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,
2
*
Department of Public Health, University of Adelaide, South Australia, Adelaide 5005, Australia;
School Health Program, Ministry of Health, Dar es Salaam, Tanzania;
**
Aboriginal Home Care Program, Mile End, South Australia, 5031 Australia and
Tanzania Partnership for Child Development, Ocean Road Hospital, Dar es Salaam, Tanzania
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • anemia • rural school children • vitamin A • iron • randomized controlled trial • Tanzania
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). World Health Organization (WHO) data suggest that up to
46% of school-aged children in developing countries have IDA
(Viteri 1998
).
In Tanzania, anemia is a widespread and important problem among school
children. Surveys conducted by the Tanzania Partnership for Child
Development, known locally as Ushirikiano wa Kumwendeleza Mtoto
Tanzania (UKUMTA), revealed that 
80% of school children have
hemoglobin concentrations of less than the 120-g/L cutoff point
recommended by the WHO (UKUMTA 1996). In some parts of
the country, a prevalence rate of 100% has been reported
(Berger and Salehe 1986
, Kavishe 1991
).
Anemia occurs when the tissue stores of iron are depleted, leading to a
lowered level of serum iron, a decrease in transferrin saturation and
an increase in erythrocyte protoporphyrin. When tissue stores are
seriously depleted, hemoglobin levels decline. Thus, low levels of
hemoglobin may be taken to indicate IDA (Seshadri and Gopaldas 1989
, Viteri 1998
)
In many developing countries, iron deficiency arises from inadequate
food intake, impaired absorption and/or utilization, excessive losses
or a combination of these factors (Viteri 1998
). In
developing African countries such as Tanzania, staple diets are plant
based and hence contain high levels of phytic acid and dietary fibers,
which can inhibit the absorption of iron (Gibson 1994
).
Both the content and bioavailability of iron in Tanzania, especially in
rural areas, are likely to be low (Tatala et al. 1998
)
Growth retardation is an important public health problem among children
living in poverty in developing countries (UNICEF 1995
).
The extent to which catch-up growth in later childhood reduces
deficits incurred in early childhood is not well documented. However,
the biological potential for catch-up growth has well been
illustrated in studies that evaluated the responses to clinical
intervention with supplementary feeding, treatment of illness or
hormone therapy (Golden 1994
). Tanner (1981)
advanced the general hypothesis that when undernourished
children are exposed to a better environment and good nutrition, the
likelihood of catch up is greater, with the degree of recovery
depending on the severity of growth retardation and the timing of
exposure. Martorell et al. (1994)
suggested that catch
up may depend on whether undernutrition is associated with delayed
maturation, which in turn could allow for a prolonged adolescent growth
spurt with greater time for recovery before skeletal growth is
complete.
Recently, it was suggested that there may be a synergistic relationship
between vitamin A and iron. Garcia-Casal et al. (1998)
,
Garcia-Casal and Layrisse (1998)
and Layrisse et al. (1997)
showed in isotopic studies that relatively low doses of vitamin A or ß-carotene can double the absorption of endogenous nonheme iron from cereal (staple) meals in anemic adults in Venezuela. More interactions between vitamin A and other essential micronutrients, which are largely deficient in diets in developing countries, have been reported in several studies. For example, Christian and West (1998)
showed that zinc in retinol binding protein (RBP)
increases lymphatic absorption of retinol and its intercellular and
intracellular transport, whereas vitamin A affects the synthesis of a
zinc-dependent binding protein and therefore the absorption and
lymphatic transport of zinc. The interaction of these two essential
nutrients when ingested by persons who are deficient in both was shown
by Udomkesmalee et al. (1992)
. They observed the
synergistic activities of these two nutrients on eye parameters and
RBP.
These findings suggest that vitamin A supplementation may have a
crucial role in the control of IDA, which is highly prevalent in many
developing countries. However, supplementation has most often been
viewed as a short-term measure to combat micronutrient
deficiencies, because there is little evidence from field trials in
developing countries regarding its efficacy (Darnton-Hill 1998
). In the current study, we investigated the impact of
dietary supplements administered with local foods on anemia and
anthropometric indices in anemic children in Tanzania, where anemia and
growth retardation are public health problems.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The study was conducted in three primary schools in the Bagamoyo
District in Tanzania. Bagamoyo is a rural district in the coastal
region 120 km from Dar es Salaam, the capital city of Tanzania. The
people in these communities of low socioeconomic status depend on
subsistence farming as the main source of income. The diets are
predominantly high in unrefined staple foods with low levels of animal
proteins. Corn is the main staple and is associated with high levels of
tanins and phytates, which inhibit the absorption of iron from staple
foods. Although vegetables are consumed on a relatively regular basis,
fruits are eaten mainly when in season. Vegetables with the potential
to provide vitamin A, such as carrots, are expensive and scarce.
