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Green College, Oxford, UK
| ABSTRACT |
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KEY WORDS: iron infection malaria morbidity clinical trial
| INTRODUCTION |
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Although this failure may be mainly one of implementation, one
often-mentioned contribution to the problem is the unresolved
concern as to the interaction among iron status, iron supplementation
and susceptibility to infection (Dhur et al. 1989
,
Farthing 1989
, Hershko et al. 1988
,
Hershko 1993
, Oppenheimer and Hendrickse 1983
, Oppenheimer 1994
and 1998
,
Scrimshaw and San Giovanni 1997
). This difficult subject
has been polarized by partisan claims either that iron deficiency
always helps (the so-called nutritional immunity hypothesis
[Kochan 1973
, Weinberg 1978
]) or always
hinders defenses against infection.
The early prospective intervention studies conducted in deprived
populations of temperate, developed countries tended to support the
value of iron supplements in reducing rates of respiratory infections
in infants (Andelman and Sered 1966
, Cantwell 1972
, MacKay 1928
). This rosy picture was not
sustained with intervention studies published from the late 1970s on.
Side effects of treatment, particularly with parenteral iron, were one
problem, and later reports from the tropics seemed to indicate a
deleterious effect on susceptibility to both malaria and respiratory
infections, thus emphasizing the fact, already
known from animal studies, that different organisms interact
differently with iron in their hosts.
The malaria issue has dominated the picture since the 1970s, and few
significant studies evaluating systematic iron supplementation and
infectious morbidity in nonmalarious areas were published in the 1980s.
The controversy has been compounded by the lack of adequate control in
earlier published prospective clinical intervention studies and the
practical impossibility of conducting adequately controlled
nonintervention (i.e., observational) studies in iron-deficient
humans. Even laboratory measures of iron deficiency are grossly
confounded by the immediate presence of infection (Oppenheimer and Hendrickse 1983
).
The result has been that although experimental iron deficiency in animals and in vitro functional effects on immunity in humans have been usefully studied for decades, numerous clinical reviews still seem unable to make clear quantitative statements about how important iron deficiency is to human infectious morbidity. Although more controlled studies must be done, there is still useful information to be gleaned from the literature as long as the older intervention studies are not all rejected out of hand because of design faults.
| Criteria for inclusion of studies and evaluation of a relationship |
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A preexisting database of reports (Oppenheimer 1994
and 1998
) was supplemented with the use of the following:
1) MEDLINE search, using combinations of the keyword
"iron" crossed separately with "supplement," "infection,"
"trial" and "immunity"; the results were hand-searched;
2) personal communications with workers involved in existing
trials; and 3) search of the Cochrane Controlled Trials
Register. All studies mentioning infectious outcome were reviewed, but
only controlled studies with quantified clinical infectious morbidity
are discussed here. The only further exclusions from the latter were
studies in which another micronutrient apart from iron was combined
with iron as an intervention but not given to the placebo group.
Design, participant selection and multiple outcomes of these studies
were so qualitatively heterogeneous that meta-analysis may have
limited meaning, and this review concentrates on the possible
ecological reasons for the different outcomes. To obtain some
consistency in tabular and graphic presentation of outcomes, however,
odds ratios
(OR)3
[with a fixed-effects model and 95% confidence intervals
(CI)RevMan 4.0.4 (Cochrane Collaboration)] based on the dichotomous
contingency "no morbid event vs. one or more events" per
individual, over a stated time periodare given, where published
data allow. In some studies, this contingency is not available because
total morbid events rather than individuals were given as the
numerator. If OR could not be calculated from available information,
the actual published rates, relative risks or both are quoted in tables
only and omitted from OR plots. In several studies, follow-up
wastage was high, thus introducing potential systematic bias in rates.
For these studies, therefore, realistic average surveillance
denominators are estimated from available information. Only clinically
relevant morbidity outcomes are cited. Functional laboratory
immunological outcomes and malarial parasite prevalence rates have been
dealt with elsewhere (Dhur et al. 1989
, Farthing 1989
, Hershko 1993
, Oppenheimer and Hendrickse 1983
, Oppenheimer 1994
and 1998
,
Scrimshaw and San Giovanni 1997
, Shankar et al. 2000
).
