Prevention of Iron Deficiency Anemia in Infants

C H A P T E R
23
Prevention of
Iron Deficiency
Anemia in
Infants
By John W. Feightner

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23 Prevention of Iron Deficiency Anemia
in Infants
Prepared by John W. Feightner, MD, MSc, FCFP1
In 1979, the Canadian Task Force on the Periodic Health
Examination concluded that there was poor justification for the
inclusion of screening for iron deficiency anemia (IDA) in the
periodic health examination, though particular attention was
considered warranted for higher risk groups.<1> This position, a
C Recommendation, was based on the lack of Level I evidence on
the value of treatment of all but the most severe iron deficiency.
Since then, several well-designed trials have provided
additional evidence concerning the consequences of iron
deficiency; the strongest evidence for an association between IDA
and clinical outcomes comes from studies of infants and children,
while for other groups the issue is even more controversial. The
screening tests are reasonably sensitive and specific, particularly
when used in combination, and there is convincing evidence that
treatment – both food fortification and supplementation – is
effective in reversing anemia and iron deficiency. The evidence
concerning whether the reversal of iron deficiency corrects the
cognitive, behavioral, and physical consequences of the
deficiency is equivocal, at best.
This review does not address the issue of IDA in pregnancy.
(see Chapter 6)
Burden of Suffering
Prevalence
In North America, the prevalence of IDA has been declining
over the last two to three decades. Recent U.S. statistics indicate a
rate of 0.2% among men and 2.6% in menstruating women. Estimates
In North America, the
of prevalence, particularly in high-risk groups, are affected by the
prevalence of iron
varying definitions used for IDA among the available studies.
deficiency anemia
has been declining
In Canada, the overall prevalence of IDA in infants and young
over the last three
children has declined significantly and in the normal population is not
decades
considered a major health issue. However, a number of high-risk
groups have been identified recently in Canadian studies.
1 Professor of Family Medicine, McMaster University, Hamilton, Ontario
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While there have been some ethnic associations with IDA, the
major risk factors are related to low socioeconomic status. Specific
high risk groups include the following:
Low Socioeconomic Status
A Montreal study evaluating children at one year of age in the
5 poorest health districts found 15% had hemoglobin below 105 g/L
and 27% below 110 g/L.<2> In a 1991 Ottawa study, 8.2% of children
from families of low socioeconomic status had hemoglobin levels
<110 g/L.<3>
Chinese Population
A study evaluating iron deficiency in a Chinese population
identified iron deficiency in 4.1% of the children and within this group
the mean hemoglobin was 91 g/L.<4>
Aboriginal Children
Forty-three percent of infants in one aboriginal community had
hemoglobin levels <110 g/L.
Infants of Low Birth Weight
A relationship exists between low birth weight and iron
deficiency.
Consumption of Whole Cow’s Milk
The risk of iron deficiency and IDA appears to be greater in
infants fed whole cow’s milk (WCM) during the first year of life. One
study found that in infants fed WCM starting at six months of age, 25%
had a hemoglobin below 110 g/L compared to 11% for infants fed iron
fortified formula over the same age range.<5> There is conflicting
evidence regarding the etiology of this phenomenon, but the main
postulated mechanisms include the fact that WCM is a poor source of
iron, and the possibility of decreased iron intake in alternate forms is
associated with poor absorption and bioavailability.
Clinical Impact
In infants iron deficiency is most prevalent between six and
24 months of age, a time of rapid brain growth and psychomotor
development. A deficiency of iron at this stage in development has the
potential for severe consequences both in terms of cognitive function
as well as psychomotor development and behaviour. While it is
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postulated that iron deficiency even before the appearance of anemia
may have an affect on brain function, the evidence is more limited.
While the evidence is strongly suggestive of a causal relationship
between IDA and deficiency in cognition and psychomotor
development, it falls short of confirming a causal relationship. Many of
the studies which have evaluated a casual relationship as well as those
which have looked at the benefits of intervention have relied solely on
laboratory outcome measures such as hemoglobin. Those which have
focused on clinical outcomes for infants have primarily used the Bayley
Scales which have two components, a mental development index and a
psychomotor development index. Some studies have used IQ tests and
other tests of cognition. While some studies have shown an
association between IDA and decreased cognitive function and
decreased psychomotor development, there is conflicting data
regarding subsequent improvement with therapy.
The issue of causal relationship is important in determining what
degree of confidence to place in studies which only use hematologic
laboratory indices as measures of outcome. This review will give
primary weighting to studies using clinical outcomes. However, where
the clinical question is relevant and the only available data from well
designed studies is expressed in terms of laboratory outcome, these
studies will also be reviewed.
