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PEDIATRICS Vol. 108 No. 3 September 2001, pp. 613-616
,
,
From the * Departments of Paediatrics and Nutritional Sciences,
University of Toronto, Toronto, Ontario, Canada; Objective. Adherence to treatment of
iron-deficiency anemia often is poor in both developed and developing
countries. The current standard therapy is ferrous sulfate drops (or
syrup) administered 3 times daily. It is possible that adherence would
improve with a single-dose daily treatment regimen. We compared the use
of single versus 3-times-daily ferrous sulfate drops, at the same total
iron dose, on treatment of anemia in infants.
Methods. To obtain a large enough cohort of anemic
subjects, we performed the study in rural Ghana. Using a prospective,
randomized, controlled design, we studied 557 anemic children (age
range: 6-24 months; hemoglobin values: 70-99 g/L). One group
(n = 280) received ferrous sulfate drops once daily
(40 mg elemental iron), and the control group (n = 277) received ferrous sulfate drops 3 times per day (total dose, 40 mg
elemental iron). Treatment lasted for 2 months. Hemoglobin and serum
ferritin values were measured at baseline and at the end of the study.
Results. Successful treatment of anemia (hemoglobin >100
g/L) occurred in 61% of the single-dose and in 56% of the
3-times-daily group. Geometric mean ferritin levels increased
significantly in each group from baseline to the final visit. Side
effects were minimal and similar between the 2 groups.
Conclusion. A single versus a 3-times-daily dose of
ferrous sulfate drops over 2 months resulted in a similar rate of
successful treatment of anemia, without side effects. To our knowledge,
this is the first demonstration of the use of a single-dose daily
regimen to treat anemia. Although not examined in the current study,
use of a single-dose daily regimen may improve adherence to treatment of anemia in infants.
Division of
Gastroenterology and Nutrition and Programs in Metabolism and
Integrative Biology, Research Institute, The Hospital for Sick
Children, Toronto, Ontario, Canada; § Kintampo Health Research Centre,
Ministry of Health, Kintampo, Ghana; and London School of Hygiene & Tropical Medicine, Maternal Child Epidemiology Unit, London, United
Kingdom.
ABSTRACT
Top
Abstract
Methods
Results
Discussion
References
Iron deficiency, the most common nutritional problem in the
world, affects two thirds of children in most developing
nations.1 In Ghana, the recent national survey revealed an
83.5% rate of anemia in preschool children, whereas in the United
States, the estimated prevalence is 3% to 5%.2,3
Iron-deficiency anemia (IDA) is a leading cause of morbidity and
mortality worldwide. Numerous studies have demonstrated that moderate
IDA (hemoglobin <100 g/L) is associated with depressed mental and
motor functions that may not be reversible.4-6 Although
many developing countries recommend iron supplementation for pregnant women and young children and treatment of documented anemia, adherence to treatment often is poor. It has been suggested that alternative treatment regimens and iron formulations may improve
outcomes.7,8
At least 4 important variables may influence the success of treatment
of IDA with oral iron: the dose per 24 hours, the frequency at which
the dose is provided, the form in which the dose is provided, and the
patient's adherence to treatment. The issue of what is considered to
be the appropriate dosage of iron has been well studied. The present
criterion standard for treatment is 1.5 to 2.0 mg of elemental iron per
kilogram of body weight provided 3 times per day (total dose: 4.5-6.0
mg/kg/d).9 The recommendation is to provide therapy for 2 months, then, to enhance iron stores, to continue therapy for an
additional 1 month or more.
With regard to the issue of the frequency of administration,
alternative therapeutic regimens, such as weekly or alternate-day dosing, have been suggested.10,11 However, too few studies
have been completed in infants and young children to warrant deviation
from the current criterion standard, especially for treatment (rather
than prevention) of anemia.12 Moreover, a single weekly
oral treatment-dose of iron may be high enough to cause side effects
that may preclude its routine use for infants. We believe that a single
daily dose is not too high to cause side effects and would achieve
better adherence compared with the standard 3-times-daily dose.
In the randomized, controlled trial that we report here, we tested the
hypothesis that the response to treatment of anemia would be lower in
patients after 2 months of once-daily treatment with ferrous sulfate
drops compared with the same drops provided 3 times daily. Our
objective, therefore, was to determine whether anemia would be treated
successfully by a single daily dose of iron or by the same dose given 3 times daily.