During the review of studies, subsidiary questions were addressed, such as whether potential causal effects are graded and what, if any, are the laboratory measurements that predict the morbidity outcome most closely. In the absence of clear answers to the primary questions in humans, such issues can only be flagged, not answered.
Before the discussion of interventions, an overview will be made of the in vitro evidence for functional immunological effects of iron deficiency and supplementation along with evidence for how this interfaces with specific infections. This is supplemented by a review of nonintervention iron deficiency and morbidity reports.
| In vitro studies of iron deficiency and functional immunity |
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Proteins in iron metabolism.
The third set of defense systems that are uniquely associated with iron metabolism are cellular and extracellular iron-binding proteins (transferrins and lactoferrin). These inhibit bacterial growth by withdrawing iron.
Almost 30 years ago, Bullen et al. (1972)
showed that
the bacteriostatic action of human milk is abolished by in vitro
addition of iron. In this context, Murray et al. (1980)
showed an increase in Entamoeba histolytica infection in
nomads who drank cows milk during supplementation with oral iron.
This was not seen in the nonrandomized control group or in those
receiving parenteral iron. They related the effect to saturation of the
cows milk lactoferrin by oral iron.
Cows milk formulas contain no active lactoferrin, and therefore iron
fortification in theory should not compromise artificially fed infants.
However, there has been debate about the advisability of giving oral
iron to breast-fed infants. One thing that is clear is that formula
milk, with or without iron, can carry a higher risk of infectious
morbidity than breast-feeding in deprived communities
(Heresi et al. 1995
). Lonnerdal et al. (1980)
pointed out that because the bulk of the iron in breast
milk is not attached to lactoferrin and yet is highly bioavailable for
the infant, an alternative method of oral iron supplementation for
infants might be to supplement lactating mothers.
"Nutritional immunity."
The growth of a variety of bacteria and fungi are inhibited in vitro by
transferrin and lactoferrin (Kochan 1973
,
Weinberg 1978
). The thesis of nutritional immunity
elaborates this well-known defense mechanism by arguing that
"further lowering of the saturation of iron in transferrin or
lactoferrin further enhances immunity." In practice, however, this
thesis appears to have been overstated for extracellular microbial
pathogens (Oppenheimer and Hendrickse 1983
). Virulent
invasive pathogens usually have their own powerful siderophores that
are quite capable of removing iron from transferrin, whereas less
virulent opportunistic infections such as Escherichia coli
are equally inhibited from growing in plasma over a wide range of
transferrin saturations, corresponding to different physiological
states of iron balance (Oppenheimer and Hendrickse 1983
). In other words, iron-deficient individuals may not
be especially protected from such opportunistic infections. Equally,
lowered transferrin saturation does not affect the virulence of
disseminating organisms with high iron avidity (Oppenheimer and Hendrickse 1983
).
One group of microorganisms with an iron requirement in a special
situation in relation to iron availability comprises the erythrocytic
forms of malaria. Although inside cells with the highest iron content
in the vertebrate body, plasmodia are apparently unable to use this
source effectively nor do they seem able to extract
transferrin-bound iron from the plasma surrounding the red cells.
Much work over the past 15 years has centered around the observation
that iron chelators can inhibit malarial growth in vitro as well as in
vivo (Hershko et al. 1988
). A recent in vitro study
appears to confirm the longstanding theory that a small labile pool of
iron in red cells (which may be crucially smaller in people with iron
deficiency) provides the iron the parasite requires (Loyevsky et al. 1999
). This may provide one mechanism that underlies
clinical observations suggesting that iron deficiency may protect from
malaria.