There are data which suggests IDA may also have a primary
affect on infant behaviour. Such studies indicate that IDA may be
associated with increased irritability and fussiness and with decreased
Iron deficiency
attention.
anemia may be
associated with
Studies focusing on children and adults have suggested an
increased irritability
association between IDA and cognition as well as strength, work
and fussiness and
capacity and endurance. In adults, those studies focusing on
with decreased
relationship to muscle strength have primarily demonstrated a
attention
relationship only to maximal performance and have not shown an
association between IDA and normal daily activity. One study
evaluating the productivity of rubber plantation workers in Indonesia
suggested that iron deficiency may be associated with decreased
endurance and, hence, decreased productivity.
Maneuver
There are essentially two approaches to dealing with IDA,
particularly in infants. The first is to embark on early detection efforts
to identify anemic infants and subsequently, embark on a course of
iron therapy. The alternate approach is one of primary prevention
wherein all infants in a population are provided iron fortified formula
or cereal in an attempt to prevent the occurrence of anemia. In this
section only the early detection efforts will be reviewed.
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There are several tests available for the diagnosis of iron
deficiency and IDA. However, from the perspective of early detection,
only a limited number of tests can realistically be considered.
Historically, the most commonly used laboratory test, clinically and in
research studies, has been the hemoglobin level. Hematocrit has been
used to some degree in the past and more recently serum ferritin has
been used for the early detection of iron deficiency.
The gold standard against which most early detection tests are
evaluated is the evaluation of iron stores in a patient’s bone marrow.
Serum Ferritin
Studies evaluating the test characteristics of serum ferritin have
largely been conducted in adults. While the results vary, the best
estimates for serum ferritin levels <12 ug/L indicate a sensitivity of 86%
and a specificity of 92%.<6>
Hemoglobin
Again, estimates of the sensitivity and specificity vary depending
on the study. However, in a key study using bone marrow as the gold
standard in an adult population, the hemoglobin was found to have a
sensitivity of 8% and a specificity of 97%.<6> A study which used
response to therapy and achieving a hemoglobin level over 133 g/L
found a sensitivity of 66% and a specificity of 65%.<7>
The test performance of hemoglobin as a screening test has
clear performance limitations which must be considered if early
detection of iron deficiency is to be used as the main approach to
dealing with IDA in infants. This will be discussed later.
Effectiveness of Prevention and Treatment
The problem of IDA (in infants) can be addressed through
primary prevention efforts or through the secondary prevention
efforts of early detection and subsequent therapy. Primary prevention
Potentially, primary
has the potential of providing benefit to a whole population and
prevention can
preventing the onset of IDA. This assumes that the strategies for
benefit the entire
ensuring adequate iron intake are available and affordable for all infants
population and
and that such interventions are effective in preventing IDA. Early
prevent the onset of
detection has the potential of focusing efforts only on those who have
iron deficiency
definitely been identified as having IDA. The success of this approach
anemia
depends both on being able to accurately identify individuals with
anemia and on proof that subsequent therapy is effective. Complete
success would assume that all infants would be screened or that high-
risk infants could be accurately identified for screening.
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Fortification of Formula and Cereal
The evidence for the benefit of iron fortification, comes from
studies evaluating programs aimed at large populations as well as from
randomized controlled trials with more carefully defined study
populations. Unfortunately, these studies have not evaluated clinical
outcomes.
Population studies have primarily focused on the impact in the
U.S. of the “WIC Program”, which provides iron fortified formula and
cereals to low income families, primarily in urban settings. These
studies have compared hemoglobin in a cross section sample of
children before the implementation of the program, with a similar
group of children selected for evaluation some years after the
implementation of the program. One such study indicated that the
percentage of children with the hemoglobin <99 g/L changed from 23%
before the program in 1971 to 1% in 1984, some years after the
program had been implemented.<8> While these results can be
attributed at least in part to the benefits of the program, there are
likely several confounding factors which are at work as well. Evidence
to support the fact that all of this improvement is not the result of the
program’s iron fortification comes from studies which have indicated a
significant decrease in anemic children screened prior to entry to the
WIC Program in 1975 compared to children screened in 1985 but also
before entering the program. The percentage of anemic children
dropped from 7.8% to 2.9% from 1975 to 1985 even before these
children were entered into the program providing iron fortified
formula in cereal.<9>
The strongest evidence comes from two randomized controlled
trials and one non-randomized trial evaluating infant formula in infant
cereal.
Walter and colleagues demonstrated the benefits of iron
fortified formula as well as iron fortified cereal.<10> Each was
successful in preventing anemia in infants whether they were weaned
from the breast prior to four months of age or whether the iron
fortified cereal was added after four months of age and with continued
breast-feeding.
