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,**,4,**
* Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA;
Kenya Medical Research Institute, Vector Biology Control and Research Center, Kisumu, Kisumu, Kenya; and
** Unit of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
4To whom correspondence should be addressed. E-mail: mdesai{at}.cdc.gov.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • iron • daily • anemia • children • Kenya
In eastern Africa, 50–75% of preschool children suffer from anemia (1). Iron deficiency is one of the predominant causes (2–5) and may lead to impaired mental development, decreased appetite, decreased resistance to infections, and increased risk of HIV infection when blood transfusions are needed (6). For documented iron deficiency anemia, iron supplementation is the treatment of choice; for the prevention of iron deficiency anemia, combined iron supplementation and food-based approaches are recommended in developing countries (7). Successful implementation of these programs is limited due to inadequate iron supplies, low coverage, and poor tolerance and adherence to the lengthy duration of required daily dosing (8–12).
In the search for strategies to reduce costs and improve compliance and effectiveness, a series of studies were conducted demonstrating that weekly or twice weekly iron supplementation was as effective in the prevention (13–16) or treatment (17–24) of mild and moderate anemia as conventional daily iron supplementation, despite a 30–70% reduction in the cumulative dose. These studies were based on observations of reduced iron absorption and transport with daily exposure to high doses in animal models, explained in part by an apparent inhibitory mucosal block, which can be overcome by giving iron intermittently at intervals of >3 d (25). However, studies in humans failed to confirm the existence of such a mucosal block (11,26). This challenged the earlier conclusion that intermittent iron was as effective as daily iron supplementation (27–30) and led to much debate (9,31). It was suggested that a true difference was missed because efficacy was evaluated only after relatively long intervention periods (
8 wk) of high-dose iron supplementation in subjects with predominantly mild iron deficiency and low-grade anemia (26).
A recent meta-analysis of 14 clinical trials demonstrated that although the beneficial effect of daily dosing vs. intermittent iron was indisputable in pregnant women, large interstudy variations make such evidence inconclusive in adolescents and preschool children (32). It also indicated that the degree of supervision was an important predictor of postintervention anemia prevalence. A more recent study demonstrated that 6 wk of supervised twice weekly iron supplementation for treatment of anemia in children is superior to unsupervised daily iron supplementation in improving hemoglobin (Hb)5 concentrations (19).
We compared the therapeutic efficacy of a short 6-wk course of twice weekly vs. daily iron supplementation in children with mild-to-moderate anemia in western Kenya. We also compared the effect of supervised vs. unsupervised iron supplementation to evaluate the role of adherence and to determine the potential benefits of directly observed therapy. The current study is part of a series of studies conducted to optimize the treatment guidelines for anemia in this area of intense malaria transmission and to address the concern that long courses of iron may increase the risk of malaria (33).
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Despite the high public health burden of anemia, most local clinics lack standardized guidelines for the use of iron supplementation in its treatment or prevention. Clinic-based surveillance in this area showed that iron supplementation was not routinely given to children with mild and moderate anemia, and prescribed for only 12% of the children < 5 y old with clinically diagnosed severe anemia, whereas all received presumptive antimalarial treatment (41). The clinics that prescribe iron for severe anemia in children use short courses of relatively high doses of iron [3–6 mg/(kg · d) for 14 d]. This is combined with presumptive antimalarial treatment to treat the malaria-attributable component of anemia, while providing partial protection against the potentiallly adverse effects on malaria associated with iron (33,42). This 2-wk regimen combined with antimalarial treatment is also used in other areas with similar intense malaria transmission (2) and reflects the controversy concerning the safety of longer iron supplementation regimens in these malaria endemic areas (33). The efficacy of this 2-wk regimen is unknown, but the short duration of supplementation is likely to result in inadequate restoration of Hb levels (which requires a minimum of 4–6 wk) (43) and particularly iron stores, which may require iron supplementation for 12 wk (44).