Study Area, Participants, and Recruitment
The study took place between May and August 1999 in the field
study area for the Kintampo Health Research Center, located in the
Kintampo district of Ghana. This is a malaria-endemic area where the
principle complementary food is a maize-based porridge. The prevalence
of anemia in young children is estimated to be >80%, a significant
proportion of which is attributable to iron deficiency.2
Eligible infants were identified from an existing surveillance database
of births in the district. To be included in the study, infants had to
be 6 to 18 months of age at the time of recruitment and have a
hemoglobin concentration between 70 and 99 g/L, measured during a
baseline assessment. Children who were severely anemic (hemoglobin <70
g/L) were excluded from the trial and treated.
Study Design
Because it would be unethical to provide a placebo to a child
with anemia, we did not include a placebo control. After the baseline
assessment, children were randomized individually to 1 of the 2 treatment groups. Randomization was done with sealed opaque envelopes
that contained group designations, which were generated randomly by
computer with Microsoft Access 97 (Microsoft Corporation, Seattle, WA).
It was not feasible to blind the field staff or the mothers to the
group to which the children were assigned. However, the people who were
responsible for the laboratory and data analyses were blinded to the
group designations.
The standard-dose group received ferrous sulfate drops (5 mg/kg/d of
elemental iron, rounded to a total of 40 mg of elemental iron) provided
in 3 equal doses per day. The intervention group received ferrous
sulfate drops at the same dose (40 mg) provided daily in a single
bolus. A single bottle of ferrous sulfate was dispensed to mothers in
both groups once every 4 weeks.
During the baseline assessment, a written questionnaire was
administered to collect demographic, nutritional, and health data for
each infant. Field workers visited infants at 2-week intervals after
the baseline visit, for a total of 5 visits. At each visit, a
questionnaire about the side effects and adherence during the preceding
7 days was completed. Data collected about side effects included the
incidence of diarrhea, constipation, and general discomfort after
ingestion of the iron drops. Questions about adherence to treatment
included whether the children objected to taking the iron and how many
doses were missed. Field workers provided parents with oral educational
reinforcement to maximize adherence to the intervention.
Capillary blood samples at baseline and final visits were obtained from
a finger prick using aseptic techniques, and hemoglobin concentration
was determined on the spot using a portable HEMOCUE B-hemoglobin
photometer (Hemocue Inc, Angelholm, Sweden) by trained technicians
using standardized techniques.13 Malaria parasite smears
were taken (at the baseline visit only), and 500-µL blood samples
were collected and preserved in ice-lined cold boxes. Blood samples
were returned to the base station within 6 hours of collection, where
the serum was separated by centrifugation (10 minutes at 1300 RPM)
before storage at Sample Size and Power
The primary outcome was successful treatment of anemia (ie, the
proportion of children with hemoglobin values Data Processing and Analysis
Data forms were checked manually for completeness and
consistency before submission for processing. Data were entered twice by 2 different data-entry clerks in Visual Fox Pro 6.0 (Microsoft Corporation), verified, and checked for range and consistency with
customized data-entry and processing programs (Microsoft Access 97).
Data queries were forwarded to the Kintampo field office and resolved,
whenever possible, by rechecking original data forms or verified in a
repeat home visit, if indicated. Monthly summary reports, including the
entered data, were sent electronically from Kintampo to the Central
Study Center in Toronto, Canada, by means of the Internet and an file
transfer protocol host site.
Data were analyzed with Statistical Analysis Software, version 6.12 (SAS Institute, Inc, Cary, NC). The proportion of children who were
treated successfully was compared between the groups with
Ethics Approval and Consent
Ethics approval for this study was obtained from the research
ethics committees at The Hospital for Sick Children, the London School
of Hygiene and Tropical Medicine, and Ghana's Ministry of Health
through the Health Research Unit. Oral consent to conduct the study in
the Kintampo district was obtained from the District Assembly of
Elected Representatives. Consent to conduct the study in each village
was obtained from village elders, and individual consent to participate
in the study was obtained from the mothers of infants included in the
study.
After the screening survey, 557 infants with hemoglobin
concentrations between 70.0 and 99.9 g/L were randomized to treatment. Fifty-seven of the 557 infants (10.2%) were absent from the survey at
the end of the trial. This loss was distributed similarly between the
treatment groups; moreover, there was no difference in baseline characteristics between these infants and the rest who successfully completed the trial. Consequently, a total of 500 infants completed the
second and final assessment, including blood sampling.
There were no significant differences in the mean age (12.80 ± 4.67 months for 3-times-daily group vs 12.98 ± 4.7 for the once-daily group; P = .75), hemoglobin
(P = .23; Table 1), or
ferritin (P = .87; Table
2) values between the 2 treatment groups at the start of the trial. Gender was represented equally between the groups (139 [51%] of 247 vs 135 [49%] of 274 boys in
3-times-daily vs once-daily drops).
