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Rapid Responses: Rapid Responses published:
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Iron supplementation and infection: another important issue remains to be answered
- Luis Huicho (18 November 2002)
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What about parenteral iron in Neonates?
- David M J Barry (18 November 2002)
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Analysis failed to take account of clustering
- Adam Jacobs (23 November 2002)
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Reply to Two Rapid Responses
- tarun gera, h p s sachdev (20 December 2002)
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Re: Analysis failed to take account of clustering
- tarun gera, h p s sachdev, clive osmond (20 December 2002)
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Iron supplementation - weigh the balance!
- Ravinder PS Makkar (21 January 2003)
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Luis Huicho, Professor of Paediatrics, Universidad Nacional Mayor de San Marcos and Instituto de Salud del Niño Av. Brasil 600, Lima 5, Peru
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The systematic review of Gera and Sachdev is an important contribution that reassures the safety of giving iron to anaemic children.
Another issue for which there is not enough information based on sound clinical research is if, in children with an active infection, iron supplementation increases the risk of aggravating it. Current recommendatios support withholding iron supplementation until the infection has been abated, particularly in children with severe malnutrition. Probably it is convenient to continue adhering this recommendation until more information confirms it is adequate or not. Maybe it is time to perform randomized controlled trials in children with iron deficient anaemia and infection, allocating them to either iron or placebo. Competing interests: None declared |
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David M J Barry, Senior Paediatrician Hawkes Bay Regional Hospital, Hastings, Hawkes Bay New Zealand
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This comprehensive article about iron gives good advice about oral iron medication but it and the editorial fail to address serious/fatal complications with the use of intramuscular iron in the newborn(Barry and Reeve).Furthermore the paper from Cantwell quoted in the article and showing minor side effects following parenteral iron only studied morbidities outside the neonatal period. We studied Cantwell's original pilot group and a larger group of babies treated in the same way with iron injections.Neonatal sepsis,mainly E.Coli occurred in 22/1000 of the iron treated group. The apparently contrary findings in our study and that of Cantwell have been noted before (Oppenheimer) and explained(Barry 1991) The prevention and treatment of iron deficiencey in infancy is important but it has not been shown that this can be achieved safely by parenteral loading during the neonatal period. D M J Barry Barry DMJ, Reeve AW. Increased incidence of gram negative neonatal sepsis with intramuscular iron administration.Pediatrics 1977;60:908-12 Oppenheimer SJ.Iron and infection:The Clinical evidence.Acta Paediatr Scand 1989;78,Suppl 361:53-62 Barry DMJ Iron and infection.Acta Paediatr Scand 1991 80:573-580 Competing interests: None declared |
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Adam Jacobs, Director Dianthus Medical Limited, London SW19 3TZ
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Gera and Sachdev say that they cannot explain the substantial statistical heterogeneity they found in their meta-analysis of iron supplementation. I think I can. We are told that they collected data on 7892 children, but figure 1 of their paper shows us that the number of infective episodes was about 3 times that number. Therefore, many children would have had several infective episodes each. However, their calculation of incidence rate ratios appears to have been done at the level of the individual infective episode, rather than at the level of the child. Their analysis was therefore flawed, as it did not take account of the clustering that would be expected within children: in other words, individual infective episodes within the same child are not statistically independent, but were nonetheless treated as such in the analysis. The failure to take account of within-subject clustering in this way has three effects on the analysis. First, it gives confidence intervals for each individual study that are too narrow. The confidence intervals shown in figure 1 of the paper are therefore misleading. Second, it may also affect the confidence interval for the pooled rate ratio (and rate difference). This is particularly worrying if it has much of an effect on the confidence interval, as it is this confidence interval on which the main conclusion of the paper is based. Third, it will lead to a substantial overestimate of the heterogeneity of the studies. Gera and Sachdev are right to attempt to explore the heterogeneity they found in their analysis, as heterogeneity can suggest important differences among the studies that might have an important bearing on the outcome, such as the route of administration. However, they may be wrong in their assertion that the heterogeneity really exists. It would be interesting to see if the heterogeneity remained statistically significant if they were to repeat their analysis in a manner that takes account of the clustering: I suspect it would not. Finally, it would also be of interest to know whether the pooled estimate of the effect of iron supplementation and its confidence interval changes much when the correct analysis is done, as that would show whether the main conclusion of the paper is affected. Competing interests: None declared |
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tarun gera, senior resident maulana azad medical college, h p s sachdev
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Re: Iron supplementation and infection: another important issue remains to be answered The issue raised by Huicho is important from clinicians’ perspective. We agree that there is an urgent need to generate evidence on this issue to guide clinical practice. Re: What about parenteral iron in Neonates? We are happy that Barry found our article comprehensive and useful, especially with regards to oral medication. With respect to the specific issue raised, as per the predetermined inclusion criteria we could locate only three studies in which iron was administered parenterally. The quoted study by Barry and Reeve was identified by us in the preliminary screening but not included, as this non-randomized trial had evaluated a retrospective cohort for comparative purposes. In the absence of details of the other data (extension of Cantwell’s original pilot group) being cited by Barry, it is not possible for us to comment on it. In our systematic review, on a stratified analysis for the parenteral route of administration no significant difference was documented in the ‘overall’ incidence of infectious illnesses in the iron supplemented and control groups (IRR= 0.94; 95% CI= 0.67, 1.31; p= 0.70). Amongst the three studies of parenteral route of dispensation included by us, neonatal subjects were given iron in only one trial (Cantwell et al) (1). The specific issue of safety of parenteral iron administration in the neonatal age group cannot be conclusively addressed by this trial alone and we have also not attempted to do so. Also in the absence of a placebo injection group, it cannot be conclusively determined if any observed complication was the effect of iron or the injection process. Reference: 1. Cantwell RJ. Iron deficiency anaemia of infancy: Some clinical principles illustrated by the response of Maori infants to neonatal parenteral iron administration. Clin Pediatr 1972; 11: 443-449. Tarun Gera, Senior Resident H.P.S. Sachdev, Professor Division of Clinical Epidemiology, Department of Pediatrics, Maulana Azad Medical College, New Delhi 110 002, India, Correspondence to: H.P.S. Sachdev
