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Is Weekly Iron and Folic Acid Supplementation as Effective as Daily Supplementation for Decreasing Incidence of Anemia in Adolescent Girls?
Arch Pediatr Adolesc Med. 2002;156:128-130.
THIS CLINICAL TRIAL1 compared the
effectiveness
of weekly vs daily administration of iron plus folic acid for the treatment
of anemia in adolescent Nepalese girls, a population with an extremely high
prevalence of anemia. The study was conducted in a single government-run school
in Dharan, an urban foothill town in Nepal. Girls from the 8th to 12th grades
aged 11 to 18 years were enrolled. Baseline characteristics measured included
sociodemographic variables, diet (vegetarian vs nonvegetarian), history of
parasites, menarcheal status, anthropometrics, and presence of specific physical
abnormalities. The baseline prevalence of anemia in this population was 69%.
Subjects were
randomized to 1 of 3 groups: group A (n = 70) 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; group B (n = 67) received the same combination
on a fixed day once a week for 14 weeks, supervised by 1 of the investigators;
and group C (n = 72) received no treatment during the study period. Of the
225 girls enrolled, 209 met inclusion criteria, and 181 completed the trial.
The primary outcomes included prevalence of anemia (defined as hematocrit
<36%), mean hematocrit, and net change in hematocrit for each group from
baseline to 15 days after completion of therapy.
The prevalence of anemia
declined from 68.6% and 70.1% in groups A and B to 20.0% and 13.4%, respectively
(P<.001). In group C, the control group, the prevalence
went from 68.1% to 65.3% (P = .81). Mean hematocrit
and net changes in mean hematocrit also increased
significantly in both treatment
groups compared with the control group. Increases in all outcomes between
the daily and weekly observed treatment regimens were statistically equivalent.
We evaluated this study using standards of design, analysis, and results
for therapeutic trials described in the "Users' Guide" series published in
the Journal of the American Medical Association.2-3 The focus is on the quality of the
study, the validity of its results, and the generalizability of the outcomes.
QUALITY OF THE STUDY
Randomization of Subjects
The study was a
randomized controlled trial. All students in grades
8 through 12 were initially enrolled, and 209 who met eligibility criteria
were randomized. Though the authors state that subjects were randomly assigned
to 1 of 3 groups, they do not state which
method of randomization was used
(eg, random number table). The resulting 3 study groups were roughly equivalent
in size, and Table 1 from the study indicates that the demographic characteristics
of the 3 groups were similar. These results suggest that, whichever randomization
process was used, it was successful in creating 3 equivalent study groups.
In the "Results" section, the authors state that all 3 groups were
"matched"
for age, anthropometrics, and personal and sociodemographic characteristics
but do not state whether this was intentional matching in the formal epidemiological
sense (ie, in order to control for
bias in those factors involved in the match).
Rather, it seems more likely that the groups were found to be matched on analysis,
which is demonstrated by the fact that the 3 groups were statistically similar
with regard to baseline characteristics (Table 1).
Accounting for Subjects
The authors account for all of the subjects in the study. Their text
and figure clearly explain the reasons for the differences between the number
originally registered (225) and the number eventually randomized (209). They
state that 10 subjects met defined medical exclusion criteria and 6 refused
participation. Of those randomized, 181 (87%) completed the trial, and reasons
for loss of subjects are explicitly described (ie, severe adverse effects,
noncompliance to treatment, and nonavailability for final hematocrit measurement).
The authors indicate that they performed an
"intention-to-treat" analysis.
Intention-to-treat is the appropriate method of analysis to use for a randomized
controlled trial because it presents the effect seen due to the treatment
assigned, regardless of patient compliance or availability for follow-up.3
Blinded Assessment
Ideally, therapeutic trials are double-blind. In this study, subjects
were blind to whether they were anemic but not to their treatment assignment.
Blinding subjects to their treatment assignment could have been accomplished
if subjects in group B had taken placebo pills on the days they were not receiving
their once-weekly combination of iron and folic acid and if subjects in group
C had taken placebo pills every day. The authors state that incidence "of adverse effects [italics ours] could have been better analyzed
if we had administered placebos to our control group" but do not address potential
biases introduced by not blinding subjects to their treatment assignments.
It is possible that subjects may have crossed over from one treatment group
to another. For instance, because subjects in group A were not as explicitly
supervised as those in group B, they may have been less conscientious about
taking their medication daily, knowing that their friends were only taking
their medication weekly. If daily administration of iron is more effective
than weekly but many of the subjects in group A actually did not take iron
daily, it may have biased the results against showing a difference.