The qualitative differences between iron-pathogen interactions in
the extracellular compartment and those that are intracellular have
recently been refocused by study of the natural resistance associated
macrophage proteins (NRAMP 1, 2) and the role of NRAMP 1 in resistance
to infection by actively removing intracellular iron. NRAMP 1 targets
the membrane of microbe-containing phagosomes in macrophages and
monocytes. Allelic variants of NRAMP 1 have recently been found to be
associated with susceptibility to tuberculosis and leprosy in humans
(Canonne-Hergaux et al. 1999
). This finding may be
relevant to the differential susceptibility of people to infection by
intracellular pathogens according to their iron status.
To summarize in vitro evidence, iron deficiency depresses certain aspects of cell-mediated immunity, including lymphocyte, neutrophil and macrophage function; humoral immunity is unaffected and the significance of hypoferremia (as opposed to normal transferrin saturation) on growth of microorganisms is uncertain. In contrast, one group of intracellular organisms, Plasmodia, may have a specific disadvantage in iron deficiency. Because there are conflicting effects of deficiency and treatment on defense systems, it becomes more important to study the situation in vivo.
| Observational studies on iron deficiency and infectious morbidity |
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In vivo studies in iron-deficient animals.
In view of the potential problems of confounding when relating iron
deficiency to immune status in humans, it is worthwhile looking at the
more controlled observations available from animal studies.
Experimental studies in laboratory animals uniformly show reversible
deleterious effects of iron administration on tests of functional
immunity. These may occur even in mild deficiency. Reports of graded
effects are contradictory (Dhur et al. 1989
,
Scrimshaw and San Giovanni 1997
). The picture is not
clear, however, with experimental studies of effects on morbidity.
Experimental studies of infectious challenge and subsequent morbidity
in iron-deficient animals have produced conflicting results
(Dhur et al. 1989
). Hart et al. (1982)
using Proteus mirabilisinduced pyelonephritis in rats
showed differential effects, with severe iron deficiency protecting
less than mild deficiency. Baggs and Miller (1973)
claimed that severe deficiency enhanced defenses in rats against
invasive Salmonella, whereas mild deficiency impaired them.
Preweaning iron deficiency produced permanent immune defects.
Puschmann and Ganzoni (1977)
showed increased resistance
of iron-deficient mice to invasive Salmonella
typhimurium infection, whereas Chu et al. (1976)
showed an increased mortality of severely iron-deficient rats
infected with Streptococcus pneumoniae compared with
controls. Harvey et al. (1985)
showed reduced
parasitemias and reduced mortalities in iron-deficient mice
infected with Plasmodium chabaudi. Perhaps the only
partially unifying message to be gained from these studies is that
effects are microorganism specific and that iron deficiency may be more
likely to protect against intracellular than extracellular pathogens.
Observational studies in iron-deficient humans.
Because of problems of control and confounding, few observational
clinical studies in iron-deficient humans convincingly relate such
deficiency to substantial morbidity due to infections. Some studies
have noted anemia in children admitted to hospital for various
infections, but these data could not establish causality (Kaplan and Oski 1980
, Lovric 1970
, Oppenheimer 1980
). Higgs and Wells (1973)
noted that of 31
patients with chronic mucocutaneous candidiasis, 23 were iron deficient
and 9 of 11 improved with oral and parenteral iron therapy alone, with
a regression of oral lesions and development of delayed
hypersensitivity to Candida. There was no control group. In
another report, 16 patients with recurrent staphylococcal furunculosis
also had nonanemic iron deficiency. Furunculosis resolved after 34 wk
of iron therapy in all but one patient (Weijmer et al. 1990
).
In one prospective study, postoperative complications, in particular,
infections after abdominal surgery, were reported to be significantly
more common in 228 patients with low preoperative serum ferritin
compared with 220 patients with normal ferritin; confounders including
hemoglobin levels were taken into account in the analysis (Harju 1988
). Reports from the tropics are difficult to evaluate
because of limited ascertainment of the causes of anemia. In an often
misquoted study, Masawe et al. (1974)
reported fewer
bacterial infections in patients admitted with simple iron deficiency
anemia than in a control inpatient group with a variety of other causes
of anemia (megaloblastic and refractory), but they also reported more
frequent malaria in the iron-deficient patients (8 of 16 cases
after initiation of therapy). Unfortunately, they did not give details
of which patients were receiving oral or parenteral therapy or whether
patients had received therapy before admission.
