Effects of iron supplementation on cognitive development in school-age children: Systematic review and meta-analysis

Befikadu Tariku Gutema; Muluken Bekele Sorrie; Nega Degefa Megersa; Gesila Endashaw Yesera; Yordanos Gizachew Yeshitila; Nele S Pauwels; Stefaan De Henauw; Souheila Abbeddou

doi:10.1371/journal.pone.0287703

. 2023 Jun 27;18(6):e0287703. doi: 10.1371/journal.pone.0287703

Effects of iron supplementation on cognitive development in school-age children: Systematic review and meta-analysis

Befikadu Tariku Gutema ^1,^2,^*, Muluken Bekele Sorrie ¹, Nega Degefa Megersa ³, Gesila Endashaw Yesera ³, Yordanos Gizachew Yeshitila ³, Nele S Pauwels ⁴, Stefaan De Henauw ², Souheila Abbeddou ²

Editor: Ammal Mokhtar Metwally⁵

PMCID: PMC10298800 PMID: 37368919

Abstract

Background

Iron deficiency is negatively associated with children’s cognitive development. Evidence showed that iron supplementation improves cognitive development. Nearly 50% of anemia is caused by iron deficiency. Anemia affects more school-age children, at an age where their brain development continues. The aim of this systematic review and meta-analysis is to review the evidence from published randomized controlled trials to evaluate the effects of iron supplementation on cognitive development and function among school-age children.

Method

Five databases including MEDLINE, EMBASE, Scopus, Web of Science and CENTRAL were used to search for articles on April 20^th, 2021. The search was reconducted on October 13^th, 2022 to retrieve new records. Studies were eligible if they included school children 6–12 years of age, were randomized controlled trials, and if they tested iron supplementation and measured cognitive development.

Result

Thirteen articles were included in the systematic review. Overall, iron supplementation significantly improved intelligence (standardized mean difference, 95% confidence interval) (SMD 0.46, 95%CI: 0.19, 0.73, P<0.001), attention and concentration (SMD 0.44, 95%CI: 0.07, 0.81, P = 0.02) and memory (SMD 0.44, 95%CI: 0.21, 0.67, P <0.001) of school-age children. There was no significant effect of iron supplementation on school achievement of school-age children (SMD 0.06, 95%CI: -0.15, 0.26, P = 0.56). In a subgroup analysis, iron-supplemented children who were anemic at baseline had had better outcomes of intelligence (SMD 0.79, 95%CI: 0.41, 1.16, P = 0.001) and memory (SMD 0.47, 95%CI: 0.13, 0.81; P = 0.006).

Conclusion

Iron supplementation has a significant positive effect on the intelligence, attention and concentration, and the memory of school-age children but there was no evidence on the effect of iron supplementation on their school achievement.

Introduction

Anemia, defined as a condition in which the red blood cell oxygen-carrying capacity is insufficient to meet physiologic needs [1, 2], is the most prevalent nutritional problem globally, and more especially in low- and middle-income countries (LMICs) [3, 4]. Anemia can result from decreased erythrocyte production, increased loss of erythrocytes, or blood loss [2, 5]. Micronutrient deficiencies, infections and genetic disorders can all cause anemia through different mechanisms. Nutritional deficiency anemia results from a poor body status in iron, folic acid, vitamin B12, and/or vitamin A [2, 4, 6]. Anemia affects more school-age children [7, 8], at an age where their brain development continues. One in four school-age children suffers of anemia worldwide [9, 10].

Iron deficiency is the leading cause of anemia. Iron deficiency anemia accounts for nearly half of the anemia cases especially in LMICs [6, 10]. Iron is an essential element for heme synthesis, a precursor of hemoglobin, transitional storage of oxygen in tissues, and for transport of electrons through the respiratory chain. Iron also acts as a cofactor to various enzymes [11, 12]. Iron is an essential nutrient for the development and functioning of the brain. Its functions include ATP production, synthesis and packaging of neurotransmitters and uptake and degradation of neurotransmitters [6, 13, 14].

Studies have found that iron supplementation has an effect on some of the domains of cognitive development among school-age children [15–17]. In addition, the evidence is strong on the relationship between anemia and cognitive development [15, 18, 19]. Iron deficiency and iron deficiency anemia can cause cognitive deficits [20, 21].

Iron supplementation of school-age children is recommended in settings where anemia is prevalent but the evidence regarding its effectiveness on cognitive development is limited [22]. Iron supplementation improved hemoglobin concentration and reduced the incidence of anemia and iron deficiency in school age children [15, 22, 23]. Furthermore, iron supplementation was shown to be effective in improving cognition, safe in malaria settings, and had no gastrointestinal adverse effects [15, 16, 24]. A systematic review assessing the evidence of the effect of iron supplementation in school-age children’s cognition dated to 2013 [15]. The aim of this systematic review and meta-analysis is to review the evidence from published randomized clinical trials to evaluate the effects of iron supplementation on cognitive development and function among school-age children.

Methods and design

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used and performed for this systematic review and meta-analysis (S1 Checklist) [25]. The systematic review protocol was developed and registered on PROSPERO (CRD42021231262) before the literature search was performed on April 20, 2021 and updated on October 13, 2022.

Data sources and search strategy

Five databases including MEDLINE (via the PubMed interface), EMBASE (via the embase.com interface), Scopus, Web of Science, and the Cochrane library (Cochrane Central Register of Controlled Trials) were used to search for articles. The search strategy included terms on the following themes: cognition, school-age children, and iron supplementation. Studies eligible for this review involved randomized control trials or clinical trials. A detailed search protocol is provided in supplementary materials (S1–S5 Tables).

Eligibility criteria

Studies were included if the study population was school-age children (age ranging between six to 12 years), the design was a randomized controlled trial, and they assessed iron supplementation effects on cognitive development indicators. There was no restriction regarding duration of the intervention, setting, language, or the year of publication. Studies conducted on children under five years only or over 12 years of age only, with chronic morbidities (e.g. HIV/AIDS), with developmental disability, or only on children exposed to known factors affecting cognitive development (e.g. lead, arsenic) were excluded. Children exposed to lead are at risk for decline in cognitive function and educational achievement [26–29]. Studies which assessed a treatment dose of iron for anemic children were also excluded. In addition, studies which did not assess the sole effect of iron supplementation on cognition were not included (for instance studies that assessed the effects of supplementation with multiple micro-nutrients with iron as one of the components with no control group that is supplemented with the same form of micronutrients excluding iron). Studies which provided iron together with folic acid or vitamin C, or provided deworming treatment were included. These were exceptionally accepted because iron is commonly provided with folic acid (a form supplemented during pregnancy), with vitamin C (as enhancer of iron absorption), and/or together with deworming because of the prevalence of intestinal parasites in LMICs.

Outcome of the studies

The main outcome of the study intervention is the change in cognitive development between baseline and after supplementation. The outcome measurements were based on one of the cognitive domain measurements: intelligence, memory, attention, concentration, or academic achievement. The additional outcomes included anemia (hemoglobin concentrations below 115.0 g/l), hemoglobin concentrations (g/l), iron deficiency (measured using indicators of iron status including ferritin <15 μg/L and transferrin saturation <15%) [5, 7, 8], iron deficiency anemia (coexistence of anemia and iron deficiency), safety outcomes (as indicated by the number of event morbidity and mortality during supplementation, diarrhea, constipation, vomiting and loss of appetite) and adherence to the supplementation.

Study selection

Identified studies using the search strategy were exported from the respective databases to EndNote X9 (www.endnote.com). EndNote was used to identify and drop duplicates. Screening of records based on the title and abstract, and of full text was carried out using DistillerSR (https://www.evidencepartners.com/), a systematic review software. The first round screening conducted in April, 2021 was carried out by two reviewers (BTG, ND, MB, and GE), who independently included relevant articles following the above mentioned eligibility criteria. Disagreements were resolved by a third reviewer and consensus-based discussions. Screening of the updated records in October, 2022 was carried out by one reviewer (BTG) [30].

Data extraction

Data extraction was carried out independently by two reviewers (BTG & ND). The format for the extraction of the data, based on the Cochrane Data collection form for intervention reviews (https://dplp.cochrane.org/data-extraction-forms), was modified based on the study question and pre-tested before use. The intervention consisted of supplementing iron compared to a control group that enables the comparison of the sole effect of iron. Details of the iron dose, form, frequency (intermittent, daily), duration of the intervention, and the provision method (at school/home, by teachers or caregivers) were considered. Data extraction form included the population description, study setting, inclusion and exclusion criteria, selection criteria, blinding, number of participants (cluster if applicable), and withdrawals from the study. Biochemical and development outcomes were reported as mean and standard deviations (SD), median or interquartile range and 95% confidence intervals (IQR, 95%CI). Disagreements were discussed to achieve a harmonized approach of data extraction.

Assessment of risk of bias

The risk of bias (RoB) was assessed using the Cochrane risk of bias assessment tool (RoB2) (https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool). Briefly, randomization, concealment of allocation prior assignment, blinding of participants, personnel, and outcome assessors; assessment of incomplete outcome data; assessment of selective reporting; and checking for possible attrition bias through withdrawals, dropouts, and protocol deviations were assessed. Two reviewers made judgments of bias independently. Disagreements were resolved by consulting with a third reviewer for arbitration as necessary.

Data synthesis

Review Manager Software (Review Manager 5.4) was used for data analysis. Descriptive statistics (means and SD, median, IQR, 95%CI and proportions) were used to summarize baseline information.

