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Weekly vs Daily Iron and Folic Acid Supplementation in Adolescent Nepalese Girls
Binay Kumar Shah, MBBS;
Piyush Gupta, MD, MAMS
Arch Pediatr Adolesc Med. 2002;156:131-135.
ABSTRACT
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Objective To compare the effectiveness of weekly vs daily iron and folic acid
supplementation for control of anemia in adolescent Nepalese girls.
Design Randomized controlled trial.
Setting A Government Girl School in Dharan, Nepal, an urban foothill town that
is 305 m above sea level.
Subjects Consecutive healthy adolescent girls (n = 209, median age 15 years)
randomized to 3 groups matched for age, anthropometry, and personal and sociodemographic
characteristics. Of 209 subjects, 181 completed the trial. Two girls had adverse
reactions to treatment and were excluded.
Intervention Group A (n = 70) received a 350-mg ferrous sulfate and 1.5-mg folic
acid combination once daily for 90 to 100 days. Group B (n = 67) received
the tablet under supervision once a week for 14 weeks. Group C (n = 72) did
not receive any drugs.
Outcome Variable Presupplementation and postsupplementation differences in prevalence
of anemia and change in hematocrit.
Results Prevalence of anemia (defined as hematocrit <36%) declined from 68.6%
and 70.1% in groups A and B to 20% and 13.4%, respectively, postsupplementation
(P<.001), whereas the prevalence in group C changed
little (68.1% to 65.3%, P = .81). There was a significant
rise in the mean hematocrit of both supplemented groups (group A, 32.9% ±
3.5% to 41.0% ± 5.6%, P<.001; group B,
33.2% ± 3.6% to 40.4% ± 4.9%, P<.001)
but no appreciable change in controls (34.2% ± 2.9% to 34.1% ±
3.3%, P = .91). Net change in mean hematocrit in
both the supplementation groups was comparable (P
= .57).
Conclusions The prevalence of anemia in adolescent Nepalese girls is high. Supervised
iron and folic acid therapy once a week is an effective alternative to daily
administration and helps lower the prevalence of anemia in adolescent girls.
INTRODUCTION
ANEMIA IS the most prevalent nutritional problem worldwide, due mainly
to iron deficiency. Its prevalence is highest among young children and women
of childbearing age, particularly pregnant women.1
The exact figure for global prevalence of anemia among adolescent girls is
not known but is estimated to be quite high. The physiological growth spurt,
with its attendant rise in mean hemoglobin level, and menarche cause an increase
in daily iron requirement, which, if not met, can rapidly result in anemia.
Diagnosis and treatment of anemia is of particular importance in adolescent
girls because they enter the reproductive cycle soon after menarche. Even
a marginal iron deficiency at this stage can precipitate severe anemia later
on due to the stress imposed by pregnancy and parturition. Adolescent girls
can be easily approached through school-based intervention programs.2
Based on study in rats, it has been suggested that iron supplementation
should not be given daily, but rather weekly or twice weekly.3
With a daily dose, the intestinal mucosal cells get saturated quickly, and
iron absorption stops. Because the turnover rate of these cells is 5 to 6
days, a single weekly dose may be as efficacious and more cost-effective.
Compliance might also improve because fewer doses of iron would be needed.
This hypothesis has been supported by studies comparing the effectiveness
of hemoglobin or hematocrit response, which was found to be similar regardless
of whether supplementation was daily, weekly, or twice weekly.2, 4-7
To the contrary, Cook and Reddy8 concluded
that there is no significant absorptive advantage in giving iron less often
than once daily. Hallberg9 reiterated that
there is no evidence that weekly supplementation better prevents iron deficiency
because the fundamental argument in its favor, that daily supplementation
causes a mucosal block, is not valid.
The aim of this study was to investigate whether supervised weekly iron
and folic acid supplementation would lower the prevalence of anemia and improve
hematocrit status as effectively as daily supplementation in adolescent Nepalese
girls, in whom baseline prevalence of anemia is suspected to be quite high.