In their report of the effects of iron treatment in Somali nomads,
Murray et al. (1978)
also noted that nomads entering a
feeding camp had no infections if they were iron deficient
(n = 26) in contrast to a high rate of infection in
those with normal iron status (19 of 64). This unblinded study is
difficult to assess. In contrast, Snow and colleagues
(1991)
attempted to determine whether measurement of iron
status in 1- to 9-y-old Gambian children before the start of the
malaria transmission season could predict malarial experience and
morbidity during that season. They did not find a significant
correlation between any hematological measures of iron status and
subsequent malarial experience in this older age group.
Possible evidence for a protective effect of low iron stores at birth
on subsequent malarial morbidity was obtained in a prospective study
conducted by the author in Papua New Guinea (described in more detail
below) (Oppenheimer et al. 1986a
and 1986b
). Infants
with lower hemoglobin values at birth were less likely to have malaria
at field follow-up and less likely to be admitted to hospital
during y 1 of life. Because birth hemoglobin is the main iron source
during the first year, this association may mean that iron deficiency
protects from malaria and other infections. This association may,
alternatively, have resulted from the associated protective effect of
homozygous single-deletion
-thalassemia, which is present in
>50% of that population. Indeed the high prevalence of
single-deletion
-thalassemia in many tropical areas may have a
confounding effect in many studies of iron, anemia and morbidity
because the mutation both causes anemia and protects against malaria
and other infections (Oppenheimer et al. 1987
).
Allen and colleagues (1997)
showed in a subsequent
case-control study in the same part of New Guinea that people with
homozygous
+-thalassemia were much less likely than controls to
develop severe malaria (OR 0.40; 95% CI: 0.220.74) and to be
admitted to hospital for nonmalarial infections (OR 0.36; 95% CI:
0.220.60).
In the study of Oppenheimer et al. (1986a)
, the
predictive value of hemoglobin measured at birth was an exception to
the generally low predictive value of hematological measures for
subsequent morbidity. Measures of iron status such as hemoglobin,
transferrin saturation and ferritin taken at birth and at 2 and 6 mo
were of no predictive value for subsequent infectious outcome. Changes
in both ferritin and transferrin saturation acted more as
acute-phase responses to acute infection. Use of hemoglobin as a
surrogate for iron status in infectious morbidity studies is thus
clearly fraught with potential for confounding. This was clearly
demonstrated in the large iron intervention study of
Gebreselassie (1996)
in Ethiopia (see also below).
Pretrial cross-sectional assessment of the cohort showed that
anemia was significantly associated with malaria (OR 1.31; 95%CI:
1.031.66), acute respiratory infection (OR 1.33; 95% CI: 1.051.69)
and diarrhea (OR 1.74; 95% CI: 1.282.40). However, no relationship
was detected between the same morbidity indicators and the more
reliable iron measures of mean cell volume and serum ferritin taken at
the same time. Whether the lower hemoglobin of the sick children
resulted from iron deficiency or was secondary to their infections is
therefore not clear.
Confounders in observational studies on iron deficiency.
Clearly there are many problems and differences in design between these observational reports on iron deficiency in the tropics that make it difficult to draw useful conclusions. Another major confounding difference is the age of the study respondents, i.e., younger immune-naive infants appear to show an advantage of low iron status, whereas older semi-immune children do not. Other confounders may interact with immediate effects of iron treatment and will be considered next.
| Iron intervention does not simply reverse iron deficiency |
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Estimation of the effects of iron treatment on body iron compartments
depends on the dose and route of administration and time elapsed since
the start of treatment. There is a massive but short-term
hyperferremia after parenteral administration of iron that lasts up to
3 wk after intramuscular iron dextran (Will 1968
) or
23 d after intravenous iron dextran (Kanakakorn et al. 1973
). Circulating iron dextran complex may be a source of iron
for bacterial growth immediately after injection, and serum
bacteriostatic action is lost during this period. This size of effect
is not seen with oral iron supplementation in normal doses
(Gross 1968
), although gut intraluminal iron may be high
(Murray et al. 1980
). The hyperferremic effect of
parenteral iron is a particular danger during the neonatal period, when
such therapy is contraindicated in all circumstances (Becroft et al. 1977
).
