Effect of iron supplementation on incidence of infectious illness in children: systematic review
BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7373.1142 (Published 16 November 2002) Cite this as: BMJ 2002;325:1142All rapid responses
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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
Competing interests: No competing interests
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
E-mail: hpssachdev@hotmail.com
Competing interests:
None declared
Competing interests: No competing interests
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
E-mail: hpssachdev@hotmail.com
Competing interests:
None declared
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
Iron should not be supplemented in isolation in malnourished children and pregnant women
It is an established fact that iron supplementation reduces
anaemia. But in malnourished children, especially severely
malnourished children (with protein-energy and vitamins deficiencies), iron
alone would cause oxidative stress and aggravate an already bad condition.
This has been shown in a rat model (1) and during pregnancy in placental
tissue (2, 3). We hypothesize that proteins should be administered in
severely malnourished children so that iron is bound and is slowly made
available for haematopoeisis and to correct anaemia.
It has been shown in clinical trials (4, 5) that the condition of iron deficient
children suffering from Malaria and other infections worsens with iron supplementation. The same is true with anaemic pregnant women
when iron is supplemented without addressing their protein needs (2,3,4,5).
References:
1. Srigiridhar, K., Nair, K. M., Subramanian, R. & Singotamu, L.
Oral repletion of iron induces free radical mediated alterations in the
gastrointestinal tract of rat. (2001). Mol. Cell. Biochem. 219: 91-98
2. Lachili B, Hininger I, Faure H et al. Increased lipid peroxidation
in pregnant women after iron and vitamin C supplementation. Biol Trace
Elem Res. 2001 Nov;83(2):103-10
3. Aune Rehema, etal. Ferrous iron administration during pregnancy
and adaptational oxidative stress (pilot study). Medicine (kaunas) 2004,
40 (6), 547-552
4. M J Murray, Anne B Murray, Megan B Murray, C J Murray. The adverse
effect of iron repletion on the course of certain Infections. British
Medical Journal, 1978, 2, 1113-1115
5. Lora L Iannotti, James M Tielsch et al. Iron supplementation in
early childhood: health benefits and risks. Am J Clin Nutr 2006;84:1261-
76.
Competing interests: No competing interests