Interventions. All study children were given a single treatment dose of sulfadoxine-pyrimethamine (SP, Fansidar Hoffman La Roche) at enrollment; the dosage was based on body weight and administered as crushed tablets mixed with water (42). In addition, children received iron daily or twice weekly for 6 wk. This was the shortest regimen recommended for the treatment of anemia (43) that, combined with SP, was expected to result in clinically relevant improvement in Hb concentrations in the majority of patients (19). It also ensured that children in the twice weekly group received a cumulative dose of iron similar to that with the conventional 2-weekly regimen. Folic acid was not considered because of the known interaction between SP (an antifolate antimalarial) and folic acid supplementation (45).
Children received their first dose of 6 wk of iron supplementation on the day of enrollment. Treatment groups included the following: 1) daily, supervised iron supplementation (DS); 2) daily, unsupervised iron supplementation (DU); 3) twice weekly, supervised iron supplementation (TS); and 4) twice weekly, unsupervised iron supplementation (TU). The target oral dose of iron (ferrous sulfate syrup 40 g/L, 27.5% elemental iron, Laboratory and Allied Ltd, Nairobi, Kenya) was 3–6 mg/(kg · d) in the daily iron groups and 6–12 mg/(kg · wk) in the intermittent iron groups (divided into two doses of 3–6 mg/kg each, separated by 3–4 d). Iron doses were based on body weight (<5 kg: 1.25 mL/d, 5–10 kg: 2.5 mL/d, >10 kg: 5.0 mL/d). Caregivers were given the complete 6-wk supply of iron supplementation for their child, and participants in both the unsupervised and supervised arms received identical instructions in the local language with regard to the method of administration, expected side effects, safety, and correct dose of iron supplementation. Plastic screw-cap bottles were used, labeled with personal identifiers and dosing instructions.
Children in the two supervised arms of the study were visited daily (DS) or twice-weekly (TS) for a period of 6 wk by a trained study staff member who administered the iron. Unsupervised participants took the iron syrup home and were not visited except for health concerns upon the caregiver’s request.
Study design. The study was a randomized trial using a 2 x 2 factorial design; participants were aware of the treatment assigned. Compounds were randomized so that all children in one compound were assigned to either a daily or twice weekly regimen that was either supervised or unsupervised. A total sample size of 1040 children was estimated to yield at least 80% power at 5% significance to detect a 5 g/L difference in mean Hb at the end of the intervention period between any of the treatment groups, allowing for 20% loss to follow-up, and assuming a mean of 2 children per compound, and a design effect of 2. Secondary end points included hematological recovery, microcytosis, all cause morbidity, clinical malaria, and malaria parasitemia.
Recruitment and randomization. After a census survey in October 2000, caregivers from all compounds containing households with children < 5 y old were invited for screening to a central location in their respective villages. A brief questionnaire was completed, and axillary body temperature and anthropometric indices were measured. Capillary blood samples (0.5 mL) were collected by finger or heel prick into EDTA microtainer tubes (Becton-Dickinson). During screening, Hb concentrations were measured using a portable Hemocue system (HemoCue). Thick and thin malaria blood smears were collected. All children were examined by a clinical officer before enrollment. Acutely ill children, children with Hb < 50 g/L, or children with higher Hb concentrations who were clinically unstable, were referred to the hospital.
After laboratory assessment, children meeting all of the following criteria were eligible for randomization: 1) age 2–59 mo; 2) Coulter Counter Hb 50–109 g/L; 3) asexual parasite count < 20,000/mm3; 4) no history of intake of iron, sulfadoxine-pyrimethamine, or amodiaquine use, or blood transfusion within the last 2 wk; and 5) no known sickle cell disease. Children 2–6 mo of age were included in accordance with the guidelines for the integrated management of childhood illness (42). A computer-generated random number listing was used to sequentially assign eligible children to 1 of 4 treatment groups, using the housing compound as the randomization unit. Balanced block randomization (12 compounds per block) ensured equal distribution in time and space among the 4 treatment groups. The allocation sequence was computer generated by F.T.K. before the start of the study. Assignment to the study groups was independently conducted by M.D.
Children fulfilling the entry criteria were approached the following day for clinical examination and a structured questionnaire was completed to record details of socioeconomic and educational status of the caregiver. Health passports were issued allowing free health care at local clinics and the hospital.