In the 1970s, several poorly controlled studies incriminated iron
therapy in acute exacerbations of preexisting or latent infections. In
most of these reports, parenteral iron was used. The report of
Masawe et al. (1974)
, which included infections after
iron therapy, was already mentioned. Byles and DSa (1970)
, in a poorly controlled study, reported 11 cases of
clinical malaria in 917 pregnant women immediately after parenteral
iron therapy.
In New Zealand, serious E. coli sepsis was reported in the
mid-1970s by Barry and Reeve (1977)
in 2% of Polynesian
neonates who received 250 mg iron dextran at birth (in five daily
doses) (Table 1
). The increase in infections was confined to the week after the last
injections and was detected retrospectively with the attendant problem
of validity. Neonatal sepsis fell to 0.2% after discontinuation of
this practice. A similar finding, also in New Zealand, was made by
Farmer and Becroft (1976)
. In this case it was neonatal
E. coli meningitis that was specifically higher in those
receiving parenteral iron (Table 1
; Fig. 1
). In confirmation of the postulated mechanism, Becroft et al. (1977)
showed a marked reduction in the bacteriostatic action
of serum of these neonates on E. coli in vitro. Despite the
obvious methodological problems of these retrospective studies, the
evidence for increased E. coli sepsis in neonates is strong.
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Although most the above immediate adverse effects were associated with
parenteral therapy, an important and often-quoted study in the
1970s used oral iron. A family team (Murray et al. 1978
)
conducted a prospective placebo-controlled randomized trial of
30 d oral iron supplementation in 137 adult Somali nomads with
iron-deficiency anemia. Iron treatment increased hemoglobin and
transferrin saturation during the study. Although no malaria was noted
at the start of the study in either group, 13 clinical attacks of
malaria occurred in the iron group (n = 71) and only 1
in the control group (n = 67) by the end of the trial;
these attacks were presumed by the authors to be reactivations
(Table 3
). Fevers were significantly more common
in the iron group and eight nomads in the iron group started excreting
Schistosoma ova in the urine compared with no new cases in
the placebo group. The study was single blind, and no follow-up was
made after the 30 d of treatment, although the treatment group
still had high reticulocyte counts and higher transferrin saturations
than the control groups at the end of this period. Documentation of
infections was limited to laboratory identification of a pathogen.
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| Long-term prospective controlled iron intervention studies |
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Prospective studies in nonmalarious areas.
The earliest longitudinal inquiry into the effects of iron
supplementation on infection rates was that of Helen MacKay
(1928)
who reported that infants in London aged 3 wk to 18 mo
given dietary supplements of iron had 50% fewer respiratory and
gastrointestinal infections than infants not supplemented. Odds ratios
estimated from her data showed a significantly reduced risk of
respiratory infections associated with iron supplementation. Both
method of administration (which included fortified milk) and dosage of
iron (
50100 mg/d) varied among infants; unfortunately,
observations on study and control groups were not blinded and, although
covering 1 y in each group, were not made in the same year (Table 1
; Fig. 2
).
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The largest longitudinal study of iron supplementation was that of
Andelman and Sered (1966)
in Chicago, in which 1048
infants were randomly assigned to receive formula milk with or without
iron fortification (
10 mg elemental Fe/L). Follow-up was for 18
mo. Anemia [hemoglobin (Hb)<100 g/L] occurred in 76% of the control
and 9% of the study group. These cases were then unfortunately removed
from analysis. No details of methods of morbidity recording were given,
and mothers recall apparently was used. Odds ratios calculated from
the presented data using estimated denominators show a significantly
reduced risk of respiratory infections associated with iron
supplementation at each 3-mo follow-up to 68 wk (Table 1
; Fig. 2
).
