrition Vol. 128 No. 8 August 1998,
pp. 1320-1327
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* School of Public Health, Free University of Brussels (ULB), Brussels, Belgium; Centre Scientifique et Médical de l'Université Libre de Bruxelles pour ses Activités de Coopération (CEMUBAC), Free University of Brussels (ULB), Brussels, Belgium; ** Queen Fabiola Children's University Hospital, Free University of Brussels (ULB), Brussels, Belgium; St-Peter's University Hospital, Free University of Brussels (ULB), Brussels, Belgium; and Centre de Recherche en Sciences Naturelles (C.R.S.N.), Zaire
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ABSTRACT |
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Abstract
Introduction
Methods
Results
References
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A randomized controlled trial was conducted in eastern Zaire to assess the effects of high dose vitamin A supplementation and regular deparasitation on the growth of 358 moderately malnourished preschool children, discharged from the hospital. The treatment groups received either vitamin A (60 mg of oily solution of retinyl palmitate, 30 mg if aged <12 mo) every 6 mo or mebendazole (500 mg) every 3 mo; the control group received no supplementation. Anthropometric data were gathered at baseline and after 6 and 12 mo of follow-up. Serum retinol concentrations were measured at baseline and after 3 mo. The three groups did not differ in sociodemographic indicators, age and sex composition, nutritional status and serum retinol concentrations at baseline. In children who were vitamin A deficient at baseline, adjusted mean weight and mid-upper arm circumference (MUAC) increments were higher in the vitamin A-supplemented group than in the control group [annual increment in weight and MUAC in vitamin A vs. control group: 2.088 vs. 1.179 kg (P = 0.029) and 2.24 vs. 0.95 cm (P = 0.012), respectively], whereas growth increment did not differ between the dewormed group and the control group. In children who were not vitiamin A deficient at baseline, growth increment did not differ between the vitamin A-supplemented and control groups, whereas weight gain was lower in the dewormed group than in the control group. Vitamin A-supplemented boys gained more weight and height than control boys, whereas vitamin A-supplemented girls gained less height than control girls. Dewormed boys and girls gained less weight than control boys and girls. Programs to improve vitamin A status by high dose vitamin A supplementation may improve growth of preschool children who are vitamin A deficient, whereas deworming does not.
KEY WORDS: vitamin A deficiency · vitamin A supplementation · growth · preschool children · malnutrition · Zaire
Xerophthalmia affects an estimated 14 million children annually; that number represents only about one tenth of those who are at risk of compromised health from subclinical deficiency. In laboratory animals, the effects of vitamin A deficiency on growth have clearly and consistently been observed; studies have shown that small amounts of vitamin A halt weight loss and re-establish normal or even catch-up ponderal growth in experimentally vitamin A-deficient rats (Anzano et al. 1979 Several observational studies have reported an association between low vitamin A intake and impaired growth (Graham et al. 1981 Parasitic infections, especially infection with Ascaris lumbricoides, is common in Zaire and may interfere with vitamin A absorption (Mahalabanis et al. 1979 In the South-Kivu Province of Zaire, protein-energy malnutrition (PEM)4 is endemic. The mortality rate of preschool children is high in outpatients (45/1000 per year) (Delacollette et al. 1989 Study design and sample.
A randomized controlled trial was conducted between April 1991 and May 1992 in Eastern Zaire. Children (n = 358) aged 0-72 mo, discharged consecutively from the Lwiro pediatric hospital, were included in the trial and followed for 1 y. The study took place in the health district of Katana, province of South Kivu. This mountainous province is located along the borders with Burundi and Rwanda. The highlands have a mean altitude of ~1500 m. The climate is temperate, and the year is divided into two rainy seasons (March to June and October to January). The population settled in the region, most of whom are farmers, live in a poor rural environment, characterized by subsistence economy, rapid demographic expansion and rudimentary sanitation. The food supply is constantly poor in energy and periodically low in protein, depending on the season. From October to December, the period of food shortage, mean protein intakes fall to 60-70% of reference needs defined by the 1973 WHO expert committee (FAO/WHO 1973). The diet is also very poor in lipids (Vis et al. 1969 Randomization and dosing.