The second component of double-blinding keeps the investigators from
knowing subjects' treatment assignments. Investigators were not blinded to
treatment assignments in this study. However, it is unlikely that this significantly
affected the results because the outcomes measured were relatively objective
(ie, hematocrit values and a clear definition of anemia: hematocrit <36%).
VALIDITY OF RESULTS
Similarity of Groups
Table 1 indicates that groups A, B, and C were similar with respect
to demographics, anthropometrics, menstrual history, past medical history,
a variety of sociodemographic characteristics, and specific physical examination
findings (ie, pallor, xeropthalmia, and goiter). Most importantly, the prevalence
of anemia is similar among groups. The fact that these groups are similar,
with respect to known
prognostic factors, lends strength to the validity of
the study results. Notably absent from baseline measures are indicators of
iron deficiency (eg, microcytosis, serum ferritin, and free erythrocyte protoporphyrin).
The authors comment that in a population with such a high prevalence of anemia,
it can be assumed that iron deficiency anemia is the root cause. However,
if iron deficiency was not evenly distributed among the 3 groups, it may have
confounded the study results.
Equal Treatment of Groups
The major difference in treatment among groups was in documentation
of compliance, though this was intentional. Direct observation of weekly therapy
in group B assured compliance, whereas the compliance of group A with the
daily regimen is unknown. If treatment were similarly observed in both groups
and this lead to improved compliance in group A, it is possible that hematocrit
levels in group A may have improved more than in group B.
Other possible differences in treatment among groups are not discussed.
The use of additional vitamins or medications may have differed among the
3 groups. Additionally, the experience of the groups during the 15-day period
after the trial prior to follow-up hematocrit evaluation may have differed.
In both these situations, it is likely that any differences were offset through
randomization, thus minimizing the possibility of bias.
Treatment Effect Size
The study found a dramatic decrease in the prevalence of anemia with
the use of daily or weekly iron plus folic acid. All 3 groups had very similar
rates of anemia at baseline (68%-70%). At follow-up, the control group had
a similar anemia prevalence of 65.3%, whereas the intervention groups had
rates of 20.0% and 13.4%, respectively. This equates to an
absolute risk reduction
of 45.3% for group A and 51.9% for group B. The
number needed to treat for
group A (daily supplementation) is 2.2.
This means that for every 2 to 3 patients
in group A treated for anemia, 1 will no longer be anemic. For group B (weekly
supplementation) the number needed to treat is 1.92. For every 2 patients
in group B treated for anemia, 1 will no longer be anemic.
Although the treatment effect of both regimens was impressive, the authors'
aim was to see whether supervised weekly iron and folic acid supplementation
was as effective as daily supplementation. The ability of a study to demonstrate
that 2 treatments are equivalent is based on its power. The authors do not
discuss sample size calculations. They do not state a priori what magnitude
of difference in effect size between daily and weekly regimens would be clinically
important to detect. With sample sizes of 70 in group A and 67 in group B,
this study has a 90% probability of detecting a difference of 25% or more.
Thus, in this study there is a chance of a
type II error (ie, failure to reject
the null hypotheses that the 2 regimens are equally effective when they actually
are not). If public health officials feel that a difference in treatment effect
of less than 25% might be important, then this study lacks adequate power.
As mentioned previously, 2 of the difficulties with this study are the
assumption that most patients with anemia had iron deficiency anemia and that
ferrous sulfate and folic acid were supplied simultaneously. Because additional
tests were not performed to confirm that the anemia was caused by iron deficiency,
we cannot be certain that the reduction in anemia is directly due to the treatment
introduced. Specifically, we do not know whether iron or folic acid supplementation
is the primary reason for a reduction in the prevalence of anemia.
Treatment Effect Precision
Precision is usually expressed using confidence intervals. This study
did not report confidence intervals for the
binomial results of presence or
absence of anemia posttreatment. The reduction in anemia in the 2 intervention
groups was pronounced, and the
P values were less
than .001. This implies that there is a 99.9% confidence that these results
were not due to chance alone.
GENERALIZABILITY
There are 2 issues of
generalizability to consider in interpreting this
study. The first is the appropriateness of applying the findings to other
populations of adolescent girls in developing countries with high rates of
anemia. It is important to recognize that this study was conducted in a single
government school in a small foothill town in Nepal. Whether the findings
would be similar in larger samples of girls, in other regions of Nepal or
other developing countries, and in non–school-based populations cannot
be determined.