The subjects were selected according to the following criteria:
1) children of either sex aged 9–12 y (only
nonmenstruating girls were invited to participate in the study),
2) children who had attended school for 
2 y,
3) children who were not ingesting any supplements and
4) children of parents or guardians from whom informed
consent (written or verbal) to participate in the study was received.
All of the children were of rural families and had a similar low
socioeconomic status. Children with obvious chronic illnesses, such as
chronic otitis media, or physical impairments, such as limb
deformities, were excluded before randomization because these would
impair performances on tests of cognitive, motor function and
educational achievement, which were also administered as part of the
study. The subjects were dewormed for helminthiasis 2 wk before the
baseline measurements were taken.
After all of the selection criteria were met, 208 children were
selected for the initial hemoglobin screening. Of these children, 197
were willing to participate in the study. Fingerprick blood samples
were screened for hemoglobin using a portable battery-operated
hemoglobinometer (Hemocue, Sheffield, U.K.) that was calibrated daily
using reference blood samples before and after the survey. Selection of
the final study sample was based on a hemoglobin concentration of <120
g/L (WHO 1968
).
One hundred thirty-eight children (70%) had hemoglobin concentrations of <120 g/L and so were regarded as anemic. Two children were found to have severe anemia (hemoglobin concentration <80 g/L); these children were excluded from the study, and their parents were notified and referred to the local health facility for further investigation. The final study population consisted of 136 children who were enrolled for the study. At the end of the study, data from 135 children were available for analysis; 1 child was lost to follow-up measurements because her parents had moved to a location far from the study area.
Study design.
A randomized, double-blind, placebo-controlled trial was used to determine the effect of the provision of vitamin A and iron supplements on anemia and the nutritional status of anemic school children. The supplements were packed in tablet form by the Department of Pharmacy, Women and Children’s Hospital, in Adelaide. The study was designed in such a manner that neither the study subjects, the teachers, the research team members nor the investigator had knowledge of the group assignments.
One hundred thirty-six children were randomly assigned to one of four treatment groups within each of six sex/school strata to help ensure sex and geographical balance of treatment allocations. The RAND function of Excel (Microsoft, Redmond WA) was used to implement randomization. The four treatments were administered 3 d/wk for 12 wk as follows:
Treatment group 1 was assigned to receive 5000 IU vitamin A (1.5 mg retinyl acetate) and placebo for iron (magnesium stearate, dextrose monohydrate and hydrogenated vegetable oil).
Treatment group 2 was assigned to receive both vitamin A and iron in tablet form; 1.5 mg retinyl acetate (5000 IU) and 200 mg ferrous sulfate were administered to each child.
Treatment group 3 was assigned to receive iron (200 mg ferrous sulfate) and placebo for vitamin A (magnesium stearate and dextrose monohydrate)
Treatment group 4 was assigned to receive both the placebo for vitamin A and the placebo for ferrous sulfate.
Procedure.
Each subject underwent a physical examination by the field investigator
(L.M.) that involved the following: 1) examination of
the eyes for pallor of conjunctiva and of the tongue, both of which are
signs of anemia, and 2) examination of the eyes for
signs of xerophthalmia (dry eye due to a deficiency of vitamin A),
Bitot’s spots (milky white spots on the eye) and corneal scars, all of
which are signs of vitamin A deficiency (Kavishe 1991
).
The children were weighed in light clothing and without shoes using a Soehnle electronic weighing scale (CMS Weighing Equipment, London, U.K.). Each child’s body weight was recorded to a precision of 0.1 kg. Height was measured to a precision of 0.1 cm using a portable fixed-base stadiometer (CMS Weighing Equipment). All measurements were made first at baseline and then at follow-up, 3 mo after treatment, by the same persons.
Provision of supplements.