SUBJECTS AND METHODS
STUDY POPULATION
The study was conducted in the Government Girl School of the Dharan
Municipality, Nepal, from March 1998 to March 1999. The school caters to families
from the lower-middle socioeconomic group. Dharan is a small foothill town
(305 m above sea level) located more than 500 km east of Kathmandu. All girls
from grades 8 to 12 between ages 11 to 18 years (N = 225) were initially enrolled.
HISTORY AND EXAMINATION
The girls were questioned and examined by B.K.S.; a detailed sociodemographic
profile was obtained, including the parents' education and occupation, type
of housing, water supply, and toilet facilities. Type of diet (vegetarian
or nonvegetarian), history of passage of worms, and menarchal status were
recorded. Presence of pallor, icterus, edema, hyperpigmentation, lymphadenopathy,
platynychia, bleeding spots, xerophthalmia, and goiter were recorded on a
predesigned form. Physical examinations were conducted to rule out any systemic
abnormalities. Weight, height, and mid-arm circumference were measured using
standard techniques.10 Girls suffering from
any chronic illnesses (eg, asthma, rheumatic heart disease) or receiving any
long-term allopathic or indigenous drug treatments were excluded from the
study. Similarly, girls who had been hospitalized for any severe illness within
the past 2 weeks were also excluded. Finally, 209 girls (median age, 15 years)
were included in the study. The baseline hematocrit of each girl was estimated
using the microhematocrit technique.
INTERVENTION
Subjects were randomly assigned to 1 of 3 groups: A (n = 70), B (n =
67), and C (n = 72). Group A received supplementation with tablets containing
350 mg of ferrous sulfate and 1.5 mg of folic acid once a day for 90 to 100
days. The drug was given to the parents on a weekly basis, and they were asked
to maintain a record of its consumption. An investigator (B.K.S.) personally
supervised administration of the same combination to group B on a fixed day
once a week for 14 weeks. Group C served as a control and did not receive
any medication. None of the participants received anthelmintics during the
study period. The girls were not told whether they were anemic or not during
the study period. Girls in the control group who were found to be anemic were
offered therapy after the study was completed. Subjects who complained of
abdominal pain and other gastrointestinal adverse effects were reassured about
the harmless nature of the tablets. A few girls whose symptoms persisted were
asked to take the tablets after a meal. Those with severe persistent symptoms
were asked to stop taking the drug.
REEVALUATION
Fifteen days after the end of the study period (100 days or 14 weeks),
the remaining subjects were reevaluated by measuring their hematocrit. Dropouts
were due to severe adverse effects, noncompliance to treatment, or nonavailability
for the final hematocrit estimation (Figure
1). Although these girls may not have completed the intervention
and reevaluation, they were still included in the analysis.
STATISTICAL METHODS
Prevalence of anemia was calculated per the World Health Organization
cut-off of hematocrit less than 36% in adolescents. Girls who were anemic
before supplementation but concluded with a hematocrit of 36% or more were
labeled responders. Analysis was carried out using Statistical Product and
Service Solutions (Chicago, Ill) software version 10.0 on a compatible PC.
We used an intention-to-treat analysis11 to
eliminate the potential bias of excluding girls who did not comply or were
not available for follow-up. In this approach, all girls who were randomized
remained in the denominator, and those for whom we did not have follow-up
hematocrit values were considered to have final hematocrit values similar
to their individual baseline values. Statistical tests including the  2 test, paired t test, analysis of variance,
and Tukey test were performed. The level of significance was set at P<.05. Free and informed verbal consent of the subjects
and their parents was obtained prior to recruitment in the study.