Burman (1972)
conducted a similar placebo-controlled
study using oral colloidal ferric hydroxide (10 mg Fe/d) in Bristol.
Again, methodology of morbidity recording was not elaborated and no
figures were actually given. No differences in illnesses were noted
between the control and study groups, but the small difference in Hb
values between the two groups reached significance only in the 2nd y,
suggesting a low rate of iron deficiency in any case in the placebo
group.
Salmi et al. (1963) reported twice the incidence of infections in the control over the study group in a prospective trial of parenteral chelated iron medication administered to premature infants in Finland. No details were given in the letter.
In a controlled 2-y prospective study in the same population and same
part of New Zealand as the study of Barry and Reeve (1977)
(see above), Cantwell (1972)
studied
Polynesian neonates who had received 250 mg iron dextran at birth (in
five daily doses) and apparently found an opposite effect (Table 1
;
Fig. 1
), namely, 42 and 32% hospitalization rates for infections in
control and iron dextran treatment groups, respectively. These effects
are apparent in the recalculated OR, although they achieve significance
only for the subset of respiratory infections (Table 1
; Figs. 1
2
3
).
The obvious difference between these contrasting reports is in the time
scale studied, i.e., the adverse effects reported in the neonates were
immediate and, although serious, affected a relatively much smaller
proportion of infants than Cantwells finding of beneficial effects
over a longer period. This contrast can be seen graphically in Figure 1
.
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In another study undertaken in Hungary by Hemminki and
co-workers (1995)
, a birth cohort received
iron-fortified milk (6.5 mg/L) and were followed for 1 y. Both
passive and active follow-up by various levels of health care
worker were combined. This intervention failed to find any differences
in morbidity; however, the only morbidity recorded was upper
respiratory and there were no hematological differences between
intervention groups. For these reasons, this study is not included in
tables.
Heresi and colleagues (1995)
conducted a controlled
study using iron fortification of full-fat powdered cows milk
(fortified with 15 mg Fe/100 g compared with unfortified milk) of
infants in Santiago, Chile. Follow-up was from birth to 15 mo of
age. By 9 mo of age, 15% of mothers had changed their children to
breast milk alone. This latter group of children was then observed as a
statistically segregated group. Partial improvement of hematological
status in the test group suggested that iron deficiency anemia in the
control group was inadequately reversed by the level of
supplementation. The authors interpreted the complex subdivided
outcomes as showing a trend of lower infectious morbidity in the
supplemented group and also in the noniron-deficient children from
both groups. However, the former differences were not significant. The
group that clearly did best with respect to lower infection rates was
the group that had changed to breast milk alone; this group had
significantly lower morbidity rates than did either the iron
intervention or control group (Table 1)
.
Milk cereals with and without iron (mean daily intake 4.15.1 mg Fe)
were given to groups of weaning infants (between 122 and 365 d of
life) in a careful but complex 10-cell study conducted by Javaid
and colleagues (1991)
in Pakistan. There was a neighboring
community control group with no nutritional supplementation. Although
the iron was associated with a measurable effect on hematological
values and infectious morbidity was reduced in all
cereal-supplemented groups compared with the control group, there
was no evidence of the iron intervention per se on such morbidity. It
was concluded that the reduction in morbidity was a result of
macronutrient supplementation (Table 1
; Figs. 2
, 3
).
Three nonfood oral iron supplementation studies have given conflicting
results in nonmalarious tropical regions. Chwang and colleagues
(1988)
gave oral ferrous sulfate [10 mg/(kg · d)] to
Indonesian school children in a placebo-controlled, double-blind
study for 12 wk. Infectious morbidity was scored on a composite scale.