After the baseline measurements had been completed, all treatments,
including placebo, were administered with a corn preparation in gruel
for 3 d/wk for 3 mo; this duration has been shown to increase
hemoglobin concentration (Pollitt et al. 1989
,
Soemantri 1989
). Supplements were provided during the
midmorning break in school by either the head teacher or the health
education teacher. This appeared to be convenient to both teachers and
children because it did not involve teaching time. After 3 mo, the
intervention was terminated, and follow-up measurements were taken.
In addition, children who had received placebo only were treated for
anemia.
Special forms were designed to record each child’s supplement use for the duration of the study; this allowed monitoring for compliance during the entire study period. All except one child (99.3%) completed the supplementation according to protocol.
The study protocol was approved by the University of Adelaide Humans Ethics Committee in Australia and the Ministries of Health, Education and Culture in Tanzania. The protocol was also revised and approved by the Ethical and Research Committee of the Tanzania Food and Nutrition Center in Tanzania.
Data analysis.
For each of the three outcome variables, hemoglobin, weight and height, we present i) mean changes within treatment groups during the 3-mo follow-up period and ii) comparisons of mean changes between pairs of treatments. Each within-treatment change and between-treatment comparison was specified a priori, but we used the Bonferroni method to control for type 1 error such that within each group of comparisons, the overall type 1 error is limited to 0.05 and the joint coverage of the confidence intervals (CI) is 95%.
Both the changes within treatments and the differences in change
between treatments were estimated from an ANCOVA model, with one model
for hemoglobin, for weight and for height. Models were adjusted for
baseline measurements. For hemoglobin, the model underlying analyses
was
 |
where 
Hb is the change in hemoglobin (follow-up value minus
baseline value); Hb0, Wt0
and Ht0 are the hemoglobin, weight and height
measurements at baseline, respectively, and, for convenience in the
model, they are centered at their overall means; VitA and Fe are dummy
variables that indicate treatment with vitamin A, iron or both,
respectively (the reference group is therefore placebo);
ß0 through ß6 are
coefficients to be estimated; 
is the error term, with the
assumption iid N(0, 
2) and
i indicates that the model holds for each of the 135
subjects.
The ANCOVA models showed no evidence of interaction between baseline covariates and treatment groups. Regression diagnostics showed no important violations of the assumptions of the linear model. Tests of contrasts of interest are based on the usual Wald statistics formed from appropriate linear combinations of estimated coefficients and standard errors derived from elements of the full variance–covariance matrix of the model.
The Stata statistical package (Stata Corporation, College Station, TX) was used for all analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Of 136 anemic children between 9 and 12 y old who were recruited
in this study, 70 (51.5%) were girls and 66 (48.5%) were boys. None
of the children who were examined showed clinical signs of vitamin A
deficiency, although most of the children had clinical signs of anemia
such as pale conjunctiva, tongue and gums. Differences among groups in
demographic and nutritional characteristics at the beginning of the
study, although not statistically significant, showed the need for
adjusted comparisons (Table 1
).
|
At the 3-mo follow-up, 135 subjects were reexamined. With
adjustments for baseline, hemoglobin levels in each group revealed
significant increases over time. The most substantial increase was seen
in the combined vitamin A and iron group (adjusted change 22.1 g/L,
95% CI 19.64–24.62; Table 2
); the group also showed the greatest change in hemoglobin relative to
that in the placebo group (adjusted differences in change 18.5 g/L,
95% CI 14.81–22.23; Table 3
). The combined group also showed significant improvements relative to
each of the vitamin A–alone and iron-alone groups.
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120 g/L) after 3 mo of supplementation compared
with only 3% of the placebo group. Most (79%) of the children who
received iron alone recovered from anemia, whereas only 50% of
children who received vitamin A alone were not anemic at the end of the
study. These results indicate that there was a 9% advantage of
correcting anemia when children were supplemented with both vitamin A
and iron compared with treatment with iron alone. A test for a linear
trend in proportions across treatment groups was significant
(
2 = 15.2 on 1 df, P
= 0.0001). Effects of supplementation on weight.