RESULTS
Overall baseline prevalence of anemia was 68.8% (144/209). Sample hematocrits
ranged from 24% to 42%, and none of the girls was severely anemic. Age-wise
prevalence of anemia was 76.9% (10/13), 70.1% (47/67), 63.6% (42/66), and
71.4% (45/63) in the age categories of 12 or fewer, 12.01-14, 14.01-16, and
more than 16 years respectively (P = .69). The mean
hematocrit in these age categories was also comparable (mean ± SD,
33.4% ± 3.4%, 33.6% ± 2.9%, 33.6% ± 3.7%, and 32.9% ±
3.5%, respectively; 1-way analysis of variance; P
= .65). Prevalence of anemia in premenarchal vs postmenarchal girls was 72.7%
(24/33) and 68.2% (120/176) (P = .60), with mean
hematocrit of 33.4% ± 3.2% and 33.4% ± 3.4%, respectively (P = .99). The demographic characteristics of study groups
indicated that all the groups were matched prior to supplementation (Table 1). The baseline prevalence of anemia
and mean hematocrit in the 3 groups was also comparable (Table 2).
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Table 1. Personal and Sociodemographic Characteristics*
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Table 2. Impact of Hematinic Therapy on Prevalence of Anemia
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Of 209 girls evaluated initially, 28 girls were excluded at the end
of the study (Figure 1). Two girls
in group A had severe gastrointestinal problems that necessitated their exclusion
from the study. The number of dropouts due to noncompliance was 8 (11.4%),
4 (6%), and 4 (5.6%), respectively, in the 3 groups. At the end of the study,
another 10 girls (2, 6, and 2 subjects in groups A, B, and C, respectively)
were not available for repeat hematocrit estimation. Reevaluation was carried
out in 58, 57, and 66 girls in the 3 groups, respectively.
Prevalence of anemia, which was matched in the 3 groups before supplementation,
dropped considerably and to an equal extent in both supplementation groups
(P<.001), but little change was observed in the
control group (P = .81) (Table 2). Following supplementation, no difference was observed
in the prevalence of anemia between the 2 supplemented groups (P = .30), whereas both groups were markedly different from controls
(P<.001). A significant rise in mean hematocrit
levels was documented in both intervention groups following supplementation
(P<.001); no rise was observed among controls
(P = .91). Postsupplemental hematocrit was not significantly
different between groups A and B (P = .73). However,
these values were significantly higher than the controls (P<.001). Net change in hematocrit was also similar in the 2 intervention
groups (P = .57) and was markedly more than in controls
(P<.001).
The number of responders and the mean hematocrit change were significantly
higher in the 2 intervention groups than in controls (P<.001) (Table 3). Among
responders, hematocrit rise was marginally more (P
= .04) in the daily supplemented group as compared with those given weekly
therapy. In the control group, more than 50% of subjects were true nonresponders
(anemic both at baseline and 3 months thereafter) as compared with a much
lower percentage in groups A and B. Whereas approximately 11% of girls slipped
from being healthy to anemic in the unsupplemented group, only 1 girl in the
supplementation groups went from healthy to anemic.
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Table 3. Response to Hematinic Supplementation*
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Further analysis did not reveal a significant relationship between means
of initial hematocrit, postsupplementation hematocrit, or net change in hematocrit
with age or menarchal status (1-way analysis of variance; P>.05). Mean hematocrit change in the responders was also not found
to be influenced by the age or menarchal status of the subjects in different
groups (3-way analysis of variance; all 2-way and 3-way interactions insignificant
at 5% level).
COMMENTS
The prevalence of anemia in this study was extraordinarily high but
matched closely with a few studies from the Indian subcontinent.12-13
This was in sharp contrast to studies in other parts of the world, where the
prevalence of anemia in adolescent girls ranges from 4% to 30% (Norway 4%,
United States 5.9%, England 10.5%, Kuwait and Peru 25%-30%).14-18
A detailed dietary history would have enabled further discussion on probable
causes of the high prevalence in our sample.
The concept of a close association between anemia and iron deficiency
is closest to correct when the prevalence of iron deficiency is high.1 Therefore, it was safe to assume that iron deficiency
was the principal cause of anemia and experiment with various modalities of
iron supplementation. The effect of hematinic supplementation indicates that
most girls had nutritional anemia, and other diagnoses may have contributed
little to the etiology. A high prevalence of anemia also justified our blanket
approach of treating all girls in intervention groups with supplements irrespective
of their iron or hematocrit levels.