Follow-up. Follow-up samples, smears, and clinical information were collected at the end of the 6-wk intervention period (±1 d). To determine differences in the duration of any treatment effect on Hb levels, children were seen again at 12 wk (±1 d), at which time the same information was collected. At the 6-wk follow-up, caregivers of participants enrolled in the 2 unsupervised groups were asked open-ended and prompted questions (yes/no/don’t know) regarding adherence, whereas all caregivers were asked prompted questions regarding perceived side effects in their children during the intervention period.
During the 12-wk study period, a passive morbidity surveillance system was used to monitor the frequency of clinic and hospital attendance. Study staff members were assigned to each of 3 local clinics and the hospital. Caregivers were asked to report to the clinic with their child when suspecting illness; a morbidity questionnaire was filled out and a medical examination performed.
Children with symptomatic malaria (axillary temperature 37.5°C with any malaria parasitemia) detected at follow-up visits or through passive case detection, and those without fever but with high-density parasitemia (>5000/mm3) were treated according to national guidelines. Children who developed severe anemia (Hb < 50 g/L) or presented with any other severe disease were referred to the hospital for further management. Their study drugs were discontinued because they all received daily iron from the hospital. They were, however, included in the analyses on a per-protocol basis. Children who were treated for other nonsevere illnesses during the intervention period continued to receive study treatments. Children who were anemic at 12 wk were given another dose of SP and 6 wk of daily iron supplementation.
Laboratory methods. An ACT 10 Coulter Counter (Coulter, Serial no. AD04108) was used to obtain Hb and mean corpuscular volume (MCV). Although Hb was also assessed by HemoCue in the field on the day of screening, only Hb values assessed by Coulter Counter at baseline and follow-up were used for data analysis. Thick blood smears were Giemsa stained and Plasmodium parasites were counted against 300 leukocytes/µL and densities presented per microliter assuming a leukocyte count of 8000/µL. Malaria parasitemia refers to the presence of any asexual Plasmodium species detected by microscopy. Serum samples were stored within 6 h at –20°C. Hemoglobin genotype was determined by Hb electrophoresis.
Informed consent. The study was approved by the institutional ethical review boards of the Kenya Medical Research Institute, Nairobi, Kenya, by the CDC, Atlanta, GA, and the Academic Medical Center, University of Amsterdam. Written informed consent was obtained from caregivers for each individual participant.
Statistical analyses. Z-scores for height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ) were calculated using Epi Info. All analyses were conducted per protocol. SUDAAN v8.0 was used for analysis of differences in proportions and medians (Research Triangle Institute), and all other analyses were conducted in SAS v8.0. The intraclass correlation coefficient and related design effect were calculated from an unconditional means model.
The study was designed to assess differences at 6 wk as the primary end point, with a 12-wk follow-up; thus all analyses were conducted separately for these two time points. Differences in mean Hb after 6 and 12 wk from enrollment were assessed by the use of 2 random effects models with supervision, iron regimen, and their interaction as main, fixed effects, and dichotomized baseline Hb and age as covariates. Age was categorized above and below 18 mo [based on results presented in the meta-analysis (32)] and Hb was dichotomized above and below 80 g/L. Standard errors were adjusted for clustering at the compound level. The analytical approach takes into account testing of 2 independent hypotheses, i.e., effect of supervision and dosing regimen. In studies using a factorial design, adjustment for testing 2 hypotheses is not recommended (46). However, because we made 2 comparisons for each treatment at 2 different time points (6 and 12 wk) within each hypothesis, P-values obtained based on a Wald 
2 statistic were adjusted for multiple (4) testing, using a sequential Bonferroni method (47).
