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Letters to the Editor |
Community Nutrition Program University of Indonesia GTZ/SEAMO PO Box 3852 Jakarta 10038 Indonesia E-mail: gtzseame{at}indo.net.id or gtzseam@ibm.net
Dear Sir:
About 10 y ago the World Health Organization (1) published recommendations on the design of large-scale iron supplementation programs with the aim of reducing the prevalence of iron deficiency anemia in populations of developing countries. One decade later, however, little has changed in the situation of iron deficiency anemia. Supplementation programs, when they exist at all, are largely ineffective for a variety of reasons, the most important being insufficient supply of iron tablets, low coverage of the target population, and poor compliance with tablet intake (2). A regimen that offers the possibility of lower cost, better compliance, and effectively raised hemoglobin concentrations in 2 or 3 mo is therefore surely worth consideration.
From the viewpoint of a clinician, Hallberg (3) appealed for the continued application in supplementation programs of the well-established, although inefficient, daily administration of iron and urged that supplementation on a weekly basis not be considered. His reason for this argument was that daily supplementation would provide a more rapid response in the treatment of anemia because the total amount of iron absorbed from a given dose would be 
6 times larger from a dose divided into daily administrations than from a corresponding weekly dose.
Community-based studies in children and nonpregnant women from China (4), Bolivia (5), Indonesia (6–8), and Vietnam (9), however, did not show a marked difference in hemoglobin response to weekly or daily iron supplementation. The existence of mild-to-moderate rather than severe anemia, a long duration of supplementation, and high doses of iron were mentioned by Hallberg as reasons daily supplementation did not have a better effect on hemoglobin status than weekly supplementation in the these studies. First, the anemia prevalence of the studied populations was 20–50%, which is typical for populations in developing countries that are generally considered in need of supplementation (1). Although the prevalence was high, most subjects had mild-to-moderate forms of anemia. Nevertheless, a high prevalence of even mild degrees of anemia (hemoglobin: 90–110 g/L) has profound consequences for human development (1). Second, the duration and the dose of the daily iron supplementation were in line with recommendations for iron supplementation programs made by the World Health Organization (1). The duration of an intervention in a long-term prevention program should not be judged by comparison with a short-term therapeutic response, even though the studies also showed an adequate therapeutic response over the period of observation.
Hallberg also argued that hemoglobin concentrations would rise faster if high amounts of iron were given on a daily basis. This argument is valid and important for therapy in individuals with severe anemia in a hospital setting. However, speed of recovery has less importance in programs aimed at broad coverage, for which factors such as distribution, cost, and compliance are of high importance.
To date, only one study has been published on the effect of weekly supplementation in pregnant women (10). Hallberg laments the lack of a control group in this study and even doubts the ethical correctness of trials without a placebo group. This remarkable statement again uncovers conceptual differences between clinical theory and practical reality. The recommendation to include a placebo group may be relevant for clinical efficacy trials but is unethical in operational research in countries such as Indonesia where every pregnant woman is entitled to receive iron supplementation according to law. Hallberg also points to the low increase in hemoglobin concentrations in both the daily and weekly intervention groups (10). Although this is true, this study was carried out under program circumstances in which tablet intake was not supervised and under these conditions the effects of weekly and daily supplementation were not significantly different.
Innovation is required to solve the repeated problem of low effectiveness of daily iron supplementation programs under practical conditions. Studies published to date indicate that weekly supplementation may be a much cheaper option (11) for improving the iron status of children and nonpregnant women because it reduces anemia prevalence similarly to daily supplementation when used for the currently recommended duration. Because of the lack of completed studies, however, conclusive recommendations for pregnant women must await additional efficacy and effectiveness studies.
This is not the first and will not be the last discussion resulting from the misleading assumption that clinical experience with treatment can be uncritically applied to practical, population-based interventions. It is important to draw a clear line between appropriate therapy of moderate-to-severe anemia in individuals and cost-effective population-based programs. Let us recognize that apples are apples, and pears are pears. Both are valuable fruit and are tasty when eaten at the right moment of ripeness. But don't try to make an apple pie from pears!