The dose and duration of iron therapy in the present study aligned with
standard recommendations. The Centers for Disease Control and Prevention advocates
60 to 120 mg of elemental iron a day for 2 to 3 months to treat anemia in
adolescent girls.1 In the Indian subcontinent,
folic acid is routinely added to iron tablets in current national programs
for control of anemia.19 Hematocrit levels
in groups supplemented with daily and weekly iron and folic acid improved
to an equal extent but significantly more than the controls following 3 months
of supplementation. A follow-up period of 6 to 9 months would have helped
to document the long-term effects of supplementation.
While refuting the mucosal block theory, Hallberg9
also questioned the methodology and design of studies suggesting a similar
hemoglobin response to weekly and daily iron administration. The controversy
appears to have been put to rest by a recent meta-analysis of 22 completed
trials on the efficacy of intermittent iron supplementation in control of
iron deficiency anemia in developing countries.20
Beaton and McCabe20 concluded that both daily
and weekly iron supplementation schedules are efficacious. Weekly iron supplementation
is likely to be less effective than daily administration except in situations
where supervision is feasible with weekly but not daily schedules. We proved
that supervised weekly iron supplementation is as effective as daily administration
but could not comment on a situation where weekly iron is given in an unsupervised
manner. The question of whether there is a mucosal block appears redundant
now, as field trials have provided ample evidence of the equal efficacy of
weekly and daily iron administration schedules.
In developing countries, hematinic supplements are distributed through
the primary health care systems. However, sustained efficacy is uncommon,
owing to factors such as irregular tablet distribution and poor compliance.
A less-frequent schedule would mean less cost and better compliance. Cook21 argued against better compliance in the weekly group
based on a dismal record of adherence to weekly programs for malarial prophylaxis.
We think this problem can be obviated with a high degree of supervision, which
is realistic and effective in school-based weekly iron supplementation programs.
Dropouts because of poor compliance were almost double in the daily
supplementation group as compared with the weekly group, and persistent adverse
effects were also limited to the daily supplementation group. However, because
there were fewer subjects, the impact of a daily vs weekly schedule on the
adverse effects of iron therapy could not be confidently demonstrated. Incidence
of adverse effects could have been better analyzed if we had administered
placebos to our control group. Also, we did not question the girls about their
perceptions and preferences with regard to daily vs weekly therapy. It would
be interesting to know whether girls liked a particular schedule, and if so,
what their reasons were.
To conclude, the prevalence of anemia in Nepalese adolescent girls is
quite high. To counter this, weekly supervised therapy is a good alternative
to daily iron and folic acid administration. Weekly therapy appears to be
equally effective yet causes fewer adverse effects, improves compliance, and
reduces the cost of supplementation.
| What This Study Adds
Daily iron supplementation is a key strategy for short-term control
of iron deficiency anemia. Control of anemia is particularly important in
adolescent girls because they may be future mothers. A reduction in the frequency
of iron supplement administration to once or twice a week is being examined
in developing countries. If effective, this schedule would improve compliance
and reduce costs.
The results of the present study indicate that weekly supervised iron
and folic acid administration is an effective alternative to daily administration.
In adolescent girls, weekly supplementation through school-based programs
lowers the prevalence of anemia in areas with high prevalence of the disease.
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AUTHOR INFORMATION
Accepted for publication September 20, 2001.
This study was supported by the Research Committee of B.P. Koirala Institute
of Health Sciences, Dharan.
Corresponding author and reprints: Piyush Gupta, MD, MAMS, Block
R-6-A, Dilshad Garden, Near Telephone Exchange, Delhi 110095, India (e-mail: drpiyush{at}satyam.net.in).
From the Department of Pediatrics, B. P. Koirala Institute of Health
Sciences, Dharan, Nepal. Dr Gupta is now with the University College of Medical
Sciences and Guru Teg Bahadur Hospital, Delhi, India.
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