Adolescence marks a critical stage of physical growth, lean body mass development, and pubertal maturation. These biological and physiological changes increase the demand for micronutrients. In particular, iron deficiency (ID) remains a global public health concern.1 Iron deficiency is the most common nutritional deficiency and the leading cause of iron deficiency anaemia (IDA). Because dietary intake is the primary source of iron for most individuals, inadequate dietary iron intake is the main cause of IDA, particularly in adolescents, who are more likely to have poor dietary patterns.2 The Global Burden of Disease 2020 report estimated that approximately 60% of the total global burden of anaemia in 2019 arose from inadequate dietary iron intake.3 Consequently, ID was identified as the most important cause of anaemia-related disability.3 4

In addition to its essential role in haemoglobin synthesis, iron is a key element in brain metabolism and is vital for multiple cellular processes, including neurotransmitter synthesis, neuron myelination, and mitochondrial function.5 Studies in young children have demonstrated that ID during early life adversely affects psychomotor development, concentration, memory, and learning ability.6 7 Notably, the attention domain has received considerable research interest because iron plays a crucial role in the regulation of dopaminergic activity, which is implicated in the pathogenesis and symptoms of attention-deficit hyperactivity disorder (ADHD). Some studies have detected lower ferritin concentrations in children diagnosed with ADHD than in non-ADHD controls.8 9 However, many cognitive studies regarding ID have involved children aged ≤15 years.8 10 Few population-based studies have examined the effect of iron status on cognitive outcomes in adolescents and young adults, and no such studies have been conducted in Chinese populations.

Our previous study11 reported a prevalence of 11.1% for ID among Chinese school-aged adolescents aged 16 to 19 years in Hong Kong, with ID and IDA affecting 17.1% and 10.9% of girls, respectively, while no male participants were affected More than one-third of these adolescents reported regularly skipping at least one meal per day.11 Notably, lower serum ferritin concentrations were observed in adolescents who skipped meals, reported infrequent intake of iron-rich foods, or had heavy menstrual bleeding.11 Consistent with findings from other studies, poor iron reserves were associated with greater self-reported fatigue, reduced physical functioning, and worse school performance.11 Adolescence represents the second most critical period for the development of higher-order cognitive functions, including attention, self-control, and executive function. The adverse effects of low iron reserves on attention span and attentiveness are particularly relevant to upper secondary students in Hong Kong, who are expected to excel academically and prepare for the Hong Kong Diploma of Secondary Education Examination, the city’s university entrance examination. This study aimed to examine the association between iron status and attention outcomes among school-aged adolescents in Hong Kong.

This cross-sectional study recruited healthy adolescent students through the Hong Kong Red Cross Blood Transfusion Service blood donation campaigns at 16 secondary schools between October 2020 and December 2021. The detailed methodology was described in our previous report,11 which aimed to identify the risk factors of ID and IDA in this cohort to facilitate future association studies on health and functional outcomes. In the present study, the dataset was used to delineate the impact of iron reserves on performance-based attention functioning, which is distinct from the self-reported daily functioning outcomes presented in the previous report.11

Students eligible for this study were aged ≥16 years and had agreed to participate in blood donation screening. Students were excluded if they exhibited signs or symptoms of an active infection, reported a history of anaemia, or were receiving treatment for anaemia. Students who did not pass the blood donation screening were still permitted to participate in the study.

A serum ferritin concentration <15 μg/L was considered indicative of ID in both male and female participants, based on the World Health Organization definition.12 Iron deficiency anaemia was defined as the presence of both ID and anaemia. In accordance with the recommendations of the World Health Organization, anaemia was defined as a haemoglobin concentration <12 g/dL in female participants and <13 g/dL in male participants.13 All assays were conducted on the same day in the Department of Pathology Laboratory at Hong Kong Children’s Hospital. The specifications of the instruments and tests have been reported in our prior study.11

Before blood donation, participants completed the Conners Continuous Performance Test Third Edition (CPT-III), a validated assessment commonly used in clinical and research settings to evaluate attention.14 The CPT-III requires 14 minutes to complete and generates specific CPT attention measures (online supplementary Tables 1 to 3). Raw scores for each CPT measure were converted into T-scores based on normative samples (mean=50, standard deviation [SD]=10). Each CPT measure was classified as indicating no/mild (T-score within <1 SD), moderate (T-score within 1-2 SDs), or severe (T-score within >2 SDs) impairment.

