University of Michigan
Department of Pediatrics
Evidence-Based Pediatrics Web Site

Question

• Does oral iron therapy improve the neurologic outcome in children with iron-deficiency anemia?

Clinical Bottom Lines

1. Anemia presumably attributable to iron-deficiency in infants identifies children with poorer overall cognitive functioning and lower school achievement test scores years later.
2. Screening and treatment with >= 3mg/kg/day of elemental iron for iron-deficiency anemia in 12-23 month old infants remains the standard of care.

Summary of Key Evidence

1. Patients
• Idjradinata:  126 infants 12-18 months old, 50 were iron-deficient/anemic (Hgb<=10.5), 29 were non-anemic iron-deficient (Hgb>=12, Tsat<=10), and 47 were iron-sufficient (Hgb>=12, Tsat>=10)
• ’96 Lozoff:  86 infants 12-23 months old, 32 were anemic (Hgb<=10), and 54 were non-anemic (Hgb>=12.5)
• ’00 Lozoff:  162 adolescents 11-14 years old, 48 who had chronic, severe iron deficiency in infancy (Non-anemic ID despite Rx) and 114 who were iron-sufficient in infancy
2. Intervention
• Idjradinata:  All groups randomized to placebo or oral iron for 4 months
• ’96 Lozoff:  Non-anemic infants randomized to placebo or oral iron for 6 months (all anemic infants were treated)
• ’00 Lozoff:  treatment of anemia as infants, then >10 year time lapse
3. Outcome Measures
• Idjradinata:  Bayley scales of mental and motor development and HOME inventory
• ’96 Lozoff:  Bayley scales mental and motor development, Bayley Infant Behavior Record, HOME inventory
• ’00 Lozoff:  Wechsler Intelligence Scale for Children, Wide-Range Achievement Test, Bender Visual-Motor Gestalt Test, measures of school functioning, and behavioral evaluations
4. Validity of Studies
• Therapy: Idjradinata and ’96 Lozoff 
• Groups similar at start of trial? Idjradinata-yes. Lozoff-anemic group ~ 1 month younger than non-anemic group 
• Randomized? Idjradinata-yes, for all groups.  Lozoff-yes, but for non-anemic group only
• Double-blinded, placebo-controlled? Idjradinata-Yes, for all groups.  Lozoff-nonanemic only 
• Equal treatment except for therapy? Yes, both
• Intention to treat? Yes, both
• Prognosis: ’00 Lozoff
• Appropriate sample gathered at early point in course of illness? Yes
• Follow-up sufficiently long and complete? Yes
• Objective outcome criteria applied in a ‘blind’ fashion? Yes
5. Results
• Idjradinata: Developmental delay and hematologic parameters observed among IDA infants before intervention reversed after 4 months of treatment. Non-anemic but iron-deficient infants scored equally to iron-sufficient infants
• ’96 Lozoff: Even when hematologic parameters of IDA infants are corrected with treatment, no reversal of developmental delay was seen after 6 months of treatment.  Non-anemic but iron-deficient infants scored equally to iron-sufficient infants
• ’00 Lozoff: Children who had severe, chronic iron-deficiency in infancy were delayed in motor/mental skills, failed more grades, were emotionally less stable than children who were iron-sufficient in infancy even 10 years later.

Additional Comments

• Iron-deficiency anemia affects 20-25% of infants worldwide, and many of the poor/minority population in the United States.
• Regarding the differences in outcome for the two treatment studies
• 5 studies of short-term treatment with iron: 1 showed reversal, 2 showed reversal with only the most severe cases of anemia, and 2 showed no reversal
• Duration, severity of anemia, and infant age not likely as were similar in both studies
• Environment, feeding practices are possibilities
• Neurologic effect of correction of iron-deficient anemia in infancy remains controversial.
• Regarding the interpretation of the prognosis study
• 5 other studies showed similar poor performances of children with histories of iron-deficiency (though none done in Indonesia)
• Why is it irreversible:  either iron plays a separate role in the early development of the human brain, or iron-deficiency is correlated to rather than causative of developmental delay
• Speculation for role of iron in brain development, dopaminergic neurotransmission, myelination
• Treatment with iron is cheap and has minimal side effects (black stool, constipation)

Citation

1.  Idjradinata P, Pollitt E. Reversal of developmental delays in iron-deficient anaemic infants treated with iron. Lancet. 1993; 341(8836):1-4.
2.  Lozoff B, Wolf A, et al. Iron-deficiency anemia and infant development: Effects of extended oral iron therapy. Journal of  Pediatrics. 1996; 129(3):382-9.
3. Lozoff B, Jimenez E, et al. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics.  2000; 105(4).

CAT Author: Julia G. Warren-Ulanch, MD

CAT Appraisers: John G. Frohna, MD

Date appraised: April 10, 2000