The application of the results of this study to adolescents in developed
countries such as the United States is even more problematic. This population
had a very high prevalence of anemia, as well as underlying medical conditions
not commonly seen in the United States (eg, other nutritional deficiencies,
parasitic infections, and goiter). The prevalence of iron deficiency in US
adolescent girls is 9% to 11%, and the prevalence of iron deficiency anemia
is 2% to 5%.4 Thus, the effect size that could
be expected from empirical treatment of school-based populations of adolescent
girls in this country with iron and folic acid would be far smaller.
Application of Results to Individual Patients
It is difficult to apply these results to individual patients in the
United States. In addition to the differences in anemia prevalence and nutritional
health, there is only limited evidence that early treatment of anemia in the
adolescent US population can reduce morbidity. Trials from developing countries
have reported conflicting results as to the benefit of iron supplementation
on work productivity, psychomotor function tests, subjective well-being, and
other outcomes. In addition, none of these studies have examined the benefits
of treating mild cases of anemia, which were common in this current study.5
Cost vs Benefits
Iron supplementation is relatively inexpensive, and it may improve some
clinical outcomes. The adverse effects of iron therapy include gastrointestinal
symptoms, iron overload in patients with an underlying iron storage disorder,
and the potential for an intentional or unintentional overdose, which can
be fatal. Currently, the
US Preventive Services Task Force states that "There
is insufficient evidence to recommend for or against routine testing for anemia
in . . . asymptomatic persons, but recommendations against such screening
may be made on the grounds of low prevalence, cost, and potential adverse
effects."5 Routine screening of nonpregnant
adolescents is not advocated by most organizations. Some organizations recommend
screening for high-risk populations, such as adolescents with increased risk
from heavy menses, weight loss, or nutritional deficits. The American Academy
of Pediatrics currently recommends that hemoglobin or hematocrit be measured
at least once for all menstruating adolescents, preferably at age 15 years.6
CONCLUSIONS
This study is a well-conducted clinical trial. It addresses a prevalent
health problem in developing countries, and it demonstrates the effectiveness
of an alternative treatment approach to anemia that may be advantageous in
certain populations. The greatest limitation of this study is the relatively
unique population that is employs. Nevertheless, public health officials interested
in the treatment of anemia can potentially use this study to justify similar
approaches in larger, more diverse populations.
Eliana Perrin, MD;
Russell Rothman, MD;
Tamera Coyne-Beasley, MD, MPH;
Carol Ford, MD
Chapel Hill
W. Clayton Bordley, MD, MPH
Department of Pediatrics
University of North Carolina, Chapel Hill
Medical School, Wing C
CB No. 7225
Chapel Hill, NC 27599-7225
(e-mail: cbordley{at}med.unc.edu)
REFERENCES
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1. Shah BK, Gupta P. Weekly vs daily iron and folic acid supplementation in adolescent Nepalese
girls. Arch Pediatr Adolesc Med. 2002;156:131-135.
FREE FULL TEXT
2. Guyatt GH, Sackett DL, Cook DJ. Users' guide to the medical literature, II: how to use an article about
therapy and prevention, B: what were the results and will they help me in
caring for my patients? Evidence-Based Medicine Working Group. JAMA. 1994;271:59-63.
FREE FULL TEXT
3. Guyatt GH, Sackett DL, Cook DJ. Users' guide to the medical literature, II: how to use an article about
therapy and prevention, A: are the results of the study valid? Evidence-Based
Medicine Working Group. JAMA. 1993;270:2598-2601.
FREE FULL TEXT
4. Looker AC, Dallman PR, Carroll MD, Guntner EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA. 1997;277:973-976.
ABSTRACT
5. US Preventive Services Task Force. Screening for iron deficiency anemia—including iron prophylaxis. In: Guide to Clinical Preventive Services.
2nd ed. Baltimore, Md: Williams & Wilkins; 1996:231-246.
6. American Academy of Pediatrics Committee on Practice and Ambulatory
Medicine. Recommendations for preventive pediatric health care. Pediatrics. 2000;105:645.
FREE FULL TEXT
SECTION EDITORS: DIMITRI A. CHRISTAKIS, MD, MPH; HAROLD P. LEHMANN,
MD, PHD
RELATED ARTICLE
Weekly vs Daily Iron and Folic Acid Supplementation in Adolescent Nepalese Girls
Binay Kumar Shah and Piyush Gupta
Arch Pediatr Adolesc Med. 2002;156(2):131-135.
ABSTRACT
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