PROJECT SUMMARY/ABSTRACT
Iron deficiency (ID) is the world’s leading nutrient deficiency, affecting more than 2 billion people worldwide,
including approximately 115 million children. Iron deficiency anemia (IDA) during infancy is of significant concern
due to the vulnerability of the developing brain. Iron is a critical nutrient for normal brain development, yet iron
homeostasis exists within a relatively narrow optimal range, with risks associated with both deficiency and
excess. While there are known adverse effects of IDA during infancy, overexposure to iron of any duration within
the 6-24-month critical window of rapid brain development is also suspected to cause harm. Scientists speculate
that the onset of impairments emerge well after the neuropathological insult caused by high-iron
supplementation. This research will examine the long-term effects of 2 exposures: 1) IDA that occurred during
infancy and, 2) high-iron supplementation given to nonanemic infants. For each condition, we will investigate
whether new neurocognitive impairments emerge in early adulthood, and whether known deficits worsen with
age, persist, or perhaps improve. We will also investigate the presence of cascade effects, or effects that emerge
as by-products of earlier deficits. To examine effects, we use data from a large longitudinal cohort of Chilean
infants studied for more than 2 decades who had high rates of IDA and participated in a double-blind randomized-
controlled IDA preventive trial that involved 3 iron supplementation conditions: high-iron, low-iron, and no-added
iron. Comprehensive assessments of neurocognitive, socioemotional, and physiologic functioning were obtained
every 5 years from 6m to 21y. The RCT design, coupled with longitudinal follow-up, allows us to address across-
time differential decline (divergence) by iron supplementation group and infant iron status. Aim 1 will investigate
whether high-dose iron supplementation in infancy has adverse effects on cognitive and executive functioning
at young adulthood, interrogating new emerging effects, intraindividual change (worsening, improvement,
lingering), differential decline by iron supplementation condition, and cascade-indirect effects. Aim 2 will identify
the long-term cognitive effects of infant IDA at young adulthood (emerging effects, intraindividual change,
differential decline by infant iron status, cascade effects), involving learning, memory, planning, IQ, inhibitory
control, attention, and mental processing. Aim 3 will examine the long-term psychosocial effects associated
with infant IDA (emerging, intraindividual change, differential decline, cascade), involving affect, social
functioning, and mental health. We will also identify who is most at risk for long-term harm using neuro-
physiologic, intraindividual, and contextual characteristics measured throughout development. There is no other
study that combines randomized iron supplementation, extensive neurocognitive and mental health
assessments, and long-term follow-up to young adulthood. Findings could have significant impact on public
health policy given the global prevalence of IDA, questions about the persistence of neuropsychosocial deficits
associated with IDA, and concerns about possible adverse effects resulting from high-iron supplementation.