For the purpose of this study, severe anemia is defined as Hb concentration < 50 g/L, moderate as 50–79 g/L, and mild anemia as 80–109 g/L (40,48–51). Microcytemia was defined as a MCV value below the age-specific cut-off: 0–5 mo, 70 fL; 6–11 mo, 73 fL; and >12 mo, 75 fL (52). Hematological recovery (Hb 110 g/L for those with mild anemia at enrollment, and Hb 80 g/L for those with moderate anemia at enrollment), absence of microcytemia, and presence of malaria parasitemia at 6 and 12 wk were compared using the 2 test adjusting for clustering at the compound level. The incidences of all visits to the clinic, first or only episode of nonmalaria morbidity (fever and negative malaria smear), or clinical malaria (fever and malaria parasitemia) were calculated based on time up to the episode, the end of the main intervention period (6 wk), or loss to follow-up. Logistic regression was used to assess the effect of treatments on side effects with the presence or absence of the symptom on admission as a covariate.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Hematological response. The interaction term between supervision (supervised vs. unsupervised) and iron regimen (daily vs. twice weekly) was significant (P = 0.03); therefore all subsequent results are presented by the four treatment groups only.
DS was associated with a significantly greater increase in Hb at 6 wk than TS and DU (Table 2 and Table 3), indicating that both the frequency of iron dosing as well as the supervised conditions of the daily dose were significant determinants of treatment efficacy. In the unsupervised groups, the Hb concentrations at 6 wk did not differ between the daily and twice weekly iron supplementation groups, but the concentrations were sustained for longer in the daily group, resulting in significantly higher Hb concentrations at 12 wk (P = 0.02) compared with the twice-weekly group.
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110 g/L) in 29.2 and 34.5% of the study children by 6 and 12 wk, respectively. Almost all children with moderate anemia (50–79 g/L) at enrollment had Hb levels > 80 g/L by 6 and 12 wk (6 wk, 98, 86, 79, and 90%; and 12 wk, 92, 91, 86, and 81% for DS, DU, TS, TU, respectively). In those with mild anemia at enrollment, however, anemia had resolved in only a small proportion of children (6 wk, 43, 34, 28, and 28%; and 12 wk, 46, 41, 34, and 29% for DS, DU, TS, and TU, respectively). The proportion of children experiencing hematological recovery was 54, 42, 36, and 36% at 6 wk, and 55, 49, 42, and 36% at 12 wk for DS, DU, TS, and TU, respectively. Hematological recovery in children administered DS was significantly higher than in the TS group (Table 3). Similarly, the probability of recovery was significantly higher in the DU compared with the TU group at 12 wk, but not at 6 wk (Table 3). Children in the DS group were less likely to be microcytemic at 6 and 12 wk than those in the TS group. Morbidity and adverse effects. The incidence of all-cause sick child visits, clinical malaria, and nonmalaria morbidity reported to the 3 clinics and the local hospital did not differ between the daily and twice weekly treatment groups at 6 and 12 wk (Table 4). Similarly, the prevalence of malaria parasitemia did not differ between the daily and twice weekly iron supplementation groups at 6 and 12 wk.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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One of the main reasons that intermittently administered iron is considered in the control of anemia is the proposed advantage that less frequent dosing results in fewer side effects and may improve compliance. Of note is that Beaton et al. (32) indicated that "supervision," as judged by the reviewers on the subjective impression of "control" in each of the clinical trials, was an important predictor of postintervention anemia prevalence, and more so in the intermittent than in the daily group. It is likely that skipping a twice weekly or weekly dose would have a greater relative effect than skipping one of the daily doses. Our data indeed confirm that difference in adherence between the daily and twice weekly regimens was an important determinant of treatment efficacy, as evidenced by the significant effect modification (P = 0.03) observed between the effects of dose regimens and the degree of supervision. It was in the daily iron regimen, however, and not in the twice weekly group, that a substantial beneficial effect was achieved by administering the dose with direct supervision. This could not be explained by a difference in side effects because the prevalence of gastrointestinal complaints as perceived by the caretaker did not differ among the 4 groups.
The lack of difference in hematological response between the twice weekly supervised and unsupervised groups suggests that low compliance was not a major obstacle to intermittent dosing in this study. The relatively short duration of the intervention may have contributed to the high compliance. A less likely explanation, which cannot be excluded in the absence of a control group administered a placebo, is that neither group benefited from twice weekly iron supplementation and that all improvements in Hb were due to the effects of antimalarial therapy received at enrollment, or seasonal trends. Regression toward the mean is also unlikely to explain these findings because indicators with a low within-subject variability such as Hb (particularly when assessed by Coulter Counter such as in our study) are not susceptible to much regression to the mean. There is, however, ample evidence suggesting that intermittent iron supplementation is efficacious under favorable conditions (15,16,19,20,28,29,32,53).