REFERENCES
Institute of Internal Medicine Department of Clinical Nutrition Sahlgrenska University Hospital University of Göteborg Annedalsklinikerna S-41345 Göteborg Sweden
Dear Sir:
It is obvious that Schultink and Gross misunderstood the essence of my critique of their recommendation to give iron weekly in combating iron deficiency (1). The concept that weekly administration of iron would be as effective as daily administration was based on the hypothesis that there is a mucosal block in the absorption of therapeutic doses of iron that makes a continuous (daily) supply of iron unnecessary, redundant, and irrational. As shown in my critical review (1), however, there is no such mucosal block during iron therapy in humans and thus no foundation for the concept of giving iron weekly. Actually, there is good quantitative evidence from 2 research groups that 6 times more iron is absorbed from daily doses than from weekly doses of the same total amount of iron (2, 3). At first glance it was then surprising that the therapeutic response—the increase in hemoglobin concentration—was almost the same after weekly compared with daily administration of iron in several studies. A reasonable explanation for these paradoxical findings, as pointed out in my analysis of these studies, is that the doses of iron given were high, the treatment periods were long, and the subjects included in the studies had only mild anemia. Because hemoglobin concentrations can reach only individual optimal concentrations, no valid comparisons of the efficacy of the 2 treatment models can be made; the therapeutic response can be expected to be the same under the conditions used. It would be expected, for example, that lower daily iron doses or much shorter treatment periods would result in the same increase in hemoglobin. Moreover, under such conditions even better compliance would be expected at a lower cost than that for administering high doses of iron weekly.
The arguments for weekly administration of iron used by Schultink and Gross are the "low effectiveness of daily iron supplementation programs under practical conditions" and that "innovation is required." It is certainly true that great efforts must be made to improve iron supplementation programs, especially in developing countries. For example, the delivery system of tablets must be improved so that tablets reach the target subjects; it is also desirable to improve the pharmaceutical properties of the iron tablets to increase their efficacy and reduce side effects. It is time to take new initiatives in this area (4). A further important area for research, initiated for example by the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF), would be the development of better methods to motivate subjects to take tablets, for example, during pregnancy. I certainly share the disappointment of Schultink and Gross that so little has been done to combat iron deficiency by the WHO, UNICEF, and the countries involved. It is important to emphasize, however, that a change to the less-efficient weekly administration of iron would not solve the key problems of good efficacy, adequate tablet distribution, and high motivation.
Schultink and Gross do not seem to understand that before starting national or regional supplementation programs or any diagnostic, prophylactic, or therapeutic program, it is important to critically examine the effectiveness of such programs, including costs. This is not just a clinical approach that is "uncritically applied to practical, population-based interventions." The use of carefully controlled studies, with inclusion of groups given placebo, is a standard not only in clinical trials but also in field studies in developing countries. This fundamental approach has been discussed in detail in different publications from the WHO over the years on the basis of work of experts from countries where iron deficiency anemia is both common and severe and is not based solely on the work of so-called "clinicians." In all these reports and recommendations it is clearly stated that subjects should first be divided into groups according to severity of anemia (because the therapeutic response is related to the severity of anemia) and then be randomly allocated to different groups that will be given, for example, different doses of iron. It is also clearly emphasized that one of the groups must be a placebo group so that both effects and side effects can be evaluated (5–7). For ethical reasons, those with more severe iron deficiency anemia are excluded. The cutoff for severe iron deficiency anemia is different in different countries. In some of the Indian studies (8) and in the WHO reports (5, 6) the limit was set at a hemoglobin concentration of 80 g/L. In other studies cutoffs as high as 
120 g/L were used (9). The details of the experimental design may also vary in different studies, for example, if the role of folate deficiency is also tested or if the effects of hookworm infestation are excluded.
The statement that controlled studies of pregnant women are not allowed in Indonesia is surprising. Even so, controlled studies can be carried out in any of the many other countries where daily and weekly administration of iron have been compared. The strict attitude of the ethics committees in Indonesia toward assignment of pregnant women to placebo groups makes it hard to believe that iron supplementation with a dose associated with one-sixth of the absorption of daily doses could ever have been approved.
The development of good iron supplementation programs is important considering our increasing awareness of the importance of an optimal supply of iron in infants, children, and adolescents. It is important that future work in developing countries be based on adequate, carefully controlled studies. The metaphor that such studies are apples and the ones carried out by Schultink and Gross are pears does not necessarily form a good basis for a fruitful discussion of an important topic.
REFERENCES
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  M. R. Desai, R. Dhar, D. H. Rosen, S. K. Kariuki, Y. P. Shi, P. A. Kager, and F. O. ter Kuile Daily Iron Supplementation Is More Efficacious than Twice Weekly Iron Supplementation for the Treatment of Childhood Anemia in Western Kenya J. Nutr., May 1, 2004; 134(5): 1167 - 1174. [Abstract] [Full Text] [PDF]
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Z. Mumtaz, S. Shahab, N. Butt, M. A. Rab, and A. DeMuynck Daily Iron Supplementation Is More Effective than Twice Weekly Iron Supplementation in Pregnant Women in Pakistan in a Randomized Double-Blind Clinical Trial J. Nutr., November 1, 2000; 130(11): 2697 - 2702. [Abstract] [Full Text] [PDF]
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