In the early weaned group, anemia rates at eight months of age
were 6% for iron fortified cereal, 4.5% for iron fortified formula, and
20% in those receiving no iron fortified products. In the breast-fed
group, the rate of anemia at eight months of age was 3.5% in those
receiving iron fortified cereal compared to 15% for those breast-fed
only.
Zlotkin and co-authors, in a study of infants six to 12 months of
age, found that in infants fed iron fortified cereal the percentage of
infants with ferritin values <10 ug/L or hemoglobin <110 g/L was 22%
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compared to 48% in a control group receiving non-iron fortified
cereal.<11>
Similarly, Pazarro and co-workers in a non-randomized trial,
demonstrated that children receiving iron fortified formula had a lower
rate of anemia (0.6%) than a comparison group fed cow’s milk
(15%).<12>
Once again, none of these studies measured outcomes in terms
of cognitive function or psycho motor development.
Supplementation
While iron supplementation provided through drops or iron
fortified cereal is not currently a common practice in North America,
two randomized controlled trials have demonstrated the effectiveness
of iron supplementation in infants.<13,14>
Breast-feeding
There is limited evidence regarding the benefits of breast-feeding
in reducing anemia in infants. While the evidence is limited, there is a
plausible biologic argument. Iron in human milk has a relatively higher
bio-availability. However, there is only a small absolute amount
absorbed. What data do exist suggest that the likelihood of anemia can
be reduced by breast-feeding, although, not to levels that match those
of children who are breast-fed plus receive iron fortified cereal after
the age of four to six months, nor compared to those children who
have received iron fortified formula and subsequently, iron fortified
cereal.<3,12>
Effectiveness of Treatment
Secondary prevention efforts rely on the early detection of IDA
in infants and the implementation of therapy in those identified as
anemic. Four randomized trials have evaluated the impact on cognitive
function and psychomotor development of iron therapy provided to
infants identified as having IDA. All studies have been conducted in
Chile, Indonesia, or Central America.
Three studies failed to show the benefit of oral iron
therapy.<15,16,17> Two of these studies provided a relatively short
course of iron therapy (six to ten days) while one provided therapy of
up to three months and still showed no benefit. A five year follow-up
of one study group showed that there was no delayed benefit of iron
therapy and that children with IDA in infancy still had lower mental and
motor function at school entry.<18> These findings have raised
concerns that one possible explanation is that lasting damage has
occurred before the IDA was discovered and treated.
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In a more recent study, Idjradinata and Pollit (1993)
demonstrated a significant improvement in cognitive function and
psychomotor development with four months of oral therapy in infants
aged 12-18 months.<19> In infants with IDA, the treatment group
showed a significantly greater improvement in mean hemoglobin and in
serum transferrin. On the Bayley Scales, there was a 20 point
improvement in mental development scores and a 14 point
improvement in motor development scores, with no significant
improvement in the placebo group. While the results of this trial are
important, it is unclear why they differ from the findings of the other
three studies.
Recommendations of Others
The Nutrition Committee of the Canadian Pediatrics Society has
recently published a position statement on meeting the iron needs of
infants and young children (Nutrition Committee, Canadian Pediatrics
Society, 1991).<20> These recommendations support the use of iron-
fortified formula for non-breast-fed infants as well as the use of iron-
fortified infant cereals and other iron rich foods for all term infants.
For premature infants the recommendations are that iron supplements
should be started by at least eight weeks of age and continued until the
first birthday. The recommendations do not include a specific
statement regarding screening of children either in the general
population or for high-risk groups.
In 1989, the U.S. Preventive Services Task Force recommended
that screening should be offered once to all infants, and that parents
should be encouraged to include iron enriched foods in the diet of
infants. This recommendation is currently under review.<21>
The American Academy of Pediatrics recommends at least one
measurement of hemoglobin or hematocrit in infancy, and at least one
at ages 1-4, 5-12, and 14-20.
Conclusions and Recommendations
In Canada, IDA in infants is most appropriately considered as
both a socioeconomic as well as a nutritional problem. The prevalence
(and, hence, the risk for newborns) in identifiable high-risk groups is
significant. However, in the general population, the risk is relatively
low. Both of these realities influence how existing data might be
converted to recommendations for clinical policy.
General Population
With a low prevalence of IDA in infants in the general
population, the inaccuracy of hemoglobin measurement, and the
conflicting evidence for iron therapy, there is insufficient evidence to
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recommend the inclusion of routine early detection of anemia by
hemoglobin measurement between ages six and 12 months
(C Recommendation).