As soon as the children were discharged from the hospital, they were randomly assigned to one of three groups. One group received an oral dose of 60 mg of vitamin A (oily solution of retinyl palmitate; 30 mg for children <12 mo) at the start of the trial (day of discharge) and after 6 mo follow-up. The second group received an oral dose of 500 mg of mebendazole at the start of the trial and then every 3 mo until the end of the 1-y follow-up period. The third group received no supplementation and served as the control group. The gelatinous capsules of vitamin A contained 30 mg of vitamin A. Supplements were stored at room temperature. To avoid degradation of vitamin A, the stock was renewed every 3 mo. All supplements were administered by two trained field workers.
Data collection and management.
Children entered the study just after discharge from the hospital. They were then visited at home every 2 wk for 3 mo, then every 3 mo until 12 mo. They were then discharged from the trial. In all, children were seen 10 times during the 1-y follow-up.
Data quality control, processing and analysis.
Several methods were used to both improve and check on data quality. These included weekly visits to each field worker by a supervisor, who attended interviews, conducted full re-interviews on a sample of recently completed interview forms and recollected anthropometric and clinical indicators. Before the start of the trial, field workers were trained by the external supervisor to minimize interindividual differences. Both field workers and supervisors received regular training courses. Data were entered locally into microcomputers by a single clerk. Ten percent of the data entered by the clerk was reviewed by the supervisor. In addition, data were listed periodically for visual checks. About 26 wk and again 52 wk after the intervention started, an external data-monitoring committee reviewed the data.
Statistical analysis and interpretation of data.
Statistical analysis was performed using the SPSS 4.0 release for Unix (Norusis 1990 Demographic, socioeconomic and nutritional characteristics did not differ among the three groups (Table 1). The sample under study was characterized by a high prevalence of stunting (low length/height for age) and underweight (low weight for age) but a relatively low prevalence of wasting (low weight for height). This indicated that chronic rather than acute growth deficit predominated. No child presented edema at enrollment.
Vitamin A supplementation selectively improved child growth in this sample of children recovering from PEM that were moderately to severely vitamin A deficient. These findings cannot be attributed to factors such as inadequate treatment exposure, measurement biases or other confounding factors. Compliance was extremely high (>97%) and similar for the three groups. The losses to follow-up due to migrations or deaths, for example, were similar in the three groups.
INTRODUCTION
Abstract
Introduction
Methods
Results
References
, McCollum and Davis 1915, Orr and Richards 1934). The putative role of vitamin A in the growth of children has been largely extrapolated from animal research. Indeed, the effect of vitamin A deficiency on growth is more difficult to demonstrate because of the different environments in which children live and the presence of other growth-limiting factors.
, Madhavan et al. 1967). Randomized, controlled vitamin A supplementation trials have shown differing results, ranging from improvement in ponderal (Kirkwood et al. 1996, West et al. 1988) and linear growth (Muhilial et al. 1988) in certain groups of children to no apparent effects in others (Lie et al. 1993, Rahamathullah et al. 1991, Ramakrishnan et al. 1995). Vitamin A supplementation could promote growth by stimulating growth factors or by decreasing either the incidence or severity of illness (Semba 1994). Most of these trials were conducted in populations with evidence of clinical signs of deficiency. Few data are available among populations with biochemical evidence of vitamin A depletion, but without associated evidence of clinical manifestations of deficiency.
, Mansour et al. 1979, Sivakumar and Reddy 1975). In some studies, deworming resulted in improving both vitamin A absorption (Mahalabanis et al. 1979, Sivakumar and Reddy 1975) and serum retinol concentrations (Jalal et al. 1990). However, a recent study in Indonesia found that treatment with mebendazole failed to improve vitamin A stores (Tanumihardjo et al. 1996).
) and in hospitalized children, most of whom are suffering from severe PEM (Dramaix et al. 1996). Vitamin A deficiency co-exists in this region with PEM and is characterized by a high prevalence of severe biochemical depletion and a low prevalence of clinical signs (Donnen et al. 1996). Deworming and vitamin A supplementation may offer efficient strategies for improving vitamin A status of deficient populations. The lack of consistency in past research and the scarcity of data among populations with biochemical evidence of vitamin A depletion, but without associated evidence of clinical manifestations of deficiency, led us to conduct a randomized, controlled trial of the effects of a 6-mo high dose vitamin A supplementation and a 3-mo deworming program on the growth of preschool children in the South Kivu Province of Zaire.