Based on the CPT-III manual and the clinical discretion of a developmental specialist (the second author), attention measures were categorised into three clinically relevant attention domains of interest,14 namely, sustained attention impairment (inability to maintain attention), inattention (inability to focus or concentrate), and impulsivity (difficulty with response inhibition).

Fatigue, a recognised risk factor for diminished neurocognitive function, is associated with ID.11 15 Participants completed the PedsQL Multidimensional Fatigue Scale, which has been validated in young adults up to 25 years of age.16 Each item was scored on a 100-point reverse scale, where lower scores indicated more severe fatigue. The Traditional Chinese version of the PedsQL Multidimensional Fatigue Scale has demonstrated good internal consistency, reliability, and content validity in the Chinese population.17 18

We previously reported that dietary patterns are associated with iron reserves in Hong Kong adolescents.11 All participants self-reported their dietary patterns, including meal-skipping habits (breakfast, lunch, or dinner) and the frequency of consuming common iron-rich foods, namely, seafood, meat, iron-fortified cereal, leafy vegetables, beans, nuts, dried fruits, and eggs.11

The demographic and haematological characteristics of the cohort, along with their attention outcomes, were summarised using descriptive analysis.

The primary outcome was attention impairment. Serum ferritin concentration was used as the predictor of interest, rather than a comparison of attention outcomes between participants with and without ID or IDA, considering that clinical thresholds for diagnosing ID and IDA may not be applicable when evaluating the effect of iron on functional outcomes. Even if an adolescent is not clinically diagnosed with ID or IDA, a low-to-normal ferritin concentration may affect functional outcomes; previous studies have shown that the impact of ID on neurodevelopment may occur before ID manifests as clinical anaemia.19 20 The Mann-Whitney U test was utilised to compare serum ferritin concentrations between participants with normal attention function (ie, those who did not exhibit impairment in any of the three attention domains) and those with moderate or severe impairment in sustained attention, inattention, or impulsivity.

Multivariable analysis using a log-binomial regression model was conducted, with serum ferritin concentration, fatigue, dietary pattern, and dietary iron intake as predictors. Models were adjusted for age and sex. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were calculated.

Given that previous studies have shown a positive association between iron reserves and functional outcomes regardless of sex,8 15 20 21 we first conducted all analyses in the overall cohort. Subsequently, analyses were performed separately for male and female participants.

The significance threshold was set at P<0.05. All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary [NC], US) and were two-tailed.

As reported in our previous study,11 a total of 523 students were recruited (participation rate: 70%). Twenty-nine students were deferred from blood donation due to low haemoglobin concentrations but still completed the study procedures. Two-thirds of participants were female (n=340, 65.0%). The demographics of the study cohort, stratified by sex, are presented in Table 1.

The median ferritin concentration in male participants was 136.17 μg/L (interquartile range [IQR]=89.89-219.83; Fig a); no male participants were diagnosed with ID. Among female participants diagnosed with ID (n=58/340, 17.1%), the median haemoglobin concentration was 11.6 g/dL (IQR=11.1-12.2; Fig b). Among female participants with normal serum ferritin concentrations (n=282/340, 82.9%), the median serum ferritin concentration was 56.07 μg/L (IQR=33.82-84.11; Fig c).

Overall, 249 participants (47.6%) exhibited normal function in all three attention domains. Approximately one-quarter of the participants demonstrated moderate-to-severe impairment in sustained attention (n=131/523, 25.0%), inattention (n=145/523, 27.7%), and impulsivity (n=157/523, 30.0%).

Among female participants with ID, the rates of moderate-to-severe impairment in sustained attention, inattention, and impulsivity were 36.2% (n=21/58), 27.6% (n=16/58), and 37.9% (n=22/58), respectively. The rates of moderate-to-severe impairment in inattention and impulsivity among female participants with IDA were numerically higher at 43.5% (n=10/23 for both domains). Among male participants, the rates of moderate-to-severe impairment in sustained attention, inattention, and impulsivity were 18.0% (n=33/183), 23.5% (n=43/183), and 22.4% (n=41/183), respectively (Table 2).

In the overall cohort, participants with sustained attention impairment had significantly lower serum ferritin concentrations relative to those with intact attention function (median=51.2 μg/L, IQR=27.1-106.8 vs median=73.9 μg/L, IQR=37.8-138.0; P=0.020). Although the associations were not statistically significant, trends of lower serum ferritin concentrations were also observed in participants with impulsivity impairment (median=68.1 μg/L, IQR=29.0-114.8 vs median=73.9 μg/L, IQR=37.8-138.0; P=0.067) and inattention impairment (median=69.9 μg/L, IQR=32.0-110.8 vs median=73.9 μg/L, IQR=37.8-138.0; P=0.142) relative to those with intact attention function.