Cognitive development outcomes were organized with respect to the cognitive domain. They were presented as pooled standard mean difference (SMD) with 95%CI. The pooled SMD was calculated using the random effect model. The approximation in case of missing mean (SD) was done based on median and IQR [31]. In case there were more than one group supplemented with iron (different doses or frequency of supplementation) or in control groups, the mean (SD) was pooled when there was no significant difference between the effects of the groups. If there was significant difference between the effect of the groups, the groups were presented separately according to Cochrane Review Manual [32].

A qualitative synthesis was performed in the case of studies where data were not sufficient to be included in the meta-analysis. The unit of analysis is the individual study participant in the case of randomized controlled trials. In cluster randomized controlled trials, clustering was also considered as recommended by the Cochrane Handbook for Systematic Reviews of Interventions. Heterogeneity was checked by Foster plot using Chi-square test and I² statistic, which describes the percentage of variability in effect estimate due to heterogeneity. In a sensitivity analysis, we 1) compared all combined iron supplemented groups with the control/placebo group, and 2) excluded studies that supplemented iron with folic acid or vitamin C. In addition, a sensitivity analysis was performed to investigate the overall effect as one study was excluded sequentially. Publication bias was assessed using Funnel plot asymmetry and Eggen test.

Analysis of subgroups

Heterogeneity was assessed for the following variables: duration of the follow-up (less than four months and four and more months of supplementation), frequency of iron supplementation (four or more times per-week and once or twice per-week), baseline anemia and iron status, and study quality. Forest plots of the subgroup analyses are presented when the data were available.

Results

In total, five databases were searched on April 20th, 2021. The data search resulted in a total of 6599 records after 124 duplicates dropped using EndNote. The screening based on the title and abstract, done in duplicate, resulted in 40 records that were screened based on full text. In total, 27 articles were excluded based on the eligibility criteria. On October 13^th, 2022, the search was run to retrieve new records published since the first search has been completed. After merging the old and the new EndNote libraries and dropping all the duplicates (i.e., records that were already in the old library), 1070 new records have been retrieved. The screening based on title and abstract resulted in one record [33], an abstract in a conference proceeding which was excluded for no full article has been published. Finally, thirteen articles were included in this systematic review (Fig 1).

Study characteristics

Using the World Bank income-based country classification, two studies were conducted in high-income countries (Croatia and United Kingdom) [35, 36], ten in middle-income countries (one in South Africa, one in Egypt, two in Indonesia, two in Thailand, and four in India) [37–46] and one study was conducted in a low-income country (Mali) [47]. In the study conducted in India by Gopaldas and collaborators, only boys were enrolled [45], while only girls were enrolled in the studies conducted by Kashyap & Gopaldas (1987) and Sen & Kanani (2009) [38, 44]. One study considered anemic and infected children with Schistosoma haematobium [47], and one study considered iron deficiency as an inclusion criterion [37]. In nine studies, iron supplements were in the form of ferrous sulfate, in doses ranging from 2 to 60 mg of elementary iron [37, 39–45, 47]. Other forms of iron supplements were also used either in a singular form (i.e. ferri-glycine sulfate) [36] or in combination with folic acid, or vitamin C [35, 38, 46]. Two studies supplemented additionally long chain fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) [37], and multiple micronutrients in a factorial design [47]. Placebo control was not included in three studies [38, 46, 47] (Table 1).

Table 1. Descriptive summary of the studies included in the systematic review.

Country (Author, year)	Number of subjects, age, intervention duration	Baseline anemia/iron status	Intervention/ control and groups	Cognition outcome assessment method
Baumgartner et al. 2012 [37] (South Africa)	n = 319, age 6–11 y, 8.5month	Included Iron deficiency only Anemia prevalence: 20.9%	50 mg iron as iron sulfate 420 mg DHA and 80 mg EPA Placebo tablets 4 groups: Iron & placebo; Placebo & DHA/EPA; Iron & DHA/EPA; Placebo & placebo, Frequency 5 day per week	Kaufman Assessment Battery (Atlantis, Atlantis Delayed, Hand movement (I) and Triangles) & HVLT (Recognition, Discrimination index & Total scores of recalls (M))
Sen & Kanani 2009 [38] (India)	N = 240 Female, 9–13 y, 1 year	Mean Hb 11.3g/dL Anemic 68.3% Unknown Iron status	100 mg elemental iron and 0.5 mg folic acid (IFA) Control: no supplementation IFA once weekly; IFA-twice weekly; IFA-Daily & control	Clerical task (AC), Digit Span (M), Mazes test (I), & Visual Memory Test
Sungthong et al. 2004 [39] (Thailand)	N = 397, 6–13 y, 16 weeks	Anemic: 27% Iron deficient: 21.5%	400 mg Albendazole for all, 300mg ferrous sulfate (60 mg elemental Fe); Placebo tablet Daily iron, weekly iron, & placebo	IQ point (TONI II) (I), Thai language, Mathematics (EA)
Soemantri 1989 [41] (Indonesia)	N = 130, 8.1–11.6y, 3 months	Iron deficiency Anemic: 58, Nonanemic: 72	10 mg per kg of body weight per day of ferrous sulfate (equals 2mg elemental Fe), Placebo: saccharin and tapioca Groups: iron suppl. &anemic; iron suppl. &non-anemic; placebo &anemic; placebo &non-anemic	IQ point (I), Language score, Mathematics score (EA), Biology scores, & Social science score
Pollitt et al. 1989 [42] (Thailand)	N = 1358, 9–11 y, 16 weeks	Iron deficiency anemia: 101 (7.44%); iron depleted: 47 (3.46%)	200mg of albendazole for all, 50mg/day ferrous sulphate first 2 weeks (2 mg elemental Fe per kg of body weight per day) then 100mg/day (4 mg per kg of body weight per day) for 14 weeks, Placebo: sweet cassava powder	Thai Language, Mathematics (EA), Raven’s Colour Progressive Metrices (I)
Kashyap & Gopaldas 1987 [44] (India)	N = 166 Female, 8–15 y, 8 months	Hb (g/dL) level of iron suppl.: 10.28; placebo: 10.39	60 mg elemental iron per day (FeSO₄), Placebo: sugar tablets	Clerical Task (AC) test, Digit Span test (M), Mazes test (I), Visual Memory test
Soemantri et al. 1985 [40] (Indonesia)	N = 119, Mean age 10.80 y, 3 months	Iron deficiency anemia status:78 Non-anemic: 41	10 mg per kg of body weight per day of ferrous sulfate (equal to 2 mg of elemental iron), Placebo: only saccharine and tapioca	Raven Progressive Matrices, The Bourden-Wisconsin test (AC), School achievement test (Mathematics, biology, social science, and language)
Gopaldas et al. 1985 [45] (India)	N = 48, Male only 8–15 y, 4 months	Mean (SD) Hb (g/dL) 11.37(0.59) No difference between groups Iron status: Unknown	Groups: 40mg iron suppl.; 30mg iron suppl in the form of ferrous sulphate; placebo: brown sugar Frequency of supplementation: Daily	Visual Recall, Digit Span (M), Mazes (I), Clerical Task (AC)
Seshadri et al. 1982 [46] (India)	N = 94, 5–8 y, 60 days	Mean (SD) of baseline Hb (g/L): 102.3(10.3) with no difference between groups Iron status: Unknown	Iron suppl.: 20 mg Fe & 0.1 mg folic acid; control: No intervention Frequency of supplementation: Daily	Verbal test (WISC), performance tests (WISC), total IQ (I)
Lynn & Harland 1998 [35] (England)	N = 413, 12–16 y, 16 weeks	Anemic = 2.9%, Iron deficiency = 16.9%	17 mg elemental iron with 70 mg ascorbic acid; Placebo tablet (not specified) Frequency of supplementation: Daily	Raven’s Colour Progressive Metrices (I)
Buzina-Suboticanec et al. 1998 [36] (Croatia)	N = 66, 8.7–9.6 y, 10 weeks	Mean (SD) Hb (g/L) 120.4 (5.2), Serum iron (mol/L) 17.4 (7.2)	100 mg of iron in the form of ferri-glycine sulfate; placebo Frequency of supplementation: 6 days/week	Verbal (Arithmetic, Similarities, Digit span) & Non-verbal (Picture completion, Block design, Coding)
Ayoya et al. 2012 [47] (Mali)	N = 439, 7–12 y, 12 weeks	Included: Anemic and infected with S. haematobium Mean (SD) Hb (g/L) 104.9(10)	60 mg ferrous sulfate; MM supplements All children treated with Praziquantel (40 mg per kg of body weight) Groups: Iron suppl. only; MM suppl. only; iron & MM suppl.; and control (no intervention) Frequency of supplementation: 5 days/week	School attendance, School achievement test (EA)
Pollitt 1997 [43] (Egypt)	N = 68, 8–11 y, 4 months	Iron deficiency anemic: 28; nonanemic: 40	50 mg ferrous sulfate (2 mg elemental iron per kg body weight); placebo: Unknown Frequency of supplementation: 6 days/week	Continuous Performance Test, Peabody Picture Vocabulary Test (PPVT), Matching Familiar Figure Test (MFFT).

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AC: attention and concentration; DHA: docosahexaenoic acid; EA: Educational achievement; EPA: Eicosapentaenoic acid; Hb: Hemoglobin concentration; I: Intelligence; IFA: Iron folic acid; M: Memory; WISC: Wechsler Intelligence Scale for Children; y:year

In most of the studies supplements were provided at least five days a week. Children were supplemented once or twice weekly, four times per week or daily in three studies [37–39]. Five included studies supplemented children for 2–3 months. Five studies provided the supplement for 4 months and three studies for 8 months to a year.