The majority of the previous studies failed to show a substantial benefit from daily over intermittent iron supplementation in young children (32). The reason for this lack of empirical difference between regimens is unclear. It may reflect a reduction in iron absorption in response to daily high-dose iron supplementation (54), but the existence of a "mucosal block" in humans has been strongly disputed (26). It was suggested that the previous studies were unlikely to detect a difference because they evaluated treatment responses at the end of long intervention periods (8 wk) in subjects with predominantly mild iron deficiency and low grade anemia, eventually resulting in the same optimal Hb levels regardless of the dose schedule used (26). Our study provides further support for the lack of a functional mucosal block in humans. We may have had a greater chance of detecting a difference between daily and twice weekly iron supplementation due to the inclusion of mild as well as moderately anemic children and by focusing on malaria as the main other cause of anemia. We also evaluated a shorter course of iron than previous studies. However, Beaton et al. (32) suggested that the relative difference between the efficacy of weekly and daily iron supplementation appeared to increase, rather than decrease with duration of intervention.
Despite the relatively short duration of iron supplementation, we observed marked increases in Hb by 6 wk in all 4 groups (Table 2). Almost all children (88%) with moderate anemia (50–79 g/L) on enrollment had Hb levels > 80 g/L by 6 wk, including those randomized to the twice weekly groups (84%). The majority of all children enrolled in the study, however, did not resolve their anemia (Hb < 110 g/L; 62% in the supervised daily group), suggesting that longer supplementation is required to increase the overall efficacy. The short course of iron was chosen due to the uncertainty regarding the safety of long-term regimens in this area of intense malaria transmission (33). We found no difference among the 4 treatment groups in the risk of clinical malaria or malaria parasitemia during the intervention period, or the 6 wk thereafter. In a recent randomized controlled companion study, we also found no indication that a longer regimen [3–6 mg/(kg · d) for 12 wk] was associated with a clinically relevant increase in the risk of malaria compared with iron placebo (55). This, together with the limited efficacy of the 6-wk regimen, suggests that the benefits of 12 wk of iron supplementation in children with anemia are likely to outweigh any potential associated adverse effects caused by increased risk of malaria in this area. This is consistent with current recommendations from the International Nutritional Anemia Consultative Group (56,57). Other causes of anemia should also be considered to maximize hematological recovery, including micronutrient deficiencies other than iron, and chronic inflammation unrelated to malaria (51,58–60). In addition, the high prevalence of HIV in this area of Kenya likely contributes to childhood anemia (61).
This study suggests that daily iron supplementation regimens when given as directly observed therapy, or unsupervised, are superior to twice weekly dosing in the treatment of anemia in children < 5 y old. It also suggests that unlike with daily iron, little additional hematological benefit can be expected from administering 6 wk of twice weekly iron supplementation as directly observed therapy. We conclude that similar to earlier recommendations for pregnant women (32), daily dosing should be the regimen of choice in the treatment of mild and moderate anemia in preschool children, irrespective of the level of compliance that can be ensured.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Funded by the Centers for Disease Control and Prevention and the Netherlands Foundation for the Advancement of Tropical Research (NWO/WOTRO; grant no. WV93-273). R.D. was supported by Pennsylvania State University College of Medicine and the Rosenbluth Foundation. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
3 Use of trade names and commercial sources is for identification only and does not imply endorsement by CDC or the U.S. Department of Health and Human Services.
5 Abbreviations used: DS, daily supervised; DU, daily unsupervised; HAZ, height-for-age Z-score; Hb, hemoglobin; MCV, mean corpuscular volume; SP, sulfadoxine-pyrimethamine; TS, twice weekly supervised; TU, twice weekly unsupervised; WAZ, weight-for-age Z-score; WHZ, weight-for-height Z-score.
Manuscript received 17 December 2003. Initial review completed 18 January 2004. Revision accepted 6 February 2004.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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