SUBJECTS AND METHODS
Abstract
Introduction
Methods
Results
References
). All forms of PEM are frequently encountered and prevail essentially among young children but also among lactating women (Hennart 1983).
). No vitamin A supplementation program existed within the study area. The study protocol was approved by the Ethical Committee of the CRSN (Centre de Recherche en Sciences Naturelles) and parental or legal guardian consent was obtained for all selected children.
20°C. The samples were transported to Brussels in cool boxes and stored at 20°C until analyzed. Retinol was determined by HPLC, a procedure adapted from Vanderpas and Vertongen (1985). Albumin, RBP and CRP were measured using a nephelometric technique (Conners et al. 1984).
).
2 SD of the reference median. For albumin and RBP, the lower limits of the laboratory norms, 35 g/L and 30 mg/L, respectively, were taken as cut-offs. For CRP, the cut-off point chosen was 20 mg/L. Serum retinol concentrations were classified according to WHO criteria (WHO 1982). Retinol values <0.35 µmol/L (10 µg/dL), between 0.35 and 0.70 µmol/L (10 and 20 µg/dL) and 
0.70 µmol/L (20 µg/dL) were classified as deficient, low and normal, respectively.
). The tests used to compare the admission data of the three groups were the chi-square for the categorical variables and one-way ANOVA for the quantitative variables. Mean growth increments (changes between admission and 6 mo, 6 mo and 12 mo and between admission and 12 mo) were used as outcome measures. To analyze these outcomes, multiple linear regression was performed (Chatterjee and Price 1977), including treatment group, age, nutritional status (albumin concentration) at baseline, vitamin A status (retinol concentration) at baseline and gender. In these models, age, baseline serum albumin and serum retinol were introduced as dichotomous variables with cut-offs at 24 mo, 35 g/L and 0.35 µmol/L respectively. Treatment group was introduced in the form of two indicators that contrasted each treated group with the control group. Interactions between treatment group and the other variables were introduced in the model and tested (F-test). When these interactions were nonsignificant, adjusted mean growth increments and their 95% confidence intervals were derived from the final regression model. When interactions were significant, adjusted mean growth increments and their 95% confidence intervals were derived in each stratum of the variable showing an interaction. For each growth increment, results in strata were presented when there was a significant interaction between treatment and the stratifying variable for at least one follow-up period.
RESULTS
Abstract
Introduction
Methods
Results
References
View this table:
Table 1.
Baseline demographic, socioeconomic and nutritional characteristics of moderately malnourished preschool children supplemented with vitamin A or mebendazole by randomized supplement group1,2
), total epg revealed that 80% of the children had light infections (1-4999 epg) and 20% had moderate infections (5000-49,999 epg). The prevalence of co-infection with Ascariasis and Trichuris ranged from 2.8 to 4.8%. Hookworm was not found in any of the children at baseline. The proportion of children who died during the 1-y follow-up period was 5.4% for the vitamin A group, 7.9% for the mebendazole group and 9.0% for the control group, respectively. These proportions did not differ significantly.
View this table:
Table 2.
Adjusted mean weight increment for the moderately malnourished preschool children
supplemented with vitamin A or mebendazole1,2
View this table:
Table 3.
Adjusted mean height increment for the moderately malnourished preschool children
supplemented with vitamin A or mebendazole1,2
View this table:
Table 4.