Different types of cognitive development tests were used (Table 1). Based on cognitive domain categorization, 11 studies assessed intelligence in general, five studies assessed attention & concentration, and five studies assessed memory. In addition, we included school achievement as an outcome which was assessed in six studies.

Risk of bias

Table 2 presents the summary of the RoB assessment of the included articles based on RoB2. Six studies were considered as high RoB [38, 40–42, 46, 47], four represent some concern [35, 36, 43, 44] and three have low RoB [37, 39, 45]. The study by Baumgartner et al. 2012 reported no significant dropout rate among the intervention groups. The frequency of supplementation was changed from 4 days per week to 5 days per week to catch up on the unexpected loss of intervention days due to the interruptions in the supplementation [37]. Sungthong et al. (2004) did not report the exact number of dropout rate by study group. However, we estimated that the number of dropout rate was higher in the placebo (≈28 children) than weekly iron supplemented group (≈20 children) and daily iron supplemented group (≈11 children). The analysis between the dropout children and the children who completed the study showed no significant difference [39]. Lynn and Harland (1998) and Soemantri (1989) did not report the randomization process of the children to the intervention groups [35, 41].

Table 2. Risk of bias among the included studies using RoB 2 tool.

First author, publication year and [reference]	Risk of bias domain					Overall risk of bias
First author, publication year and [reference]	D1	D2	D3	D4	D5	Overall risk of bias
Baumgartner et al. 2012 [37]	L	L	L	L	L	L
Sen & Kanani 2009 [38]	H	H	H	L	SC	H
Sungthong et al. 2004 [39]	L	L	L	L	L	L
Soemantri 1989 [41]	SC	SC	L	L	SC	H
Pollitt et al. 1989 [42]	SC	SC	SC	L	L	H
Kashyap & Gopaldas 1987 [44]	SC	L	L	L	L	SC
Soemantri et al. 1985 [40]	H	L	L	L	L	H
Gopaldas et al. 1985 [45]	L	L	L	L	L	L
Seshadri et al. 1982 [46]	SC	SC	L	SC	L	H
Lynn & Harland 1998 [35]	SC	L	L	L	L	SC
Buzina-Suboticanec et al. 1998 [36]	SC	L	L	L	L	SC
Ayoya et al. 2012 [47]	SC	SC	L	L	L	H
Pollitt 1997 [43]	SC	L	L	L	L	SC

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Risk of bias domain

D1: Randomization process

D3: Intervention Deviations

D3: Missing outcome data

D4: Measurement of the outcome

D5: Selection of the reported result

Judgment

L Low risk of bias

SC Some concern

H High risk of bias

Effect of iron supplementation on cognitive development of school-age children

Cognitive outcomes were categorized into three domains: intelligence, attention and concentration, and memory. In addition, educational achievement was also included.

Effect of iron supplementation on general intelligence of the school-age children

Eleven studies assessed the general intelligence of the children using five tools. The tests used in the assessment are Kaufman Assessment Battery (Hand movement), Mazes test, test of Nonverbal Intelligence (TONI II), Raven’s Color progressive matrices, and Wechsler Intelligence Scale [35–39, 41–46]. Five studies showed that iron supplementation increased significantly the intelligence of the children [36, 38, 44–46]. A study by Kashyap and Gopaldas (1987) indicated that the intelligence of the schoolgirls was significantly improved among iron supplemented groups (supplemented 60 mg elemental Fe/day for four months). The effect was sustained after suspending the supplementation for 4 months [44]. However, the study conducted by Soemantri (1989) showed no effect of daily 2 mg per kg of body weight, elemental iron supplementation provided in the form of iron sulfate during 3 months on intelligence of the children [41]. Study by Gopaldas et al. (1985), showed that schoolboys who were supplemented with 40 mg iron for four months scored significantly higher in intelligence compared to the baseline and to those who had placebo supplements. Both 30 mg and 40 mg doses of iron improved significantly intelligence of anemic children [45]. Iron supplementation had significant effect on intelligence only among mildly anemic schoolchildren from Croatia [36]. Lynn and Harland (1998) demonstrated that iron supplementation did not affect significantly children’s intelligence. But in subgroup analysis, supplementation of 17 mg of elemental iron combined with 70 mg of vitamin C for 16 weeks had significant effect on the intelligence of children with low iron status [35]. Sen and Kanani assessed the effect of once-weekly, twice-weekly, and daily iron-folic acid supplementation of schoolgirls with no intervention. Intelligence increased significantly compared to the non-supplemented group, but the effect was greater in the more-frequent iron-folic acid supplementation (daily and twice- weekly) than in the once-weekly supplemented group [38]. Paradoxically, the study conducted by Sungthong and colleagues found that improvement in intelligence of children was significantly lower in the daily iron supplemented children than in the group who received weekly iron supplementation or placebo [39].

Six studies reported no significant effect of iron supplementation on intelligence of school-age children [35, 37, 39, 41–43]. A study conducted by Pollitt (1997) in Egypt showed that iron sulfate supplementation of children aged 8–11 years had no significant effect on their intelligence [43].

Effect of iron supplementation on general intelligence of the school-age children—Meta-analysis

A total of 1703 and 1402 school-age children were assigned to iron supplement and placebo (or no intervention) groups in ten studies, respectively, included for meta-analysis [35–39, 41, 42, 44–46]. Overall, iron supplementation had significant effect on intelligence of school-age children (SMD 0.46, 95%CI: 0.19, 0.73, P<0.001, n = 3105; test for heterogeneity I² = 89%, P<0.001) (Fig 2). Iron supplementation improved significantly the intelligence in studies categorized with high RoB (SMD 0.77, 95%CI: 0.11, 1.43, P = 0.02, n = 1744; test for heterogeneity I² = 94%, P<0.01). There was no significant effect in studies with low and moderate RoB (SMD 0.25, 95%CI: -0.05, 0.54; P = 0.10, n = 1361; test for heterogeneity I² = 82%, P<0.01) (S1 Fig). There was no significant effect of iron supplementation on the intelligence after the studies which supplemented iron with folic acid [38, 46] or vitamin C [35] were excluded (SMD 0.20, 95%CI: -0.04, 0.44; P = 0.10, n = 2434; test for heterogeneity I² = 81%, P<0.01) (S2 Fig).

Four studies supplemented the children for less than four months and six studies for longer periods. The results showed that iron supplementation for shorter periods improved significantly the intelligence of school-age children (SMD 0.93, 95%CI: 0.12, 1.75; P = 0.03, n = 335; test for heterogeneity I² = 90%, P<0.01) (Fig 2). The effect remained significant after the study supplementing iron-folic acid [46] was excluded (S2 Fig). The effect was not significant when children were supplemented for longer periods (for four and more months) (SMD 0.21, 95%CI: -0.02, 0.43, P = 0.07, n = 2770; test for heterogeneity I² = 82%, P<0.01) (Fig 2). The sensitivity analysis showed similar finding after excluding the studies supplementing iron with folic acid [38] or vitamin C [35] (S2 Fig).

Iron supplementation for four and more times per week (including daily supplementation) has significant effect on intelligence (SMD 0.48, 95%CI: 0.17, 0.79, P = 0.003, n = 2806; test for heterogeneity I² = 91%, P<0.01) (Fig 2). However, there was no significant effect of iron supplementation for four and more times per week (SMD 0.24, 95%CI: -0.03, 0.52, P = 0.08, n = 2243; test for heterogeneity I² = 83%, P<0.01) on intelligence after excluding studies that supplemented iron with folic acid [38, 46] or vitamin C [35] (S2 Fig). Weekly iron supplementation does not affect significantly the intelligence of school-age children (SMD 0.18, 95%CI: -0.31, 0.67, P = 0.47, n = 246; test for heterogeneity I² = 52%, P = 0.15) (Fig 2). There was not sufficient studies to carry out the sensitivity analysis regarding the effect of the sole weekly supplementation of iron.

In a subgroup analysis, iron supplementation significantly improved the intelligence of anemic children (SMD 0.79, 95%CI: 0.41, 1.16, P = 0.001, n = 236; test for heterogeneity I² = 40%, P = 0.17) (Fig 3). The effect of iron supplementation was not significant in non-anemic (SMD 0.01, 95%CI: -0.10, 0.12, P = 0.89, n = 1295; test for heterogeneity I² = 0%, P = 0.73), iron deficient (SMD -0.45, 95%CI: -2.07, 1.17, P = 0.59, n = 174; test for heterogeneity I² = 96%, P<0.01), and iron replete (SMD 0.09, 95%CI: -0.10, 0.29, P = 0.35, n = 1655; test for heterogeneity I² = 90%, P<0.01) school-age children at baseline (Fig 3). The effect of iron supplementation solely (excluding iron-vitamin C [35]) on intelligence among iron deficient and iron replete school-age children at baseline were similar (S2 Fig). The sensitivity analysis showed that iron supplementation significantly improved the intelligence of iron deficient children (SMD 0.52, 95%CI: 0.16, 0.87, P = 0.005, n = 128; test for heterogeneity I² = 0%, P = 0.77) after dropping the study of Pollitt et al. (1989) [42].