Mean changes in weight for each group, with adjustment for baseline,
after 3 mo are shown in Table 4
. There were significant increases in weight over time in each group,
with the most substantial increase seen in the combined vitamin A and
iron group (0.9 kg, 95% CI 0.73–1.04)
|
shows comparisons of change in mean weight over time between treatment
groups. There were significant increases in mean weight in each
actively treated group compared with the placebo group. The combined
treatment was better than either vitamin A or iron alone. Although the
combined treatment with vitamin A and iron compared with vitamin A
alone produced a significant weight increment (0.2 kg, 95% CI
0.01–0.46), there was no significant difference in mean weight
increase between the group who was treated with combined vitamin A and
iron and the group who were treated with iron alone (95% CI
-0.04–0.42).
|
There were slight increases in mean height over time in each group,
with the least increase seen in the placebo group (Table 6
). As with the changes in hemoglobin and weight, height increased most
in the group of children who received both vitamin A and iron (0.5 cm,
P < 0.0001, 95% CI 0.42–0.65).
|
). However, there was no significant difference in the change between
combined supplementation and iron alone.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The results of our study reveal that supplementation with iron or vitamin A either singly or in combination had major effects on the anemic status and growth of these children. After the combined treatment, only 12% of the subjects remained anemic compared with 97% of the children who received placebo. Similarly, supplementation with iron or vitamin A either singly or in combination had a significant effect on weight and height compared with the children who received placebo.
Iron deficiency occurs when insufficient iron is absorbed to meet the
requirements of the body (Viteri 1998
). Iron and vitamin
A deficiencies are widespread in many developing countries and may
coexist (Bloem et al. 1989
, Mejia and Arroyave 1982
). Many programs have been implemented to reduce IDA,
including iron supplementation, fortification and dietary modification.
Similar but separate programs have been implemented to combat vitamin A
deficiency.
The relative simplicity and low cost of the current intervention strongly suggest that vitamin A and iron supplementation has a place in the prevention of IDA and growth retardation. Rather than being seen as an exclusive alternative to long-term changes in the food supply, supplementation may be used to enhance normal diets and to effect major improvement in the health of children.
The mechanism by which combined vitamin A and iron led to improvements in hemoglobin concentration was not established in this study. Possible mechanisms include improved iron absorption from the corn-based food, increased mobilization of iron from the tissue stores through increased receptor synthesis, decreased sequestration resulting from decreased (probably subclinical) infections, increased erythropoiesis or formation of a complex between vitamin A and nonheme iron, keeping it soluble in the intestinal lumen and preventing the inhibitory effects of inhibitors of iron absorption.
In developing countries, growth retardation arises primarily as a
result of malnutrition and infection. Rapid rates of catch-up
growth have been described in extremely severe and prolonged cases of
growth retardation from children recovering from severe malnutrition,
provided epiphyseal fusion has not occurred (Ashworth and Millward 1986
, Martorall et al. 1994
).
Furthermore, these authors reviewed many instances in which
catch-up growth occurred. For example, they cite the case of a
3-y-old child who had had severe anorexia for more that half of her
life yet achieved full catch up in height, weight and skeletal
maturation by 5 y of age. In other settings, researchers have
observed prolonged growth spurts that resulted in a reduction in adult
height deficits (Cameron and Kgamphe 1993
), which were
hypothesized to be the result of delayed pubertal age. In a
noninterventional longitudinal study of 2- to 12-y-old Filipino
children, Adair (1999)
described the potential for
catch-up growth in children into preadolescent years. These
observations suggest a considerable degree of possible catch-up
growth at different age groups in childhood when there is the removal
of growth-retarding factors. The findings of our study suggest that
dietary supplementation has some potential to effect catch-up
growth in later childhood in undernourished children.
In addition, our findings provide the strongest evidence that vitamin A may have a useful role in combating vitamin A deficiency, IDA and growth retardation. The consistency in improvements in anemia and growth among the treatment groups suggests that supplementation programs are likely to bring about major reductions in the numbers of anemic and malnourished children. The role of vitamin A in combating micronutrient deficiencies, which remain a serious global and public health scourge, requires further investigation.
In the long term, the substitution of high iron plus vitamin A staples (e.g., corn, which is now available) for the current lower-yield varieties would also help prevent IDA and growth retardation when combined with other preventive measures, such as anthelminthic programs.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: CI, confidence interval; IDA, iron deficiency anemia; RBP, retinol binding protein; UKUMTA, The Tanzania Partnership for Child Development known in Swahili as Ushirikiano wa Kumwendeleza Mtoto Tanzania; WHO, World Health Organization.
Manuscript received April 11, 2000. Initial review completed May 18, 2000. Revision accepted July 14, 2000.
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