Pooled analysis of the overall cohort, adjusted for age and sex, showed a significant association between lower serum ferritin concentration and sustained attention impairment (RR=0.825, 95% CI=0.732-0.946; P=0.040), suggesting that each 10 μg/L increase in serum ferritin concentration was associated with a 17.6% decrease in the risk of sustained attention impairment. A higher level of fatigue was associated with impairment in sustained attention (RR=0.772, 95% CI=0.652-0.926; P=0.004), inattention (RR=0.824, 95% CI=0.733-0.942; P=0.016), and impulsivity (RR=0.792, 95% CI=0.683-0.922; P=0.004). Serum ferritin concentration was not significantly associated with risks of impairment in inattention or impulsivity (Table 3).

Female participants with sustained attention impairment had marginally lower serum ferritin concentrations relative to those with intact attention function (median=40.0 μg/L, IQR=18.8-52.1 vs median=48.5 μg/L, IQR=21.8-73.8; P=0.038). Although the associations were not statistically significant, trends for lower serum ferritin concentrations were also observed in participants with impulsivity impairment (median=43.0 μg/L, 95% CI=19.5-63.2 vs median=48.5 μg/L, IQR=21.8-73.8; P=0.071) relative to those with intact attention function. No significant difference was observed for inattention impairment. Additionally, no significant association was detected between iron reserves and attention impairment in male participants.

Multivariable analysis revealed that the association between iron reserves and sustained attention impairment in female participants was attenuated and not statistically significant (RR=0.954, 95% CI=0.904-1.005; P=0.073). A higher level of fatigue was associated with an increased risk of sustained attention impairment (RR=0.793, 95% CI=0.652-0.964; P=0.021). Among male participants, iron reserves did not affect attention outcomes, but fatigue was associated with impulsivity impairment (RR=0.712, 95% CI=0.548-0.942; P=0.018). Dietary patterns were not significantly associated with attention outcomes in either male or female participants (Table 3).

In the overall cohort, a lower serum ferritin concentration was associated with a higher risk of sustained attention impairment, consistent with previous reports that iron reserves play an essential role in functional performance in adolescents.6 7 8 21 When the analysis was stratified by sex, a similar but modest association between low iron reserves and sustained attention impairment was observed in female school-aged adolescents. This finding is supported by studies regarding the neurobiology of attention-related developmental disorders associated with ID.6 7 9 10 A meta-analysis of 10 studies, comprising 2191 healthy children and 1196 children with ADHD, showed that serum ferritin concentrations were 0.4-fold lower in children with ADHD than in those without developmental disorders.8 Iron deficiency may be associated with disruptions in monoamine synthesis and monoamine signal transduction, which manifest as attention deficits.10 22 Adequate iron intake and iron stores may, therefore, be important factors influencing the onset of attention problems in the developing brain. This finding should be prospectively validated in larger cohorts with a comprehensive assessment of cognitive domains beyond attention. However, from a developmental perspective, sustained attention is closely related to performance on targeted assessments, such as mathematical fluency and reading comprehension, as well as broader academic measures in national standardised examinations.23 24 This relationship is particularly relevant because the Hong Kong educational system is well known for its examination-dominated culture. Most examinations range from 2 to 3 hours, requiring students to maintain a high level of sustained attention. Therefore, these findings may have long-term implications for students’ academic success. Future research should investigate the effects of ID and IDA on subsequent academic achievement in Hong Kong adolescents.

Evidence regarding the effectiveness of iron supplementation in terms of improving neurocognitive function in children and adolescents has been inconclusive. Furthermore, iron supplements are associated with gastrointestinal symptoms and constipation, which contribute to non-adherence, particularly in adolescents.25 A systematic review of 14 randomised controlled trials indicated that iron supplementation improved attention and intelligence quotient in anaemic older children and adults.26 However, these effects were inconsistent across studies; they were influenced by socio-economic factors, participant age, and the clinical thresholds used to define ID and IDA.20 25 26 The benefits for cognitive development in older adolescents remain uncertain and warrant further investigation.26