Effect of iron supplementation on attention and concentration of school-age children

Five studies assessed the effect of iron supplementation on attention and concentration of school-age children using Clerical Task, the Bourden-Wisconsin test, and Continuous Performance Test [38, 40, 43–45]. Four studies found that iron supplementation had significant improved attention and concentration of school-age children [38, 40, 43–45]. In a yearlong interventional study by Sen & Kanani (2009) indicated that frequent iron-folic acid supplementation (daily or twice weekly) was found to improve significantly attention and concentration compared to less frequent supplementation (once weekly) [38]. Soemantri and colleagues reported a significant effect of iron supplementation in all the children. They also showed that the improvement in attention and concentration was significant among iron deficient anemic children but not in those who were non-anemic [40]. Similarly, the study conducted by Pollitt (1997) demonstrated that iron supplementation improved significantly the attention and concentration of anemic but not non-anemic school-age children [43].

Effect of iron supplementation on attention and concentration of school-age children—Meta-analysis

Only three out of five studies were included in the meta-analysis. In total, 224 and 115 children were respectively supplemented with iron and placebo (or no supplement) [38, 44, 45]. Overall, iron supplementation improved significantly the attention and concentration of school-age children (SMD 0.45, 95%CI: 0.09, 0.80, P = 0.01, n = 339; test for heterogeneity I² = 49%, P = 0.10). Assessed for the RoB, one study had a high RoB while two had low and moderate RoB. When the high RoB study was excluded from the analysis, iron supplementation had no significant effect on the attention and concentration of school-age children (SMD 0.33, 95%CI: -0.39, 1.05, P = 0.37, n = 178; test for heterogeneity I² = 77%, P = 0.04) (S3 Fig). Similarly, iron supplementation had no significant effect on the attention and concentration of school-age children after excluding the study that supplemented iron-folic acid [38] (SMD 0.33, 95%CI: -0.39, 1.05, P = 0.37, n = 178; test for heterogeneity I² = 77%, P = 0.04) (S4 Fig).

Iron supplementation for short duration (less than four months, two studies [44, 45]) had no significant effect on the attention and concentration of school-age children (SMD 0.33, 95%CI: -0.39, 1.05, P = 0.37, n = 178; test for heterogeneity I² = 77%, P = 0.04). Similarly, frequent iron supplementation (four or more times per-week) had no significant effect on the attention and concentration of children (SMD 0.41, 95%CI: -0.04, 0.86, P = 0.07, n = 231; test for heterogeneity I² = 54%, P = 0.11) (Fig 4). The effect remained non-significant after excluding the study with iron-folic acid supplementation [38] (S4 Fig). There was no evidence on effects of supplementation of iron for long duration (four or more months) or intermittently.

Effect of iron supplementation on the memory of school-age children

Five studies reported the effect of iron supplementation of school-age children on their memory using Digit Span, Visual Memory Test and Hopkins Verbal Learning Test tools [36–38, 44, 45]. Iron supplementation was found to have significant effect on the memory of the children in four out of five studies [37, 38, 44, 45]. The study by Baumgartner and colleagues assessed the sole and combined effects of supplementing iron and long chain fatty-acids (EPA/DHA) compared to placebo on the memory of school children. Iron supplementation improved significantly children’s memory compared to children who received placebo. The effect of supplementation on memory of the school-age children was significantly higher among iron supplemented girls compared to boys and in anemic compared to non-anemic children [37]. Sen & Kanani reported that iron-folic acid supplementation increased memory in schoolgirls in India. Improvement in memory was greater in the frequently iron-folic acid supplemented groups, that is daily and twice weekly, than in the once weekly supplemented group [38]. Another study in India by Gopaldas and colleagues among boys showed that the mean test score for digit span increased significantly from 3.43 to 4.42 in the two iron supplemented groups (from 3.40 to 4.21 in children supplemented with 30mg iron and from 3.46 to 4.62 in those supplemented with 40mg iron), while there was no significant change in the placebo group (from 3.06 to 3.16). Significant improvement in visual recall test but not in digit span test compared to the placebo were found among the 30 mg iron supplemented group. In the 40 mg iron supplemented group, both digit span and visual recall tests were significantly higher compared to the placebo group [45]. The study conducted by Buzina-Suboticanec et al. (1998) did not find any effect in digit span after 10 weeks of iron supplementation compared to placebo [36].

Effect of iron supplementation on the memory of school-age children—Meta-analysis

In the five studies, a total of 414 and 304 children were assigned to receive iron supplementation and placebo (or non-intervention), respectively [36–38, 44, 45]. The meta-analysis showed that iron supplementation significantly improved the memory of school-age children (SMD 0.45, 95%CI: 0.04, 0.69, P <0.001, n = 718; test for heterogeneity I² = 45%, P = 0.09). After excluding the study with high RoB [38], the effect of iron supplementation on improving the memory of school-age children remained significant (SMD 0.30, 95%CI: 0.09, 0.51, P = 0.004, n = 557; test for heterogeneity I² = 18%, P = 0.30) (S5 Fig). The effect of iron supplementation on improving the memory of school-age children remained significant after excluding iron-folic acid supplementation study [38] (SMD 0.33, 95%CI: 0.08, 0.57, P = 0.008, n = 581; test for heterogeneity I² = 38%, P = 0.18) (S6 Fig).

The subgroup analysis showed that frequent iron supplementation (four or more times per-week) had significant effect on the memory of school-age children (SMD 0.45, 95%CI: 0.15, 0.74, P = 0.003, n = 610; test for heterogeneity I² = 58%, P = 0.05) (Fig 5). Similarly, the effect remained significant after the exclusion of iron-folic acid supplementation study [38] (S6 Fig). There was no evidence regarding twice or once weekly iron supplementation (Fig 5). The three studies which reported the effect of iron supplementation based on child’s anemic status found that iron supplementation had significant effect on the memory of anemic children (SMD 0.47, 95%CI: 0.13, 0.81; P = 0.006, n = 145; test for heterogeneity I² = 0%, P = 0.99) but not on non-anemics (SMD -0.02, 95%CI: -1.01, 0.97; P<0.97, n = 266; test for heterogeneity I² = 65%, P = 0.09) (Fig 5).

Effect of iron supplementation on educational achievement and school performance of school-age children

Educational achievement was assessed by six studies using school attendance, overall grade, tests related to mathematics, language, biology, and social science courses [36, 39–42, 47]. Iron supplementation significantly improved the school performance of children in two studies [40, 41]. According to the study conducted by Soemantri (1989), iron supplementation had significant effect on math’s score but not on language score in all children. In a subgroup analysis, educational achievement in both math’s and language scores improved significantly in anemic children [41]. These results are in line with the study conducted by Soemantri et al. (1985), which found that improvement in educational achievement was greater in anemic children than in non-anemics [40]. Even if the effect of iron supplementation on educational achievement in a study conducted by Ayoya et al. (2012) in Bamako Mali was not significant, it showed a borderline effect with p-value of 0.08 [47].

Effect of iron supplementation on educational achievement and school performance of school-age children—Meta-analysis

Five studies were included in the meta-analysis [36, 39, 41, 42, 47]. One thousand two hundred nine (1209) and 1063 school-age children received iron supplementation and placebo/non-intervention, respectively. Iron supplementation did not have a significant effect on school achievement of the children (SMD 0.00, 95%CI: -0.21, 0.21, P = 1.00, n = 2272; test for heterogeneity I² = 76%, P<0.001) (Fig 6). Similar results were found when only two studies with low and moderate RoB were included in the analysis (SMD -0.16, 95%CI: -0.38, 0.05, P = 0.13, n = 382; test for heterogeneity I² = 0%, P = 0.65) (S7 Fig). In a subgroup analysis, school achievement of children was not affected by the child anemic status, nor by the duration of iron supplementation (Fig 6).

Effect of iron supplementation on nutritional outcomes

Eleven studies [35–38, 41, 44–46, 48–50] out of the thirteen included in this systematic review reported on the effect of iron supplementation on hemoglobin concentrations of school-age children. Iron supplementation significantly increased the hemoglobin concentrations of the children (SMD 1.08, 95%CI: 0.68, 1.49, P<0.001, n = 3613; test for heterogeneity I² = 96%, P<0.001) (S8 Fig). In a separate analysis that assessed the effect of iron supplementation on hemoglobin concentration categorized per the domain of the cognitive outcome, hemoglobin concentrations increased significantly in all categories compared to the placebo/non-intervention groups (S9 Fig). Only four studies reported on the effect of iron supplementation on serum ferritin [35, 48–50] and serum transferrin [36, 41, 48, 50]. The analysis indicated that iron supplementation did not have a significant effect on serum ferritin (SMD 1.93, 95%CI: -0.27, 4.14, P = 0.08, n = 2570; test for heterogeneity I² = 100%, P<0.01) and transferrin concentrations (SMD 1.01, 95%CI: -0.50, 2.51, P = 0.19, n = 1970; test for heterogeneity I² = 99%, P<0.01) (S10 & S11 Figs).

Risk of iron supplementation on morbidity—Safety outcomes

Morbidity was reported by two studies. Malan and colleagues reported that iron supplementation, provided alone, significantly increased the number of days of illness (mostly respiratory), duration of episode of illness and the number of episodes [51]. Contrarily, Chwang and collaborators (1988) indicated that iron supplemented children had significantly lower morbidity scores, especially among those who were anemic [52]. Three studies were conducted in malaria-free areas [42, 49, 51]. Ayoya et al. (2009) indicated that malaria incidence and parasite density were higher in the iron supplemented group [48].