Children were assessed as anemic or nonanemic at the start of the study
by hemoglobin and transferrin saturation, thus giving four cells. Those
who were anemic were smaller and had a significantly higher morbidity
score at the start. They were also the stratum that benefited from iron
intervention in terms of significantly reduced infectious morbidity and
improved growth and hematological status as assessed from the analysis
of covariance. The presentation of their results does not allow
calculation of OR; thus the study is not tabulated, but the ratio of
morbidity scores by iron intervention in the anemic subgroup was an
impressive 4.0. This is one of the few studies in the literature to
show an effect of iron intervention on length velocity.
Another oral iron study (Fe 30 mg/d for 2 mo) in Indonesia was carried
out with anemic malnourished preschoolers by Angeles and
co-workers (1993)
. Reductions in rates of fever,
respiratory infections and diarrhea were associated with iron therapy,
although there were small cell numbers and these differences were not
significant (Table 1
; Figs. 2
, 3
). Conversely, Mitra and
co-workers (1997)
gave 125 mg of ferrous gluconate daily
for 15 mo to half of a group of 349 Bangladeshi children aged 248 mo.
No differences were noted in attack rates for diarrhea, dysentery or
acute respiratory infections. The only exception to this was found on
stratification of outcome by age. Children <1 y of age in the iron
group had significantly more episodes of dysentery and more days of
illness with this disease than their placebo counterparts. This last
result could be important because it represents the only hint in the
literature that oral iron may have any deleterious effects for
infection at all in nonmalarious regions. Numbers of infants, however,
were small (iron, n = 34; control, n = 44), and no overall effect was detected in the whole group (Table 1)
.
Overview of iron intervention studies in nonmalarious areas.
In summary, iron intervention studies in nonmalarious regions can be
divided into two types, i.e., parenteral and oral. Parenteral iron
administration at birth carries significant risk of severe sepsis and
meningitis (Barry and Reeve 1977
, Farmer and Becroft 1976
). Delay of this risky practice to the postneonatal
period dramatically reduces such risks. Paradoxically, when
parenterally dosed infants were followed long-term, subsequent
morbidity due to respiratory, gastrointestinal and other infections
was, on balance, reduced (Table 1
; Fig. 1
). This overall direction of
benefit is shared with the oral supplementation studies (Figs. 1
2
3)
.
Oral iron supplementation was delivered by milk or cereal fortification
in six of the studies reviewed. Two large studies carried out earlier
in the past century both indicated that iron fortification carried an
impressively lower risk of respiratory infections and a less clear
reduction in diarrheal disease (Figs. 2
, 3)
. This promise in these
unreliable studies was not realized in four iron food-fortification
studies performed in the 1990s that failed to show effects either way
(Table 1)
. Perhaps the real message to be drawn from the latter studies
was that breast milk is best. Although, in principle, more careful work
is required in nonmalarious regions, it is unlikely in practice that
much more will now be learned with fortification studies. There is a
strong case for iron fortification of formula milk and no evidence at
all that this fortification per se increases infectious morbidity.
If any area is understudied in nonmalarious regions, it is the effect of oral iron supplementation on infectious morbidity in breast-fed infants. Three oral iron therapy interventions to mainly older children gave conflicting results. Two interventions showed a reduction in infectious morbidity and a third did not detect any change except an increase in dysentery in infants.
The least that can be said of the evidence from iron supplementation
studies in the nonmalarious areas in the 1990s is that there is little
or no evidence of harm. The study of Chwang et al. 1988
was the only one to show clear evidence of benefit. From the public
health point of view, arguments for oral iron supplementation in
nonmalarious areas should be determined more by its other known
benefits.
| Long-term studies in malaria-endemic regions |
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The earliest of the prospective studies, the report of Murray et al. (1978)
of infectious recrudescence during iron therapy, has
already been mentioned under immediate treatment effects (Tables 2
and 3;
Fig. 4
). This study followed up only for 30 d, the final observations
coinciding with the end of supplementation.