Adjusted mean mid-upper arm circumference (MUAC) increment for the moderately malnourished
preschool children supplemented with vitamin A or mebendazole1,2
DISCUSSION
) in which wasted, xerophthalmic children treated with high dose of vitamin A gained significantly more weight and height than vitamin A-supplemented children who were wasted but not xerophthalmic. This growth increment was noticed only within the initial 4 mo of treatment with vitamin A. In a randomized controlled field trial in south India (Ramakrishnan et al. 1995) in a population with high prevalence of xerophtalmia and low prevalence of deficient retinol concentrations, high dose vitamin A supplementation every 4 mo for 1 y had no significant effect on growth increments in preschool children. Growth changes were not significantly different for different levels of baseline serum retinol. However children with serum retinol <0.35 µmol/L were excluded. Results of that study are thus consistent with the present trial for children with mild-to-moderate vitamin A deficiency. Results of another trial conducted in India among undernourished children with a high prevalence of both xerophtalmia and deficient retinol concentrations (Rahamathullah et al. 1991) also showed no discernible effects of weekly low dose vitamin A supplement on growth. However, growth increments were not studied for different levels of retinol concentrations, although 21% of children had baseline serum retinol <0.35 µmol/L. In Indonesia, community trials showed a significantly increased gain in weight and MUAC among older male children (West et al. 1988) and an increased linear growth among children at every age (Muhilial et al. 1988) in the groups receiving vitamin A supplementation. These populations were characterized by a high prevalence of signs of both clinical and biochemical vitamin A deficiency. In Ghana, where biochemical signs of vitamin A deficiency were present, vitamin A supplementation significantly improved weight gain among older children (Kirkwood et al. 1996). In all of these studies, children with severe xerophtalmia were excluded from the trials after being treated with a high dose of vitamin A even if a greater response to vitamin A replenishment would be expected among them. Furthermore, the effect of vitamin A supplementation was not compared among children with different serum retinol concentrations. The effect of vitamin A supplementation on growth among children with severe vitamin A deficiency (serum retinol <0.35 µmol/L or xerophthalmia) suggests that in these children, vitamin A deficiency was more likely to have been growth limiting. The effect of vitamin A supplementation in children who were less deficient appears variable, depending on environmental factors.
) in which boys 4 y of age who were supplemented with vitamin A gained significantly more weight than controls after 1 y of follow-up. However, no significant differences in linear growth were observed at any age. In girls, vitamin A supplementation had no positive effect on linear and ponderal growth. The efficacy of vitamin A supplementation on linear growth in our study could be explained by the higher prevalence of stunting among the children at the start of the trial compared with the Aceh study. In south India (Ramakrishnan et al. 1995), annual growth increments after vitamin A supplementation were not significantly different in male and female children. Sex-specific results were not described in other trials (Kirkwood et al. 1996, Muhilial et al. 1988, Rahmathullah et al. 1991). Reasons that explain gender differences in growth increment after vitamin A dosing remain unclear. It may reflect a phenotypic variation as observed in animals. Male animals respond more rapidly and completely to vitamin A repletion (Jagannathan and Patwardhan 1960, Lamb et al. 1974). It could also be explained in part by environmental factors such as sex-related differences in dietary intake of vitamin A (Brown et al. 1982). However, at the start of our study, vitamin A status, as assessed by serum retinol concentration, was not significantly different in male and female children.
, Kloetzel et al. 1982). We administrated 500 mg of mebendazole every 3 mo. At baseline, the prevalence of Ascaris infection was low (9.6-14.2%) because children had just been discharged from hospital, but it increased similarly in the three groups during the follow-up. In the infected children, median epg at 12 mo follow-up was not significantly different in the dewormed group than in the two other groups, but the proportion of children with light infections was significantly higher in the mebendazole-treated group (Table 5). Thus, even with repeated treatment, children were reinfected, but the intensity of infection was lower than in the two other groups. Potential benefits of deworming on growth were not expected during the first months but were anticipated later when reinfestation was more important. The adverse effect of deworming on growth is unclear because benzimidazole carbamates cause gastrointestinal side effects only infrequently. The instance of disease during the first 3 mo follow-up, especially diarrhea, was not more frequent in the deparasitized group. In a recent study in Indonesia (Tanumihardjo et al. 1996), treatment of Ascaris-infected preschool children with albendazole failed to improve their vitamin A stores, whereas vitamin A supplementation did. However, change in serum retinol concentrations is not as reliable an indicator of changes in vitamin A status as the modified relative dose response test.
View this table:
Table 5.
Prevalence and intensity of Ascaris in the moderately malnourished preschool children at baseline and at 12 mo
), children discharged from hospital after treatment for severe PEM showed no significant acceleration in growth for height or weight during the year after discharge. The proportion of children who died after one year was 9.4%, which is similar to the 9% of children who died in the control group of this trial. Thus vitamin A supplementation appeared to reduce mortality of all of the children and to improve the growth of those who were severely vitamin A deficient at baseline.
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FOOTNOTES |
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Manuscript received 13 May 1997. Initial reviews completed 4 July 1997. Revision accepted 6 April 1998.
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LITERATURE CITED |
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Abstract
Introduction
Methods
Results
References
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-carotene in the rat.
Ind. J. Med. Res.
1960;
48:775-784 
a follow-up study.
J. Trop. Pediatr.
1982;
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