Adherence to iron supplementation

Adherence to supplementation was reported in four studies. Overall adherence was reportedly high in the studies conducted by Baumgartner and colleagues (≃95%) [51] and Sungthong and colleagues (more than 93%) with no significant difference among intervention groups [37, 39, 49]. Sen & Kanani (2009) reported a mean adherence of 72% in the iron supplemented group (≥70% iron dose consumed in > 50% of participants), while the control group received no supplementation [38]. Soemantri (1989) included in the analyses only participants whose adherence was greater than 80% [41].

Discussion

Thirteen randomized trials that evaluated the effect of iron supplementation on cognition of school-age children were included in the systematic review and twelve were included in the meta-analysis. Most of the studies included in this systematic review and meta-analysis were conducted in middle income countries. Only one study was conducted in low-income countries [47], despite the high prevalence of iron deficiency anemia in this setting [53].

Five out of the eleven studies which evaluated general intelligence showed that iron supplementation improved school-age children’s intelligence. Eight out of ten studies included in a review by Lam & Lawlis (2017) on the effect of different micronutrients intervention on cognitive performance among school-age children indicated significant improvement in nonverbal fluid intelligence [18]. This meta-analysis showed that iron supplementation improved intelligence of school-age children, with moderate effect size. However, the effect on improved intelligence resulted only from four studies classified as high RoB [38, 41, 42, 46] and three studies classified as moderate RoB [35, 36, 44]. There was no evidence of effect of iron supplementation on the intelligence of school-age children in studies with low RoB [37, 39, 45]. The effect of iron supplementation on the intelligence of school-age children was not significant after excluding studies that supplemented children with iron with folic acid or vitamin C [35, 38, 46]. Studies showed that both folic acid and vitamin C (in animal studies) influence functionality of the brain. For instance, folic acid deficiency may result in the raise of homocysteine concentration which is associated with poor cognitive performance [54–56]. Animal studies have shown that vitamin C affects neurodevelopment by influencing neuronal differentiation and myelin formation, and plays a role in neurotransmitters function [57, 58]. The study by Sungthong and colleagues reported that the general intelligence was lower among children who were supplemented daily than those in groups receiving weekly iron supplementation or placebo [39]. This might be due to the oxidative stress caused by high iron stores on cognitive function [59, 60], in case of iron replete status (6% iron deficiency anemia) and non-anemia (26% anemia) [39, 49].

Short periods (less than four months) of iron supplementation improved significantly intelligence of school-age children. Frequent administration (daily) of iron supplementation also improved intelligence of school-age children. However, our findings showed that frequent supplementation of iron, solely, has no effect on the intelligence of school-age children [36, 41, 45]. Additionally, iron supplementation had a greater significant effect on the intelligence of children who were anemic at baseline. Similar findings were reported in two previous meta-analyses [15, 16]. This effect was not found in children who were non-anemic and iron replete at baseline (Fig 3). Similarly, there was no effect of iron supplementation on the intelligence of children who were iron deficient at baseline. However this result was mainly driven by the findings of Pollitt et al. (1989), where iron-depleted children assigned to placebo, scored higher in Raven’s Colour Progressive Metrices test (IQ) at baseline compared to iron-depleted children who received the iron treatment [42].

Iron supplementation improved attention and concentration of school-age children with moderate effect. Iron deficiency is associated with altered dopamine metabolism; dopamine is involved in regulating attention [61, 62]. The effect of iron supplementation was not significant after excluding the study with high RoB, which is also the study that supplemented children with iron- folic acid [38]. A previous review conducted on older children (6–18 years) and adults indicated that iron supplementation had statistically significant beneficial effects on attention or concentration [16]. Folic acid deficiency is associated with the reduction in the synthesis of S-adenosylmethionine, which inhibits S-adenosylmethionine-dependent methylenation reactions and neurotransmitters including dopamine [56].

Iron supplementation had a moderate effect in improving the memory of school-age children [37, 38, 44, 45]. This result remained significant when including all the studies, and after excluding the one study with high RoB [38]. In addition, the meta-analysis found that iron supplementation effects on memory was greater among anemic children. A systematic review and meta-analysis of iron supplementation on cognition of older children (6-18years) and adult found no evidence supporting that iron supplementation improves memory [16]. In animal studies, neuronal iron uptake is essential for normal hippocampal neuronal development and memory behavior [63, 64].

From the six studies which assessed the effect of iron supplementation on educational achievement of school-age children, only two showed a benefit of the interventions. This meta-analysis found no evidence that iron supplementation, regardless of its frequency and duration, and baseline anemic status of the children, had an effect on the educational achievement of school-age children. Similar results were reported in the review conducted by Falkingham et al. (2010), which indicated that there was no suggestion of the effect of iron supplementation on scholastic ability of children, regardless of their baseline anemic status [16]. The lack of effect of iron supplementation on educational achievement and school performance in children could be due to the longer time required to affect the domains of cognitive development compared to the time required to restore iron status [65, 66].

Concerns regarding possible side effects

Iron supplementation can cause gastrointestinal side effects including loose stool/diarrhea, hard stool/constipation, abdominal pain, nausea, change in stool color, reflux/heartburn and headache [67]. Low doses of iron supplementation are reportedly not associated with an increased risk of infectious illness in children, except for a slight increase in the risk of developing diarrhea. Iron supplementation may increase the risk of malaria [60], and the WHO recommends monitoring fever in preschool and school children receiving intermittent iron supplementation in malaria settings [22]. Despite the serious risk that is evidenced with iron supplementation, side effects were reported in two studies only [51, 52], while the increased risk of malaria infection was reported in one study only [48] and three studies indicated that the setting was malaria-free [42, 49, 51]. It is important that morbidity and potential side effects are assessed in studies and programs that supplement iron to children.

Strengths and weaknesses of the systematic review and meta-analysis

This systematic review updated the current evidence on the effects of iron supplementation on cognitive development and school achievement of school-age children. The review and the analyses were performed to report separately on the effects based on cognitive development domain of the children. In addition, school achievement was reported as a separate outcome.

Our study has limitations that are inherent to cognition as an outcome in research trials. The analysis was performed per domain of cognition. However, different tools were used to evaluate a specific domain which makes the comparison between the interventions’ outcomes difficult. In addition, there were large differences in the intervention design including, the dose and the form of the iron supplements, and the frequency and duration of the supplementation. An optimal dose, frequency or duration of iron that results in improved cognitive development outcomes could not be established. Furthermore, the duration of the intervention to detect a change in cognitive development outcomes should be reconsidered. In addition, the role of other micronutrients in some studies, that might have affected the results could not be disentangled. Subgroup analysis was done based on overall RoB of the studies, frequency and duration of intervention, and anemia and iron status at baseline to explore the benefit per risk group. Because of the limited number of studies which reported on the micronutrient status of children at baseline, it was difficult to conduct meta-analysis with all the subgroups indicated above. Overall, six studies had high RoB and only three studies were evaluated as low overall RoB. Finally, even if we used extensively the search strategies to include all the potential studies, the researchers cannot exclude the possibility that some relevant studies have been missed out.

Conclusion

Iron supplementation improved intelligence, attention and concentration, and memory of school-age children but did not affect school achievement. Iron supplementation benefitted the intelligence and memory of anemic school-age children, who are at higher risk of impaired cognitive development. Frequent iron administration had a greater effect on the intelligence and memory of the children, while short supplementation periods improved intelligence.

Our systematic review and meta-analysis showed overall that iron supplementation remains an effective intervention that can affect the cognition of school-age children. Further research should be encouraged in low-income settings using up-to-date, adapted and validated tools for the assessment of cognition.

Supporting information

S1 Checklist. PRISMA 2020 checklist.

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S1 Table. Medline search strategy for the effects of iron supplementation on cognitive development in school-age children.

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S2 Table. Embase search strategy for the effects of iron supplementation on cognitive development in school-age children.

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S3 Table. Scopus search strategy for the effects of iron supplementation on cognitive development in school-age children.

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S4 Table. Web of Science search strategy for the effects of iron supplementation on cognitive development in school-age children.

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S5 Table. Cochrane Library search strategy for the effects of iron supplementation on cognitive development in school-age children.

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S1 Fig. Frost plot, SMD analysis of the effect of iron supplementation on intelligence of school-age children (subgroup analysis for risk of bias of the study).

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S2 Fig. Sensitivity analysis: Forest plot, SMD analysis of the effect of iron supplementation on intelligence of school-age children by excluding studies supplemented iron with folic acid or vitamin C.

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S3 Fig. Frost plot, SMD analysis of the effect of iron supplementation on attention and concentration of school-age children (subgroup analysis for risk of bias of the study).

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S4 Fig. Sensitivity analysis: Forest plot, SMD analysis of the effect of iron supplementation on attention and concentration of school-age children by excluding studies supplemented iron with folic acid or vitamin C.

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S5 Fig. Frost plot, SMD analysis of the effect of iron supplementation on memory of school-age children (subgroup analysis for risk of bias of the study).

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S6 Fig. Sensitivity analysis: Forest plot, SMD analysis of the effect of iron supplementation on memory of school-age children by excluding studies supplemented iron with folic acid or vitamin C.

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S7 Fig. Frost plot, SMD analysis of the effect of iron supplementation on educational achievement of school-age children (subgroup analysis for risk of bias of the study).

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S8 Fig. Forest plot, SMD analysis of the effect of iron supplementation on hemoglobin level of the school-age children (all included studies).

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S9 Fig. Forest plot, SMD analysis of the effect of iron supplementation on hemoglobin level of the school-age children (categorized based on the cognitive domain).