TABLE 1 TABLE 2
METHODS
Top
Abstract
Methods
Results
Discussion
References
40°C. Serum ferritin was assayed in duplicate by
a commercial enzyme-linked immunosorbent assay, using a Spectro
Ferritin Kit (Ramco Laboratories, Houston, TX).14 Baseline
and final ferritin samples from an individual patient were assayed on
the same day (in a single batch) on one 96-well microtiter plate to
minimize interassay variation. An external reference standard
(Lyphochek Anemia Control; Bio-Rad, Anaheim, CA) was assayed in
duplicate on each microtiter plate for the ferritin assay.
100 g/L). On the
assumption of 90% cure rates in the control group (drops 3 times/d)
and 80% in the experimental group, with a type I error set at 0.05, and a 0.9 probability of detecting a true difference, the final sample
size estimate was 286 patients per group. We expected that 65% of the
infants in the Kintampo region would have hemoglobin values within our
target range (70-99 g/L), so a total of 880 infants were actually
screened to obtain the needed number of patients for the study.
2 analysis. Paired t tests were
used to analyze the change in hemoglobin and ferritin measurements over
time. Differences between groups in hemoglobin and ferritin
measurements at the beginning and at the end of the study were assessed
by analysis of variance (with proc General Linear Models in SAS 6.12).
All analysis of ferritin values was conducted on log-transformed data
because of their skewed frequency distribution. The acceptable level of
statistical significance for all tests was P < .05.
RESULTS
Top
Abstract
Methods
Results
Discussion
References
Mean Hemoglobin and Percentage Anemic by Treatment Group at Baseline
and After 2 Months of Treatment
Geometric Mean Ferritin Values and Range, by Treatment Group, at
Baseline and After 2 Months of Treatment
At baseline, 318 (66.8%) of the 476 infants for whom blood samples were available tested positive for malaria parasites (160 [66.7%] of 240) in the 3-times-daily group versus 158 (66.9%) of 236. Eighteen samples were discarded for technical reasons (inadequate slide preparation), and malaria data were not obtained for 131 patients. There were no significant differences among the 2 groups in the prevalence of positive malaria smears (P = .95). The World Health Organization recommendation for the treatment of malaria was followed during the study. That is, if a patient were asymptomatic (ie, no fever) yet had a positive malaria smear, then he or she was not treated. None of the patients at baseline were febrile, thus none were treated.
Hemoglobin
In both groups, there was a significant increase in hemoglobin concentrations from baseline to the end of the study (P < .001; Table 1). The change in hemoglobin concentrations was similar between groups.
Fifty-nine percent (294 of 500) of infants advanced from an anemic to a
nonanemic state (hemoglobin values 100 g/L). This rate was similar
between groups: 61% (155 of 253 patients) for the once-daily ferrous
sulfate group and 56% (139 of 247 patients) for the 3-times-daily
group (P = .51). The relative risk of remaining anemic
after 2 months of treatment was 0.92 times lower for the once-daily
group (95% confidence interval: 0.79-1.06; P = .26) than that for the 3-times-daily group, but the difference was not
significant.
Ferritin
The geometric mean ferritin values at baseline were similar in both groups and somewhat higher than was expected, likely reflecting the burden of concurrent infection (Table 2). There was a significant increase after 2 months of treatment (P < .0001). The variance for ferritin values was wide at both baseline and the end of the study, as is usual with the wide interindividual and analytic variance associated with this measure, especially in a malaria-endemic region.15,16
Adherence to Treatment and Side Effects
For children who took drops 3 times daily, 80% (462 of 578 responses from the 4 monitoring visits) received all of the prescribed doses compared with 81% (487 of 602) in the once-daily group. There was no difference in adherence to treatment between the children whose anemia did or did not resolve. Missing values were similar among groups. Seventy-four percent (933 of 1277) of mothers reported that their children objected to taking the drops in some way (children cried, made a funny face, and tried to keep their mouth shut when the drops were administered). Reported side effects were rare and mild and consisted mainly of diarrhea. There were no differences between the groups (diarrhea reported in 108 [18.7%] of 578 of those in the 3-times-daily group vs 109 [18.1%] of 602 in the once-daily group; P = .80).