In this study, we found that students who reported higher levels of fatigue were more likely to have worse attention outcomes. We also previously reported that lower serum ferritin concentrations are associated with self-reported fatigue in adolescents.11 Evidence supporting the role of iron supplementation in fatigue reduction is more consistent than its effects on cognitive function in young adults, particularly among non-anaemic menstruating women with low ferritin concentrations.21 27 Notably, iron supplementation has been associated with reductions in subjective measures of fatigue among non-anaemic iron-deficient adults.21 The present findings suggest that ID correction in adolescents could reduce fatigue levels, which may indirectly improve attention outcomes. Using a serum ferritin concentration threshold of 15 μg/L to diagnose clinical ID, some researchers have demonstrated that iron supplementation can improve fatigue and physical performance among individuals with serum ferritin concentrations at the lower end of the normal range (30-50 μg/L).21 Collectively, the known health risks of ID, including impaired physical growth, fatigue, and reduced fitness in adolescents, underscore the need to educate students about maintaining a balanced diet with adequate iron intake. Adolescents with low ferritin concentrations should receive counselling focused on the consumption of iron-rich foods and iron supplementation to alleviate fatigue, even in the absence of documented anaemia.

Dietary patterns and self-reported intake of iron-rich foods were not directly associated with attention outcomes in the multivariate analysis, likely because neurocognitive function is a multifactorial and complex phenotype influenced by both nutritional and non-nutritional factors. Additionally, we did not use a comprehensive measure of dietary iron intake. However, we previously showed that skipping at least one meal per day or exhibiting low dietary iron intake was associated with lower iron reserves.11 Iron deficiency prevention in adolescents requires effective management of knowledge gaps related to food nutrition, dieting, and body image. Collectively, these findings highlight the importance of developing nutrition education programmes to encourage proactive adoption of dietary and other nutrition-related behaviours that promote health and well-being.

Despite the relatively large cohort of school-aged adolescents and the well-characterised haematological assessments, this study had several important limitations. First, the participation rate in the blood donation programme was affected by the coronavirus disease 2019 pandemic and school closures. This change in participation rate may have introduced sampling bias because students with worse health statuses may have been more likely to decline blood donation. Second, we only assessed attention measures in this study. It was not feasible to administer a full neurocognitive test battery, which typically requires >1 hour, in a school-based environment with limited time, space, and supervisory personnel. Future studies should include a more comprehensive evaluation of neurocognitive function. Finally, we did not evaluate factors potentially associated with the causes of anaemia and cognitive function, such as markers of socio-economic status, family functioning, living environment, and physical activity.28 29 Nevertheless, our findings regarding the association between iron status and attention outcomes provide valuable local population data and guidance for future iron supplementation initiatives.

Lower serum ferritin concentrations and self-reported fatigue were associated with an increased risk of sustained attention impairment among school-aged adolescents in Hong Kong. The potential health consequences of ID without anaemia, particularly its effects on physical well-being and school performance, should be effectively communicated to the Hong Kong population, especially to female adolescents. Dietary interventions should target

Concept or design: All authors.
Acquisition of data: CK Lee, WC Tsoi, CW Lau, JNS Leung, STY Tsang, CLP Wong, YYL Chu, CK Li.
Analysis of data: YT Cheung, DFY Chan.
Interpretation of data: All authors.
Drafting of the manuscript: YT Cheung.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

The authors thank the principals and staff of the participating schools, as well as Mr Calvin Lam from Department of Paediatrics of The Chinese University of Hong Kong for assistance with data collection.

Part of the results was presented at the Joint Annual Scientific Meeting 2022 (hybrid meeting) of The Hong Kong Paediatric Society, Hong Kong College of Paediatricians, Hong Kong Paediatric Nurses Association, and Hong Kong College of Paediatric Nursing in Hong Kong on 26 September 2022.

This research was funded by the Health and Medical Research Fund, the former Food and Health Bureau, Hong Kong SAR Government (Ref No.: 17180441). The funder had no role in study design, data collection, analysis, interpretation, or manuscript preparation.

This research was approved by the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee, Hong Kong (Ref No.: 2019.107). Participants aged ≥18 years provided written informed consent, whereas those aged <18 years provided written assent along with informed consent from a parent or legal guardian.

The supplementary material was provided by the authors and some information may not have been peer reviewed. Accepted supplementary material will be published as submitted by the authors, without any editing or formatting. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by the Hong Kong Academy of Medicine and the Hong Kong Medical Association. The Hong Kong Academy of Medicine and the Hong Kong Medical Association disclaim all liability and responsibility arising from any reliance placed on the content.

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