Invisible Anemia: Iron Deficiency Without Anemia and Cognitive Fatigue in SchoolchildrenSystematic Review and Meta-Analysis

Rihab Khattab¹, Hagir Elsofi², Hiba Badr ³, Shamail Elmustafa ⁴, Sharifa Ahmed ⁵

Abstract

 Doi : https://doi.org/10.5281/zenodo.17833375 

Background:

Iron deficiency without anemia (IDWA) is an under-recognized condition in children that may impair neurocognitive development even in the absence of overt anemia . School-aged children with IDWA often exhibit “invisible” cognitive fatigue and performance issues in class despite normal hemoglobin levels. We conducted a systematic review and meta-analysis to examine the prevalence of IDWA in schoolchildren, its impact on cognitive and behavioral outcomes, the diagnostic criteria applied, and the efficacy of iron interventions in this population.

Methods: We followed PRISMA guidelines to search PubMed, Scopus, Web of Science, and Google Scholar (through November 2025) for studies of children aged 5–18 with iron deficiency (low ferritin or transferrin saturation) but normal hemoglobin. Eligible designs included cross-sectional, case–control, cohort studies, and randomized controlled trials (RCTs), excluding those involving anemic children or preschool/adult populations. Data on IDWA definitions, cognitive/academic outcomes, and intervention results were extracted. Risk of bias was assessed with the Cochrane ROB-2 tool for RCTs and appropriate tools for observational studies. Meta-analyses were performed for cognitive outcomes of iron supplementation in non-anemic versus anemic subgroups.

Results: The search identified 50 potential articles; 7 high-quality studies met inclusion criteria after screening. These included large cross-sectional studies, a targeted case-control study, two systematic reviews with meta-analyses, and one RCT. IDWA was prevalent in schoolchildren (ranging from 14% to >36% across regions) often exceeding the prevalence of iron deficiency anemia . Included studies consistently linked IDWA to impaired cognitive performance: e.g., non-anemic iron-deficient children scored significantly lower in math achievement (mean scores 6 points below iron-replete peers) and had over twice the risk of below-average academic performance . IDWA was associated with deficits in attention, working memory, and learning, as well as increased behavioral problems and subjective fatigue . Despite these associations, meta-analysis of RCT data showed no significant short-term cognitive benefit from iron supplementation in IDWA children (e.g., Standardized Mean Difference for IQ 0.01, p = 0.89) . By contrast, anemic children (IDA) in the same trials exhibited large, significant cognitive improvements with iron (e.g., IQ SMD 0.79, p = 0.001) . Risk of bias was low in the RCT and moderate in observational studies, with the main limitations being difficulty isolating IDWA effects and variability in iron status assessment.

Conclusions: IDWA is a common “invisible” condition in schoolchildren that is associated with measurable cognitive and behavioral deficits. However, short-term iron supplementation in mid-childhood yields little cognitive improvement in non-anemic children, in stark contrast to its benefits in anemic children. This suggests that subclinical iron deficiency may cause subtler or more long-standing neurodevelopmental impacts that are not rapidly reversible. Routine ferritin screening in at-risk children could help detect IDWA early, and interventions may need to occur earlier in life or for longer durations to mitigate cognitive fatigue and learning difficulties.