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
References
|
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Both treatment arms resulted in similar increases in hemoglobin and ferritin from the beginning to the end of the study and had similar success rates in the treatment of anemia. To our knowledge, this is the first formal demonstration of the use of a single versus multiple daily dose of iron for the treatment of anemia, although the concept has been discussed previously.17,18
There are a number of possible explanations for why nearly 40% of
infants remained anemic after 2 months of treatment. Sixty-five percent
of the infants in the study tested positive for malaria, which has been
shown to be a significant contributor to the cause of anemia in young
infants in highly endemic areas.16,19 The mechanism that
causes anemia with malaria is multifactorial, including enhanced
destruction of infected red blood cells, removal of uninfected as well
as infected red blood cells by the spleen, an immune-mediated
hemolysis, and bone marrow unresponsiveness to
erythropoietin.20 Parasitic infections, common in West
Africa, also may have contributed to continuing blood losses, although
less so in infants who were younger than 30 months21; and,
Helicobacter pylori infection, also common in children in West Africa, is associated with occult blood loss and refractory anemia.22,23 We did not check for the presence of sickle
cell disease or 
thalassemia trait, both of which are prevalent in
Ghana. Thus, it is very likely that those who did not respond to iron
drops were anemic for reasons other than iron deficiency. We were
unable to define iron status accurately to confirm this because of the
limited access to laboratory facilities in the region. Even if
facilities had been available, Das et al16 demonstrated in
a carefully controlled study that in a malaria-endemic area, markers of
iron status are notoriously unreliable. If we assume that the majority
who did not respond were not iron deficient, then the rate of
successful treatment with either intervention would be significantly
higher than 60%.
The definition of anemia in the current study was based on a hemoglobin
concentration below which adverse functional outcomes have been
observed.4- 6 Lozoff et al5 demonstrated that
at a hemoglobin above 100 g/L, infants seemed to be protected from the
adverse mental and motor outcomes of anemia. Had we used the World
Health Organization definition of anemia (hemoglobin 
110 g/L), the
number of infants who advanced from an anemic to a nonanemic state
would have been proportionately lower: 39% (99 of 253) for the
once-daily group and 30% (75 of 247) for the 3-times-daily group
(P = .24), but still similar between
groups.24 One could argue the merits of either hemoglobin
standard. We used the lower hemoglobin standard believing that it was
more realistic in Ghana, with its extremely high prevalence of anemia
and limited resources, to aim for a potentially achievable target.
Our findings suggest important policy and program implications for the treatment of anemia, although the protocol was not designed to measure directly the adherence to treatment with the different dosing regimens (the protocol was not designed as an effectiveness study). For the past 150 years or more, oral ferrous sulfate has been the primary therapeutic (and preventive) source of iron for the treatment of IDA.25 When a soluble form of iron (eg, ferrous sulfate) is ingested in the proper dose, this intervention is effective. However, adherence to long-term ingestion of oral iron drops (in an unsupervised setting) often is poor.7 In fact, there is very little evidence of the large-scale effectiveness of iron supplementation in young children. An effectiveness trial in Romania that included more than 2000 infants demonstrated only a limited reduction in anemia prevalence of 6- to 9-month-old infants. Low parental compliance with the administration of multiple daily doses of iron drops was implicated as one explanation of the results.26
Although the use of drops, even once daily, still is complicated by a strong and unpleasant taste and the staining of teeth if the drops are not placed carefully at the back of the infant's mouth or the teeth are not immediately wiped, from a practical perspective, the option of using drops once daily may improve adherence to treatment and thus the success rate for the treatment of anemia.
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ACKNOWLEDGMENTS |
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Dr. Zlotkin is an occasional consultant to Mead Johnson Nutritionals.
This study was supported by a grant from USAID's OMNI Research Program through the Human Nutrition Institute of the International Life Sciences Institute. Material support was from Mead Johnson Canada.
We thank Ana Piekarz and Claudia Schauer for technical assistance and ongoing data management support of this project.
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FOOTNOTES |
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Received for publication Oct 12, 2000; accepted Jan 19, 2001.
Reprint requests to (S.Z.) Division of GI/Nutrition, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada. E-mail: zlotkin{at}sickkids.on.ca
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ABBREVIATIONS |
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IDA, iron-deficiency anemia.
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REFERENCES |
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Abstract
Methods
Results
Discussion
References
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This article has been cited by other articles:
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  C R Wall, C C Grant, N Taua, C Wilson, and J M D Thompson Milk versus medicine for the treatment of iron deficiency anaemia in hospitalised infants Arch. Dis. Child., October 1, 2005; 90(10): 1033 - 1038. [Abstract] [Full Text] [PDF]
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 S. Zlotkin Clinical nutrition: 8. The role of nutrition in the prevention of iron deficiency anemia in infants, children and adolescents Can. Med. Assoc. J., January 7, 2003; 168(1): 59 - 63. [Full Text] [PDF]
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 Single-Dose Daily Treatment of Anemia in Infants Journal Watch (General), September 11, 2001; 2001(911): 8 - 8. [Full Text]
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