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S10 Fig. Forest plot, SMD analysis of the effect of iron supplementation on ferritin level of the school-age children.

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S11 Fig. Forest plot, SMD analysis of the effect of iron supplementation on Serum transferrin level of the school-age children.

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Acknowledgments

The authors are grateful to Dr. Ellen Deschepper from Ghent University Faculty of Medicine and Health Sciences for her support in the meta-analysis.

Abbreviations

DHA: Docosahexaenoic acid
EPA: Eicosapentaenoic acid
LMICs: Low- and middle-income countries
RoB: Risk of bias
RoB2: Cochrane risk of bias assessment tool
SD: Standard deviation
SMD: Standardized mean difference

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

This work was conducted under the PhD studies of BTG, whose scholarship was partially funded by the Flemish Interuniversity Council (VLIR-UOS) in the context of the Institutional University Cooperation Program (IUC) with Arba Minch University https://www.vliruos.be/en/projects/project/22?pid=3604. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0287703.r001

Decision Letter 0

Ammal Mokhtar Metwally

14 Mar 2023

PONE-D-22-28873Effects of preventive iron supplementation on cognitive development in school-age children: Systematic Review and Meta-analysisPLOS ONE

Dear Dr. Gutema,

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: I Don't Know

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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5. Review Comments to the Author

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Reviewer #1: The topic of the study is very important as understanding the effects of iron supplementation on cognition among school age children is essential for the proper design of targeted strategies.

However, some aspects of the manuscript should be addressed:

Title:

“Effects of preventive iron supplementation on cognitive development in school-age children: Systematic Review and Meta-analysis”

I don’t understand what did the word (preventive) refer to? Did the authors intend to discuss iron supplementation to prevent iron deficiency anemia in school age children? I don’t think so, as the selected articles included anemic and non-anemic children.

Introduction

References in this section are not updated, most of them had been published one to two decades before.

This section lacks a paragraph illustrating the impact of iron deficiency status or iron deficiency anemia on cognitive development of school age children and consequently on their professional future.

Authors did not clarify the controversy between previous studies as regard the benefits and hazards of iron supplementation for this age group.

Objective

Is clear and well defined except for the word (preventive).

Methods

This section was written in a good technical standard and described in sufficient details. However, the part of statistical analysis was missed.

Methods of statistical analysis must be elaborated.

Readers must be prepared to understand the Forest plot figures which represented most of results. Values and significance of heterogeneity must be explained. If sensitivity analysis was applied or not.

Repeated sentences were detected in page 5 at lines 94-96.

As regards the definition of outcomes at page 5, I think no need for adding the biochemical outcomes as Hb concentration, serum ferritin level and transferrin saturation. These outcomes were not mentioned in the aims of the study and they will increase the diversity of results. Meanwhile, other outcomes as safety and adherence to the supplementation are closely related to the main outcomes.

Results

I was surprised that only one study out of the included 13 studies was performed in a low-income country, while anemia & iron deficiency are prevalent in these countries.

Comments on results were much confusing. These comments need rearrangement to rewrite the results of subgroups in a more structured manner. Authors can create a multilevel numbering to organize the comments on the main outcome domains and the underlying subgroups.

Results about safety outcome and adherence to the supplementation were missed.

Discussion

In the first page of discussion (page 20), the authors tried lengthily to prove that the studies included in the current review were also included in previous reviews, which added nothing to discussion.

The authors did not discuss explanation or hypothesis for the study findings. For example, the authors have to explain the underlying causes of non-improved school achievement in the studies included in this review, or non-improved cognitive functions in non-anemic participants, etc..

I think the authors need to revise the discussion to enrich it with causes of contradict or findings clarify the language, and adding updated references.

Strengths and weaknesses

These points were well documented.

Conclusions

Conclusions are presented in an organized and suitable manner.

Decision: Minor revision

Reviewer #2: We think this is a good systematic review and meta-analysis about the benefits of iron supplementation for the cognitive development in children. It has been well understood that in the school-aged children, iron supplementation has positive effects for improving age-adjusted height among anemic children, risk of anemia and iron deficiency, and the cognitive scores, including intelligence quotient, attention, and concentration.

Gutema et al has done a thorough work to apply their search strategy resulted in 6559 articles in the first phase and 1070 in the second phase. After which they screened again carefully and resulted in 13 articles included for the qualitative synthesis. We note that in 2022 there was a systematic review and meta-analysis published with the title of “Effect of Oral Iron Supplementation on Cognitive Function among Children and Adolescents in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis” which focused on studies in LMICs and in the age of children (and adolescents). Therefore, we acknowledge that Gutema et al implemented a different search strategy and inclusion criteria.

With the current title of “Effects of Preventive Iron Supplementation on Cognitive Development in School-Aged Children: Systematic Review and Meta-Analysis”, there are a few issues we would like to share:

1. The term ‘preventive’ used in the title does not seem to be suitable with the search strategy, analysis, and discussion. Page 26, Discussion section, line 389-390 also elaborated the aim of the review. Majority of the articles reviewed by Gutema et al recommended on the effects of iron in increasing the cognitive development parameters over 2 to 12 months supplementation. Therefore, we believe omitting the ‘preventive’ term would be more suitable.

2. The term ‘school-aged children’ does not match with the strategy applied by Gutema et al, because for example Gopaldas et al (1985 and 1987) included children aged 8-15 years, and Lynn and Harland (1998) included children aged 12-16 years.

We also would like to give input on some details below:

Page 8, line 39–40

Two keywords in the abstract: ‘iron supplementation’ and ‘school-aged children’ are not listed in the MeSH. We advise to choose the keywords based on the MeSH to increase the paper’s readability.

Page 10, line 81–82

“Studies conducted on children under five years or over 12 years of age were excluded.” However, Gopaldas et al (1985) and Kashyap and Gopaldas (1987) included children aged 8-15 years, Lynn and Harland (1998) included children aged 12-16 years, Sen and Kanani (2009) included children aged 9-13 years, Sungthong et al (2004) included children aged 6-13 years. Therefore, Gutema et al included studies in children aged more than 12 years old.

Page 10, line 82

The exclusion criteria applied by Gutema et al did not include other factors leading to bias, such as chronic morbidities and developmental disability. Whereas in Figure 1, there is an exclusion of 1 study due to Lead exposure. For this reason, we believe Gutema et al needs to add the exclusion criteria.

Page 10, line 87–89

“Observational study designs including case-report, case-series, ecological, cross-sectional, case-control, and cohort, quasi-experimental design, and reviews were excluded.”

This exclusion criteria is not needed because these other study designs are not included in the first place, as Gutema et al mentioned in the early paragraph that they only included RCTs.

Page 10 line 84-87

“Studies with multiple micronutrients are not included.” However, in page 14 line 178-180, some studies in combination with other supplementations (folic acid, albendazole, and ascorbic acid) were included in the review. While the studies involving EPA/DHA and multiple micronutrients were assessed properly by Gutema et al in separated groups.

Page 11 line 94–96

“The additional outcomes included anemia (hemoglobin concentrations below 115.0 g/l), hemoglobin concentrations (g/l), iron deficiency (measured using indicators of iron status including ferritin <15 μg/L and transferrin saturation <15%)”. We recommend the authors to mention the references for these cut off.

Page 11, line 106

“Screening in both phases was carried out by two reviewers (BTG, ND, MB, and GE), who independently included relevant articles and the above mentioned eligibility criteria. Disagreements were resolved by a third reviewer and consensus-based discussions. Screening of the updated records was carried out by one reviewer (BTG).”

We would like to confirm about the phases mentioned by the authors: Is the April search considered as the first phase, and the October search as the second phase? If they are, the authors need to inform about the reason for performing the second phase screening only by one person, while they stated that both phases involved two reviewers.

Page 19 line 220-221

“… daily 2 mg elemental iron”. This needs to be corrected to be 2 mg/kg, as is stated in the original paper, that is Soemantri (1989).

Table 2

Risk of bias for Sungthong (2004) indicated the paper has Low risk of bias in all domains (D1-D5). Figure 2 (Forest plot) suggested that iron daily and weekly were disadvantageous for cognitive development compared to placebo. We would suggest the authors to provide some possible explanations about this result, because it does not make sense for iron supplementations to have a more inferior outcome than ‘not giving iron supplementation’ (placebo). Gutema et al need to share their analysis about some factors in the study that could result in such unexpected outcome.

Table 2

The table indicated that Pollitt has a high overall risk of bias. Moreover, Figure 3 section D (iron deficient participants) displayed patients receiving iron supplementation has a lower SMD compared with the patients receiving placebo. We recommend Gutema et al to share their analysis about this result.

Figure 1

‘memroy’ is a typo, which is supposed to be memory.

Figure 3C

The figure showed that Pollit has only 100 patients with anemia and 1210 patients without anemia (in total is 1310 patients), whereas Table 1 mentioned that Pollit has 1775 subjects. Would it be possible there are significant numbers of missing data from Pollit?

Result section

Gutema et al occasionally mentioned the location name to refer to some particular studies, such as Kalibawang (when referring to Soemantri studies) and Vadodara (when referring to Sen and Kanani). I would suggest to mention the name of first author and year, i.e Soemantri (1985) than mentioning the place (Kalibawang).

Page 26, Discussion section

Gutema et al restated again about the inclusion and exclusion methods which we consider is unnecessary because these have been elaborated in the Results section.

Page 27 Line 419-420

Gutema et al need to mention ‘Figure 3’ as a reference for the description about prominent changes in the anemic groups.