Competing interests: None declared |
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tarun gera, senior resident maulana azad medical college, h p s sachdev, clive osmond
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Jacobs raises an interesting statistical issue. However, our objective was to evaluate the effect of iron supplementation on the incidence of infectious illnesses in children. From a clinical perspective, we are of the opinion that the disability and economic impact of each episode is equally relevant, irrespective of the fact that some individual episodes may be clustered in certain children. With this reasoning, statistical adjustment for the expected clustering within- children is not important. In order to account for the within-subject clustering, one would need to know at the very least the frequency distribution of the numbers of infections in each arm of the trial. Unfortunately, this information can be extracted from only one of the twenty-eight included studies, and that too in a condensed form. Other factors, like the duration of follow-up period, the precise age at acquiring the infection and gender can also influence the frequency distribution of number of infections. This information is not available in any of the studies. We are therefore not in a position to address this theoretically interesting criticism of our analysis. Tarun Gera, Senior Resident H.P.S. Sachdev, Professor Division of Clinical Epidemiology, Department of Pediatrics, Maulana Azad Medical College, New Delhi 110 002, India, Clive Osmond, Senior Statistician Medical Research Council Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, U.K. Correspondence to: H.P.S. Sachdev
Competing interests: None declared |
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Ravinder PS Makkar, Attending Physician Sitaram Bhartia Institute of Science & Research, New Delhi-110016, India
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The systematic review by Gera and Sachdev seems to have put to rest the long standing debate over the interaction of iron and infections in the clinical setting. The article gives a clear message to the medical community and health-nutritionists at large that iron supplementation has no harmful effect on the overall incidence of infectious illnesses in children, and that iron supplementation in safe. But at the same time, considering the potential role of iron in several oxidant related perinatal disorders, it needs to be stressed that indiscriminate iron supplementation is not without dangers. It is known that at high intake levels, the homeostatic regulatory mechanisms required to down-regulate the absorption of iron are insufficient to prevent accumulation of high iron stores and can lead to iron overload states (1,2). Though low, there is a potential but real risk of iatrogenic iron overload by indiscriminate iron supplementation, especially in those geographic and ethnic regions where hereditary hemochromatosis and hemoglobinopathies e.g. thalessemia are common as in African blacks (3). The controlled study by Murray et al (reference 12 in the article) among the Massaii tribals of Africa showed that administration of iron to correct their dietary iron deficiency sharply increased their susceptibility to E. histolytica infection and led to increased incidence of amoebiasis. Also, the high iron stores can be a risk factor for hepatic amoebic abscesses as was seen by Bothwell et al (4) in their study in which iron overload was found to be more common in black patients with hepatic amoebiasis than in the general population. It is also known that the high iron stores in the liver are responsible for increased incidence of Yersinia enterocolitica infection in the liver in the form of multiple pyogenic abscesses (5). Indiscriminate iron supplementation can also facilitate hepatitis C infection as seen by the fact that hepatitis C replication increases 10 times in the presence of iron (6), and therefore there is a reason to believe that hepatitis C infection is more common in alcoholics, partly because the alcohol-induced hepatic iron load (7); though the assumption needs a case-controlled study. The issues raised by Huicho and Barry on the role of iron supplementation during active infection and the use of parenteral iron in neonates respectively, have also been rightly addressed and need further studies for issuance of safe guidelines for iron supplementation at population levels. At present, the safety concerns of iron supplementation must be weighed against the real need to correct iron deficiency. The mass supplementation programs should be planned keeping in mind the prevalence of hemoglobinopathies to avoid iatrogenic iron overload. The iron fortification programs need to include provisions against iron overload, and it is strongly recommended not to increase iron intake beyond physiological requirements. Adequacy of iron supplementation should be based on the amount of iron needed to sufficiently achieve target hemoglobin and hematocrit levels of around 11-12 g/dL and 33-36%, respectively (8). 1.Schumann K. Safety aspects of iron in food. Ann Nutr Metab 2001;45(3):91-101. 2.Omara FO, Blakley BR, Wanjala LS. Hepatotoxicity associated with dietary iron overload in mice. Hum Exp Toxicol 1993;12(6):463-7 3.Schumann K, Elsenhans B, Maurer A. Iron supplementation. J Trace Elem Med Biol 1998;12(3):129-40. 4.Bothwell TH, Adams EB, Simon M, Simjee AE, Kallichurun S, Gathiram V. The iron status of Black subjects with amoebiasis. S Afr Med J 1984; 65(15): 601-604. 5.Hart HH. The potentiation of yersinial infections in iron storage disorders. Hepatology 12(2): 370-372, 1990 6.Kakizaki S, Takagi H, Horiguchi N, Toyoda M, Takayama H, Nagamine T, Mori M, Kato N. Iron enhances hepatitis C virus replication in cultured human hepatocytes. Liver 2000 ;20(2):125-128 7.Vento S, Cainelli F. Does hepatitis C virus cause severe liver disease only in people who drink alcohol? Lancet Infect Dis 2002 ;2(5):303-309. 8.Schumann K, Borch-Iohnsen B, Hentze MW, Marx JJ. Tolerable upper intakes for dietary iron set by the US Food and Nutrition Board. Am J Clin Nutr 2002 ;76(3):499-500. Competing interests: None declared |
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