majority of infants with iron-deficiency anemia continued to have lower developmental test scores (Aukett et al., 1986; Lozoff et al., 1987, 1996; Walter et al., 1989), despite iron therapy for 2-6 months and correction of anemia; other behavioral differences were also still observed (Lozoff et al., 1998). Differences thus appear to persist.

Follow-up studies have sought to determine if differences persist beyond infancy. Several studies have shown that, at early school age, children who were anemic as infants continue to have lower test scores than their peers who did not experience anemia (Dommergues et al., 1989; Lozoff et al., 1991; Palti et al., 1983, 1985; Walter et al., 1990). A comprehensive follow-up at the transition to adolescence (Lozoff et al., 2000) found that children who had been treated for severe, chronic iron deficiency in infancy still scored lower on measures of mental and motor functioning, specifically in arithmetic achievement and written expression, motor functioning, and some specific cognitive processes such as spatial memory and selective recall. They were also more likely to have repeated a grade. Parents and teachers rated the formerly iron-deficient children as showing more anxiety or depression, social problems, and attention problems. In a different, population-based study (Hurtado et al., 1999), children who were anemic in infancy (presumably due to iron deficiency) were at increased risk for mild to moderate mental retardation at age 10. Thus, severe, chronic iron deficiency in infancy identifies children who continue to be at developmental and behavioral risk more than 10 years later.

Basic research and animal studies indicate some possible mechanisms for such behavioral and developmental differences. Iron is required for many processes, including neurotransmitter synthesis (dopamine being the most studied), myelination, and oxidative metabolism (reviewed in Georgieff and Rao, 1999). Maximal transport of iron into the brain corresponds with the brain growth spurt, and iron deficiency during this period results in a deficit of brain iron in animal models. These observations suggest that the developing brain may be particularly vulnerable to the effects of this nutrient deficiency. Conversely, free or excess iron is toxic to cell membranes and may contribute to neuronal damage following a brain injury.

New studies that utilize neurophysiological and electrophysiological methods are now providing data on iron-deficient human infants and demonstrating close links to results in animal models. In one such study (Roncagliolo et al., 1998), 6-month-old infants with iron-deficiency anemia had slower nerve conduction in the auditory pathway. Differences in nerve conduction velocity between anemic and nonanemic infants increased over the following year despite iron therapy. A disruption or defect in myelination was considered to be a promising explanation, given that brain iron is required for myelination, young iron-deficient animals have been noted to

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