Page 27 Discussion

For every aspect being compared, we believe the authors need to analyse about the reasons behind the results. The studies reviewed have different conclusions, which could be affected by the differences in population characteristics and dosages given. One example for this is the study by Sungthong (2004) which had significantly different outcomes compared with other studies, that is the placebo group had better outcomes than the iron-supplemented group.

Page 28 Strengths and Weaknesses of the Systematic Review and Meta-Analysis

From our perspectives, three limitations could be added, as follow:

1) Inability to conclude a specific dosage which would result in better cognitive development outcomes.

2) The observation period was relatively short: 2-3 months (in 5 studies), 4 months (in 5 studies), and 8-12 months (in 3 studies). The observation period in majority of studies could be too short for assessing a cognitive development.

3) The role of other micronutrients in some studies, that might affect the results.

Page 35, Figure 1

Records identified through database searching: 9041

Records after duplicates removed: 7669

Records screened: 6774

The authors need to provide information about what was done to reduce the number of articles from 7669 to 6774.

Reviewer #3: I have reviewed the study by Gutema et al.,

This systematic review and meta-analysis is an important study in its field. The high prevalence of iron deficiency related problems is still a burden in several developing countries. I have several things to be considered at:

1. There were several mistyping found in the text, I suggest the authors to double check the text again. One of the errors was memroy ("memory").

2. The systematic review process explained in the Discussion section (Line 392-407) should probably be written in Methods section as it was already written. My suggestion might need to be discussed further within the authors.

3. I did not find the Discussion section to be enticing as most of it was repeated sentences from Result section. I suggest the authors to consider putting more relevant things to be discussed or probably elaborate further with previous evidences.

Reviewer #4: I do not have any comments for the authors.

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Reviewer #1: Yes: Ebtissam M. Salah El-Din

Reviewer #2: No

Reviewer #3: Yes: Surya Adhi

Reviewer #4: No

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PLoS One. 2023 Jun 27;18(6):e0287703. doi: 10.1371/journal.pone.0287703.r002

Author response to Decision Letter 0

27 Apr 2023

PONE-D-22-28873

Effects of iron supplementation on cognitive development in school-age children: Systematic review and Meta-analysis

Dear Editor

We thank the reviewers for their constructive comments, which helped us to improve our paper. Our responses to the reviewers are provided below, and all changes in the manuscript are marked with track changes. We hope that the revisions meet your expectations and that the manuscript will now be acceptable for publication.

Sincerely,

Befikadu Tariku Gutema

Reviewer #1:

However, some aspects of the manuscript should be addressed:

Title: “Effects of preventive iron supplementation on cognitive development in school-age children: Systematic Review and Meta-analysis”

Response: Thank you for the comments and suggestions. “Preventive” in this case means that iron supplementation was given only for the prevention not treatment. However, we agree with the reviewer that this could have also a different signification. The term ‘preventive’ is dropped now from the title. It reads now “Effects of iron supplementation on cognitive development in school-age children: Systematic Review and Meta-analysis”.

Introduction

References in this section are not updated, most of them had been published one to two decades before.

Response: References were updated when possible.

Response: We added three related statements on the impact of iron deficiency or iron deficiency anemia. Lines 65-66 read now “Iron deficiency and iron deficiency anemia can cause cognitive deficits (Jáuregui-Lobera, 2014; Samson, Fischer, & Roche, 2022).”

Authors did not clarify the controversy between previous studies as regard the benefits and hazards of iron supplementation for this age group.

Response: We added a statement regarding the safety of iron supplementation and the effect of iron supplementation on other parameters including hemoglobin concentration, anemia and iron deficiency. The text reads now in Lines 72-73 “Furthermore, iron supplementation was shown to be effective in improving cognition, safe in malaria settings, and had no gastrointestinal adverse effects.”

Objective

Is clear and well defined except for the word (preventive).

Response: The term preventive is dropped from the whole text.

Methods

This section was written in a good technical standard and described in sufficient details. However, the part of statistical analysis was missed.

Methods of statistical analysis must be elaborated.

Response: We corrected by including additional information regarding the use Forest plot and sensitivity analysis.

Repeated sentences were detected in page 5 at lines 94-96.

Response: Corrected, and the sentence is dropped.

Response: We planned to perform sub-group analysis based on the cut-off point for anemia, iron deficiency and iron deficiency anemia based on the availability of the data. That is why we defined the cut-off points based on the Hb concentration, serum ferritin and transferrin saturation.

Results

I was surprised that only one study out of the included 13 studies was performed in a low-income country, while anemia & iron deficiency are prevalent in these countries.

Response: Indeed, we assume that this is because of the scarcity of studies assessing cognitive development in low-income countries.

Response: Yes, there were long paragraphs which include the subgroup analysis part. We created addition layers of paragraphs based on the outcome with the number of subgroup analysis made for the domain.

Results about safety outcome and adherence to the supplementation were missed.

Response: We added the results of safety and adherence to the supplementation.

Discussion

Response: we agree with the reviewer. This section has been dropped now.

Response: We considered by adding statements reflecting the cause of non-improvement for some of the findings

I think the authors need to revise the discussion to enrich it with causes of contradict or findings clarify the language, and adding updated references.

Response: Considered

Strengths and weaknesses

These points were well documented.

Conclusions

Conclusions are presented in an organized and suitable manner.

Decision: Minor revision

Response: Thank you!

Reviewer #2

We think this is a good systematic review and meta-analysis about the benefits of iron supplementation for the cognitive development in children. It has been well understood that in the school-aged children, iron supplementation has positive effects for improving age-adjusted height among anemic children, risk of anemia and iron deficiency, and the cognitive scores, including intelligence quotient, attention, and concentration.

Response: Thank you your thorough review and comment. The intention to use ‘preventive iron supplementation’ is to show the iron supplementation was given only for the prevention not treatment. Of course, if we consider supplementation (the primary intention is for apparently well population) is a dose for prevention. So, we dropped the word ‘preventive’ from the title, which reads now “Effects of iron supplementation on cognitive development in school-age children: Systematic Review and Meta-analysis”.

Response: Yes, we considered school-age children. One of the exclusion criteria were if the article was based on only under five or only children above 12. These articles (Gopaldas et al (1985 and 1987), and Lynn and Harland (1998)) included children within our inclusion age categories but they also include beyond our age limit. To make it clear for the reader, we corrected the statement regarding the exclusion criteria by adding ‘only’ (page 4 line 87-88) to the age limits as follow: ‘…Studies conducted on children under five years only or over 12 years of age only,’.

Page 8, line 39–40

Response: We changed ‘Iron supplementation’ to ‘Supplementations’ which is a Emtree for Embase. We could not find appropriate term for ‘school-aged children’. So, we opted to use as it is.

Page 10, line 81–82

Response: The response is indicated above.

Page 10, line 82

Response: It is documented that lead exposure is one of the causes for the decline in cognition and educational achievement. So, it showed that using the articles may affect the finding and conclusion because of the exposure rather than the supplementation. Based on your recommendation and to make it clear, we added an exclusion regarding to the exposure for the factors known to cause cognitive decline by adding the following phrase “….. or only on children exposed to known factors affecting cognitive decline (e.g. lead, arsenic) were excluded.”

Page 10, line 87–89

“Observational study designs including case-report, case-series, ecological, cross-sectional, case-control, and cohort, quasi-experimental design, and reviews were excluded.”

This exclusion criteria is not needed because these other study designs are not included in the first place, as Gutema et al mentioned in the early paragraph that they only included RCTs.

Response: We removed the statement.

Page 10 line 84-87

Response: Yes, we based on a sole supplementation of iron as an intervention. Regarding the EPA/DHA (27) and multiple micronutrients (37), at least one of the arms of the intervention was iron only. In addition, deworming was common practices for schoolchildren in place where helminth infection is prevalent, so we did not consider it as an additional intervention. Regarding iron folic acid is the common preparation form of iron supplementation and ascorbic acid was used as enhancer of the absorption of iron. We included this micronutrient and also did analysis based on the supplementation type separately as a subgroup. However, the issues of folic acid, ascorbic acid and deworming were not indicated in the criteria. So, we added the following statement to the ‘Eligibility criteria’ section. “However, iron with folic acid (one of the common supplement forms), iron with vitamin C (vitamin C was used as enhancer for absorption) and deworming were included in the study.”

Page 11 line 94–96

Response: We added references.

Page 11, line 106

Response: The first phase was the screening based on title and abstract, whereas the second phase was screening based on the full test based. Yes, we considered two reviewers to review for both phases. However, during the second-round search, which was carried out during the October 13th, 2022, we did the screening (for 1070 studies) using one reviewer. That was indeed an error and now corrected.

Page 19 line 220-221

“… daily 2 mg elemental iron”. This needs to be corrected to be 2 mg/kg, as is stated in the original paper, that is Soemantri (1989).

Response: Corrected

Table 2

Response: Yes, the result was controversial. We checked the magnitude of anemia (around 26%) and iron deficiency anemia (around 6%) among the study subject (on another publication). In this population, iron deficiency was not the major cause for anemia, so that the effect was also not insignificant or in another direction (may be over intake of iron due to supplementation where there was no deficiency). Now we included the characteristics of the study participants as a possible explanation for the finding.

Table 2

Response: The Pollitt study reported that the baseline value of IQ assigned to placebo were higher value than the iron supplementation group. Even if the study reported that there was no significant effect of iron supplementation, it also showed that the lower value was maintained for iron supplemented group compared to the placebo. On subgroup analysis, we used the endpoint value (unadjusted for baseline). Now we included a possible explanation for the finding.