For the general population it is recommended that physicians
encourage breast-feeding for at least six months and the introduction
of iron fortified formula and/or cereal after six months of age
(B Recommendation). It should be noted that the Task Force strongly
recommends breast-feeding for other reasons (A Recommendation;
see Chapter 22). For children weaned from the breast early or who
are not breast-fed from birth, iron fortified formula followed by iron
fortified cereal at a later age should be recommended. Whole cow’s
milk should be avoided, certainly before nine months of age and
perhaps until after 12 months.
High-risk Groups
This approach can be a difficult one for families of lower
socioeconomic status because the cost of iron fortified formulas and
cereals may be beyond their means. This is even more problematic if
nutritional habits and/or income preclude the provision of iron
enriched foods and foods rich in ascorbic acid. For infants of all high-
risk groups, it is recommended that physicians take particular care to
determine the nutritional intake and consider a hemoglobin
measurement between ages six and 12 months, perhaps optimally at
nine months of age (B Recommendation).
A hemoglobin measurement in any infant between ages six and
12 months of age where there is a suspicion of poor iron and general
nutritional intake is prudent even if the child is not from a high-risk
group. While serum ferritin has not been evaluated as a screening test,
it measures poor iron stores and allows the identification of iron
deficiency prior to the development of anemia. It may be considered as
an additional test in selected infants.
Unanswered Questions (Research Agenda)
Randomized controlled trials evaluating the impact of iron
fortified formula and cereal on clinical outcomes are a high priority.
Studies evaluating clinical outcomes of strategies to prevent and/or
treat IDA in high risk groups, including the evaluation of early
detection measures are likewise of high priority.
Evidence
The evidence in this review was identified using a MEDLINE
search with the key words: anemia, hypochromic for the years
1984 to October 1993. The review was initiated in June 1991 and
recommendations were finalized by the Task Force in February 1994.
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Selected References
1.
Canadian Task Force on the Periodic Health Examination: The
periodic health examination. Can Med Assoc J 1979; 121:
1193-1254
2.
Lehmann F, Gray-Donald K, Mongeon M, et al : Iron deficiency
anemia in 1-year-old children of disadvantaged families in
Montreal. Can Med Assoc J 1992; 146: 1571-1577
3.
Greene-Finestone L, Feldman W, Heick H, et al : Prevalence
and risk factors of iron depletion and iron deficiency anemia
among infants in Ottawa-Carlton. Can Diet Assoc J 1991; 52:
20-23
4.
Chan-Yip A, Gray-Donald K: Prevalence of iron deficiency
among Chinese children aged 6 to 36 months in Montreal. Can
Med Assoc J 1987; 136: 373-378
5.
Tunnessen WW Jr, Oski FA: Consequences of starting whole
cow milk at 6 months of age. J Pediatr 1987; 111: 813-816
6.
Rybo E: Diagnosis of iron deficiency. Scand J Hemotol Suppl
1985; 43: 5-39
7.
Freire WB: Hemoglobin as a predictor of response to iron
therapy and its use in screening and prevalence estimates. Am
J Clin Nutr 1989; 50: 1442-1449
8.
Vazquez-Seoane P, Windom R, Pearson HA: Disappearance of
iron deficiency anemia in high-risk population given
supplemental iron. N Engl J Med 1985; 313: 1239-1240
9.
Yip R, Binkin NJ, Fleshood L, et al : Declining prevalence of
anemia among low-income children in the United States. JAMA
1987; 258: 1619-1623
10.
Walter T, Dallman PR, Pizarro F, et al : Effectiveness of iron-
fortified infant cereal in prevention of iron deficiency anemia.
Pediatrics 1993; 91: 976-982
11.
Zlotkin SH, Beaton GH, Tanaka P, et al : Double-blind trial of
iron fortification of infant cereals: effect on growth and
hemotologic status. Pediatric Research 1993; 33: (abstract
no.113a)
12.
Pizarro F, Yip R, Dallman PR, et al : Iron status with different
infant feeding regimens: relevance to screening and prevention
of iron deficiency. J Pediatr 1991; 118: 687-692
13.
Smith AW, Hendrickse RG, Harrison C, et al : Iron deficiency
anemia and its response to oral iron: report of a study in rural
Gambian children treated at home by their mothers. Ann Trop
Paediatr 1989; 9: 6-16
14.
Chwang LC, Soemantri AG, Pollitt E: Iron supplementation and
physical growth of rural Indonesian children. Am J Clin Nutr
1988; 47: 496-501
15.
Lozoff B, Brittenham GM, Viteri FE, et al : The effects of short-
term oral iron therapy on developmental deficits of iron-deficient
anemic infants. J Pediat 1982; 100: 351-357
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