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A large prospective, randomized, double-blind, placebo-controlled
trial of parenteral iron supplementation in infancy was carried out in
Papua New Guinea, in the early 1980s by Oppenheimer and colleagues (1984a
, 1984b
, 1986a
and 1986b)
. It had been
established that iron deficiency was prevalent among infants in the
study population and that malarial transmission was intense. To avoid
the known risks of iron therapy in the neonatal period (Barry and Reeve 1977
), a single dose of iron dextran (150 mg
elemental iron) was administered at 2 mo of age to the treatment group
(n = 236); control infants (n = 250)
received an injection of sterile pyrogen-free saline. Infants were
reexamined and relevant blood samples were taken 1 wk after the
injection and at 6 and 12 mo of age. All admissions to hospital were
documented (Tables 2
and 3
; Figs. 4
5
6
7
8
).
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Increased malaria associated with increased pneumonia morbidity
rates.
Although increased malaria rates both in hospital admissions and
in the field were the most clearly demonstrable morbid effect of iron
supplementation found in this study, clinical attacks of malaria were a
relatively less common primary reason for admission than acute lower
respiratory infections (16 vs. 63%) (Table 3
; Fig. 6
). All 12 deaths in the study were due primarily to pneumonia (5 iron
group, 7 placebo).
Rates of admission for pneumonia and time spent in hospital with
pneumonia were higher in the iron dextran group (Table 3
; Fig. 6
)
(Oppenheimer et al. 1986b
). Because this conflicts with
the results of longitudinal studies reported previously in infants from
nonmalarious areas, it is worth examining the possibility that malaria
might have had an effect on susceptibility to pneumonia. Indirect
evidence is available for this, i.e., 89% of pneumonia admissions had
evidence of malaria (blood slide positive, significant splenomegaly or
both), a much higher rate than that observed among the study children
in the field. Support for the idea of a promoting effect of malaria on
other infectious morbidity, particularly pneumonia, through a presumed
influence on immune susceptibility comes from a recent study in the
same community (Allen et al. 1997
). Studies with the
permethrin-impregnated bed net have also shown a dramatic reduction
in nonmalarial as well as malarial infectious morbidity, again
supporting the protean nature of malaria (Alonso et al. 1991
). If such a close interaction between malaria and
pneumonia is substantiated, it will go a long way to explain the
opposite effects of iron supplementation on respiratory disease in
temperate and tropical countries. It also underlines the importance of
measuring all infectious morbidity, not just malaria.
Hyperferremic effects of parenteral iron are short-lived. It has been argued that any general interpretation of the results of the Oppenheimer study for iron intervention in malarious areas is limited because a parenteral iron preparation was used. This position may be overstated. At the current state of knowledge, the immediate hyperferraemic effects of parenteral iron do not last longer than several weeks (see above). Further, no significant morbidity difference was recorded at the 1-wk check after the injection, and clinically significant hyperferremia was not noted at the subsequent field follow-up visits up to 1 y of age. Differences in morbidity observed all relate to periods well after the intervention.
Oral iron intervention.
Effect of age and malarial immunity.
A more relevant issue is that the study group used by Oppenheimer was
an age-defined cohort of infants aged 2 mo who may be regarded as
less immune than other children in malaria-endemic areas. In
contrast, in a report of a 16-wk study in the same area, Harvey et al. (1989)
failed to show any adverse effects of oral iron
supplementation to prepubescent schoolchildren, particularly in
relation to malaria indices (Figs. 4
and
7). Morbidity assessment, however, was based on mothers recall (Table 3)
. Harvey and colleagues speculated that acquired malarial immunity in
their schoolchildren may have masked the potential interaction between
iron and malaria. Harveys report is now in a minority. Two subsequent
intervention studies in schoolchildren that gave oral iron for anemia
(Adam 1996
, Smith et al. 1989
) and a
further two in adults (Adam 1996
, Murray et al. 1978
) have shown an increased risk of clinical malaria. One
other showed a similar trend that did not achieve statistical
significance (Table 3
, Fig. 4
) (Gebreselassie 1996
).
The potential effect of age on immunity to malaria is actually a strong
argument in favor of using age-defined cohorts in randomized
controlled trials. The Tanzanian trial of Menendez et al. (1997)
was the only other childhood trial in the literature to
use an ag