Prevention of Iron Deficiency Anemia in Infants

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Prevention of
Iron Deficiency
Anemia in

By John W. Feightner
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
                              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.

                            Professor of Family Medicine, McMaster University, Hamilton, Ontario

       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

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

                         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
                         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.

                               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.

       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>

       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
has the potential of providing benefit to a whole population and             Potentially, primary
                                                                             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.

      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
              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
              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
            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
             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%

compared to 48% in a control group receiving non-iron fortified
      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
      Once again, none of these studies measured outcomes in terms
of cognitive function or psycho motor development.

        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>

       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

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.

            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

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.

      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.

      Selected References
       1.   Canadian Task Force on the Periodic Health Examination: The
            periodic health examination. Can Med Assoc J 1979; 121:
       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:
       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
      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

16.   Lozoff B, Brittenham GM, Wolf AW, et al : Iron deficiency
      anemia and iron therapy effects on infants developmental test
      performance. Pediatrics 1987; 79: 981-995
17.   Walter T, DeAndraca I, Chadud P, et al : Iron deficiency anemia:
      adverse effects on infant psychomotor development. Pediatrics
      1989; 84: 7-17
18.   Lozoff B, Jimenez E, Wolf AW: Long-term developmental
      outcomes of infants with iron deficiency. N Engl J Med 1991;
      325: 687-694
19.   Idjradinata P, Pollitt E: Reversal of developmental delays in
      iron-deficient anemic infants treated with iron. Lancet 1993;
      341: 1-4
20.   National Committee, Canadian Pediatrics Society: Meeting the
      iron needs of infants and young children: an update. Can Med
      Assoc J 1991; 144: 1451-1453
21.   U.S. Preventive Services Task Force: Guide to Clinical
      Preventive Services: an Assessment of the Effectiveness of
      169 Interventions. Williams & Wilkins, Baltimore, Md, 1989:

        S    U    M      M   A   R Y        T   A    B      L   E     C    H      A   P   T    E   R     2 3

                      Prevention of Iron Deficiency Anemia
                                    in Infants

 MANEUVER                        EFFECTIVENESS                  LEVEL OF EVIDENCE              RECOMMENDATION
 Iron fortified formula          Use of fortified               Randomized controlled          There is fair evidence
 (if not breast-feeding)         formula lowers rates           trial<10> (I); quasi-          to recommend fortified
                                 of iron deficiency             randomized trial<12>           formula for non-
                                 anemia (IDA). Studies          (II-1)                         breast-fed infants (B)
                                 measuring clinical
                                 outcomes have not
                                 been conducted.

 Iron fortified cereal           Lower IDA rates, for           Randomized controlled          There is fair evidence
                                 infants consuming              trials<10,11> (I)              to recommend iron
                                 iron fortified cereal                                         fortified cereal for
                                 compared to placebo,                                          infants beginning at
                                 after the age of 4-6                                          4-6 months of age (B)
                                 months. Studies
                                 measuring clinical
                                 outcomes have not
                                 been conducted.

 Breast-feeding                  Decrease in iron               Quasi-randomized               There is fair evidence
                                 deficiency in breast-          study<12> (II-1)               to recommend breast-
                                 fed infants compared                                          feeding in newborn
                                 to infants fed cows                                           infants to lower the
                                 milk (but not as low as                                       risk of iron deficiency
                                 the prevalence in                                             anemia* (B); however,
                                 those fed iron fortified                                      infants breast-fed
                                 formula).                                                     beyond 6 months of
                                                                                               age benefit from iron
                                 Decreased IDA in               Cohort analytic                fortified cereal to
                                 breast-fed infants;            study<3> (II-3)                prevent the
                                 breast-feeding has                                            development of IDA
                                 been recommended on
                                 other grounds as

 Iron Supplementation            Two trials have                Randomized controlled          There is fair evidence
                                 demonstrated the               trials<13,14> (I)              to recommend iron
                                 benefit of iron oral                                          supplementation in
                                 supplements in                                                infancy but iron
                                 infants. In North                                             fortified formula and
                                 American the use of                                           cereal may be more
                                 iron fortified formula                                        feasible in most
                                 and cereal is more                                            settings (B)
                                 widely used and may
                                 be more feasible.

  *    There is good evidence to recommend breast feeding for other reasons (A recommendation for
       preventing infection; see Chapter 22).

254                                                                                           (Continued on next page)
      S   U   M   M   A   R Y        T   A   B    L   E     C   H   A   P     T   E   R     2 3

                  Prevention of Iron Deficiency Anemia
                           in Infants (concl’d)

Routine Hemoglobin        Conflicting evidence        Randomized controlled       Conflicting and
measurement at 6-12       from randomized             trials<15-19> (I)           insufficient evidence to
months                    controlled trials                                       recommend the
                          evaluating clinical                                     inclusion or the
                          outcomes. Three                                         exclusion of routine
                          studies showed no                                       hemoglobin
                          benefit from therapy;                                   determination in
                          one recent study                                        normal-risk infants
                          demonstrated                                            (C); on the basis of a
                          improvement in both                                     higher prevalence in
                          cognitive and motor                                     certain risk groups**
                          development.                                            and a greater
                                                                                  likelihood of inability
                                                                                  to consume iron
                                                                                  fortified products,
                                                                                  there is fair evidence
                                                                                  to recommend a
                                                                                  routine hemoglobin
                                                                                  measurement for high-
                                                                                  risk infants (B)

**   High-risk infants include: infants of families of low socioeconomic status, Chinese or
     aboriginal ethnic origin, low birth weight (<2,500 grams) or fed only whole cow's milk during
     the first year of life.