Impact of Iron Deficiency on Pediatric Cognitive and Neurological Outcomes

Introduction Globally, iron deficiency has been acknowledged as a public health problem, with children under five being predominantly affected.1 The findings of a meta-analysis revealed that 16%–18% of children under five are suffering from iron-deficiency and iron-deficiency anemia, with estimates being significantly higher in low- and middle-income nations.1 Similar results are reported in another recent systematic review, which suggests that pediatric iron deficiency is a major public health concern.2 A recent meta-analysis among children aged 5–12 years reported a pooled prevalence of iron deficiency anemia of 9.4%, with higher estimates reported in sub-Saharan Africa and the South Asia region.3 Iron is critically involved in synaptogenesis, myelin sheath formation, production of neurotransmitters, and mitochondrial energy metabolism, and all these are crucial for optimal cognitive development, especially during infancy and early childhood.4 Iron Deficiency and Irreversible Changes in Brain Function During early infancy and toddlerhood, brain growth happens at a rapid pace, and iron deficiency during this critical neurodevelopment phase can result in structural deficits that might not be reversible even with iron repletion at a later stage.5 Moreover, early iron deficiency can change mitochondrial and neuronal energy pathways, which interfere with neuroplasticity and chronic energy metabolism even after restoration of normal iron levels in the body.6 In addition, the disruption of myelin formation in the early stages of life eventually slows neuronal transmission, which manifests as cognitive deficits.7 Iron deficiency also casues permanent alterations in the process of formation of dopamine neurotransmitters, which can result in interference with attention and functioning, and these outcomes become detectable in adolescence.8 In continuation, iron deficiency during early neurodevelopmental stages can result in changes in the regulation of gene expression related to synaptogenesis and neural growth, resulting in long-term functional deficits.9 Iron Deficiency During Infancy, Early Childhood, and Adolescence Iron deficiency during pregnancy accounts for limited availability of iron to the fetus, resulting in lower iron levels in the newborn brain and augmenting the risk of delayed neurodevelopment, including delays in attention and poor cognition.5,6 The results from a longitudinal study showcased that suboptimal iron levels at 5 months of age are a positive predictor of poor cognitive development and delayed attention, which often persists in early childhood.10 Moreover, infants with early iron deficiency demonstrate poor motor and recognition memory outcomes, which can be detected by standardized tests even in the late childhood phase.8 In addition, iron deficiency in infancy can manifest as deficits in executive functions (like attention and inhibitory control) and poor educational outcomes in young adulthood, even after hematological recovery.8,11 Infants exposed to iron deficiency demonstrate lower verbal intelligence, language abilities, less engagement, and less socially responsive, especially in the early childhood phase.8,12 The findings from a prospective study revealed that toddlers with iron deficiency have lower early learning scores, reflecting an impact on memory, processing, and early executive functions.13 At the same time, such infants also demonstrate attention-deficit hyperactivity disorder (ADHD)-like symptoms later in childhood and adolescence, which adversely impact school readiness and learning in classrooms.11 The results from a study highlighted that iron-deficient infants are usually less responsive and often socially withdrawn, due to which they often are not effectively handled by caregivers, which further complicates language and cognitive delays.12 A cross-sectional study done among 363 children in Brazil reported that iron-deficiency anemia was more prevalent among preschoolers from low socioeconomic groups, suggesting the presence of multiple other factors (e.g., nutritional, educational resources, etc.) that cumulatively impact attention, learning, and early executive functions.14 Increased iron requirements have been reported during growth spurts in adolescence (e.g., expansion of total blood volume and lean body mass) and with the onset of menstruation, which adds to iron loss among girls.15 The results from a cross-sectional study done among 523 adolescents found that lower serum ferritin was significantly linked with impaired sustained attention and inattention, highlighting the role of iron in attention regulation.16 A systematic review envisaged the linkage between iron status and behavioral and cognitive outcomes, such as increased fatiguability and impaired task performance.17 Finally, adolescents with iron deficiency also present with fatigue and decreased concentration that can minimize engagement in school and social activities, which results in diminished psychosocial well-being and school connectedness.18 Neuroimaging and Neurophysiological Evidence A systematic review of neuroimaging studies reported that children and adolescents with conditions linked to iron dysregulation (scuh as ADHD) have reduced iron concentrations in deep gray matter structures (such as the caudate and putamen) compared with other developing peers without iron deficiency.19 In another study, it was found that pediatric cohorts with iron dysregulation tend to have lower susceptibility values in the basal ganglia, which correlates with neural circuits involved in attention and motor control in magnetic resonance imaging scans.20 The findings from a randomized controlled trial among adolescents reported that improvement in iron biomarkers correlates with changes in electroencephalogram features (namely, α and γ power bands and evoked potentials), which are linked to attention and memory performance.21 Another research work demonstrated that early iron-deficiency anemia during infancy often presents as altered functional connectivity patterns in adulthood, especially in networks related to cognitive control and attention.22 Implications and Future Direction The above-mentioned evidence demonstrates that iron deficiency in early life has profound and persistent effects on cognitive, behavioral, and neurophysiological development, justifying the need for proactive prevention and early detection.8,10,17 The need of the hour is to develop sensitive screening biomarkers that can detect iron insufficiency before the onset of anemia, especially because traditional hematological markers become obvious much later than iron depletion in the brain.23 The results of an interventional study depicted that iron supplementation in non-anemic children and adolescents can improve cognitive and psychosocial outcomes.24 However, there is a definite need for large, multicentric cohort studies examining the linkage between iron deficiency and environmental-cum-socioeconomic attributes to aid in the formulation of equitable public health approaches.25 Similarly, studies that can integrate neuroimaging, electrophysiology, and molecular markers can improve our understanding of neural pathways affected by iron deficiency.19 Conclusion To conclude, iron deficiency is a modifiable risk factor for adverse pediatric cognitive and neurological outcomes. The available neuroimaging and neurophysiological evidence reinforces the presence of persistent network-level changes, envisaging the limited reversibility of early deficits. There arises the pressing need to address iron deficiency during critical neurodevelopmental periods, namely pregnancy, infancy, and adolescence, through informed pediatric nutrition policies. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Author contributions SRS contributed in the conception or design of the work, drafting of the work, approval of the final version of the manuscript, and agreed to all aspects of the work. PSB contributed in the literature review, revision of the manuscript for important intellectual content, approval of the final version of the manuscript, and agreed to all aspects of the work. SJ contributed in the literature review, revision of the manuscript for important intellectual content, approval of the final version of the manuscript, and agreed to all aspects of the work. NP contributed in the literature review, revision of the manuscript for important intellectual content, approval of the final version of the manuscript, and agreed to all aspects of the work.