Figure 1

‘memroy’ is a typo, which is supposed to be memory.

Response: Corrected

Figure 3C

Response: 1775 children were assessed and 417 were excluded. The total children included for the analysis were 1358 (101, 47 and 1210 children in the IDA, iron depleted, and iron-replete groups, respectively). The document did not indicate the exact number of children for each intervention group. So, we estimate half of the total sample for each group. We corrected the number in the table 1 to 1358.

Result section

Response: Corrected

Page 26, Discussion section

Gutema et al restated again about the inclusion and exclusion methods which we consider is unnecessary because these have been elaborated in the Results section.

Response: We removed the first two sentences as suggested.

Page 27 Line 419-420

Gutema et al need to mention ‘Figure 3’ as a reference for the description about prominent changes in the anemic groups.

Response: Corrected

Page 27 Discussion

Response: Done

Page 28 Strengths and Weaknesses of the Systematic Review and Meta-Analysis

From our perspectives, three limitations could be added, as follow:

1) Inability to conclude a specific dosage which would result in better cognitive development outcomes.

Response: Done

3) The role of other micronutrients in some studies, that might affect the results.

Response: Done

Page 35, Figure 1

Records identified through database searching: 9041

Records after duplicates removed: 7669

Records screened: 6774

The authors need to provide information about what was done to reduce the number of articles from 7669 to 6774.

Response: We used DistillerSR for screening the articles. The gap between 7669 to 6774 was the number of articles uploaded during the 2nd round search and reviewed by one reviewer. Now we corrected it.

Reviewer #3

Reviewer #3: I have reviewed the study by Gutema et al.,

1. There were several mistyping found in the text, I suggest the authors to double check the text again. One of the errors was memroy ("memory").

Response: Corrected

Reviewer #4

Reviewer #4: I do not have any comments for the authors.

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PLoS One. doi: 10.1371/journal.pone.0287703.r003

Decision Letter 1

Ammal Mokhtar Metwally

30 May 2023

PONE-D-22-28873R1Effects of iron supplementation on cognitive development in school-age children: Systematic review and Meta-analysisPLOS ONE

Dear Dr. Gutema,

Please submit your revised manuscript by Jul 14 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Ammal Mokhtar Metwally, Ph.D (MD)

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: Thank you for giving me the opportunity to revise the re-submitted manuscript PONE-D-22-28873R1 under the title: “Effects of iron supplementation on cognitive development in school-age children: Systematic review and Meta-analysis”

Thanks for the authors for their thorough revision of the manuscript and their earnest response to most of reviewers’ comments. I enjoyed revising this manuscript, and believe that it is very promising.

• The authors corrected the title of the manuscript as most of reviewers have asked

• They have updated the section of introduction by adding new references (from 2014-2022)

• They have illustrated briefly the impact of iron deficiency on cognitive development.

• They have added a statement regarding the safety of iron supplementation, but they didn’t illustrate the possible hazards of iron supplementation for this age group. Daily iron supplementation can cause gastrointestinal symptoms as upset stomach, constipation, nausea, abdominal pain, vomiting, and diarrhea. High doses of iron might also cause more serious effects, including inflammation of the stomach lining and ulcers. Therefore, it is necessary to pay attention to the suitable formula and the appropriate effective dose to avoid serious side effects.

• The objective has been rephrased.

• I think the added information concerned with statistical analysis were not sufficient.

• Adding eligibility criteria has enriched the methodology section. However, inclusion of studies provided folic acid or vitamin C together with iron may affect the precision of analysis due to the known effect of folic acid on cognition and the enhancement of iron absorption induced by vitamin C.

• Though it was better to control the duration, frequency, and dose of iron supplementation to avoid the risk of bias. Practically, it is difficult to uniform the design of the available intervention trials.

• Authors have restructured results on the base of subgroup analysis, and have added the results of the previously missed parts about safety and adherence to the supplementation.

• They have modified the section of discussion to omit unnecessary paragraphs and add needed ones. However, they didn’t provide explanations for the unexpected outcomes. Some findings are still ambiguous (e.g., there was no effect of iron supplementation on the intelligence of children who were iron deficient at baseline. Iron-depleted children assigned to placebo, scored higher in RCPM test (IQ) at baseline compared to iron-depleted children who received the iron treatment [42]).

• I appreciate all authors efforts and consider this manuscript as an important addition to the field of child mental development.

Reviewer #2: I greatly appreciate the authors' effort to improve the manuscript. The authors have done a nice job of revising this manuscript and addressing the reviewers' questions/issues raised in the initial review. The revised manuscript is more logical; I am able to understand the methodology, study flow, and results. I recommend that the revised paper be accepted with very minor revisions. My comments below are related to the Conclusion presented in the paper.

"Targeting anemic children, and a more frequent supplementation for shorter duration showed promising results."

Reviewer #3: I have reviewed the revised version of the manuscript from Gutema et al. I sincerely want to say thank you for the major improvements in the writings, especially in correcting for the typographical errors and other certain incorrect use of words in a sentence. The comments from other reviewer have also been addressed. However, I suggest to put the full form of abbreviated words as they first appeared on the text (e.g. RoB hasn't been explained until the end of the manuscript, the full word for RCPM hasn't been written) before this manuscript will be published.

The discussion sections is greatly improved and the authors have put great reasoning and comparations within their findings. I'm looking forward for this manuscript to be published as this study will provide important insights upon iron supplementation on cognitive development in children.

**********

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Reviewer #1: Yes: Ebtissam Mohamed Salah El-Din, Professor of Child Health, National Research Centre of Egypt

Reviewer #2: Yes: Cahyani Gita Ambarsari

Reviewer #3: Yes: Surya Adhi

**********

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PLoS One. 2023 Jun 27;18(6):e0287703. doi: 10.1371/journal.pone.0287703.r004

Author response to Decision Letter 1

7 Jun 2023

Dear Dr. Ammal Mokhtar Metwally,

Thank you for your reply sent on May 31, 2023.

Enclosed we are submitting the revised manuscript PONE-D-22-28873R1, entitled “Effects of iron supplementation on cognitive development in school-age children: Systematic review and Meta-analysis”

By Befikadu Tariku Gutema, Muluken Bekele Sorrie, Nega Degefa Megersa, Gesila Endashaw Yesera, Yordanos Gizachew Yeshitila, Nele S. Pauwels, Stefaan De Henauw, and Souheila Abbeddou.

We thank the reviewers for their constructive comments, which helped us to improve our paper. Our responses addressing the concerns of the reviewers are provided below, and all changes in the manuscript are marked with track changes. We hope that the revisions meet your expectations and that the manuscript will now be acceptable for publication.

Sincerely,

Befikadu Tariku Gutema

Reviewer #1

Thank you for your very positive feedback. We will address the remaining points.

• The authors corrected the title of the manuscript as most of reviewers have asked

Indeed.

• They have updated the section of introduction by adding new references (from 2014-2022)

Yes, we thank the reviewer as well from brining this up.

• They have illustrated briefly the impact of iron deficiency on cognitive development.

Yes, that you.

Response: We agree that this part should be added to the discussion. Now added under the paragraph Lines 515-526 which reads:

Concerns regarding possible side effects

Iron supplementation can cause gastrointestinal side effects including loose stool/diarrhea, hard stool/constipation, abdominal pain, nausea, change in stool color, reflux/heartburn and headache [67]. Low doses of iron supplementation are reportedly not associated with an increased risk of infectious illness in children, except for a slight increase in the risk of developing diarrhea. Iron supplementation may increase the risk of malaria [reference 63], and the WHO recommends monitoring fever in preschool and school children receiving intermittent iron supplementation in malaria settings [22]. Despite the serious risk that is evidenced with iron supplementation, side effects were reported in two studies only [51, 52], while the increased risk of malaria infection was reported in one study only [48] and three studies indicated that the setting was malaria-free [42, 49, 51]. It is important that morbidity and potential side effects are assessed in studies and programs that supplement iron to children.

• The objective has been rephrased.

Indeed, we rephrased it based on the previous revision.

• I think the added information concerned with statistical analysis were not sufficient.

Response: Now, on the tope of sensitivity analysis for the studies for trials with multiple form of supplementation of iron (frequency of administration or dose difference) we included to check iron supplementations combined with other micronutrients, and to check the effect of each study on the overall effect of the intervention by removing one trial at a time.

Response: These studies were included because of the form that is commonly distributed of iron with folic acid. But we agree that this could affect the analysis. We have carried out a sensitivity analysis and included the finding in the document.

Response: Definitely, with the diverse design of the studies, it is almost impossible to uniform the findings. However, we tried in the subgroup analyses to provide at least an insight.

• Authors have restructured results on the base of subgroup analysis, and have added the results of the previously missed parts about safety and adherence to the supplementation.

Thanks.

Response: The controversial results were driven by the study of Pollitt et al. (1989), where indeed baseline data were different between placebo and intervention groups. After conducting the same analysis without this study, the result showed significant improvement in cognition among iron deficient children in intelligence. We included the following in the result part. Lines 294-297 which reads: “The sensitivity analysis showed that iron supplementation significantly improved the intelligence of iron deficient children (SMD 0.52, 95%CI: 0.16, 0.87, P= 0.005, n=128; test for heterogeneity I2=0%, P=0.77) after dropping the study of Pollitt et al. (1989) [42].”

• I appreciate all authors efforts and consider this manuscript as an important addition to the field of child mental development.

We thank the reviewer and we hope that the additional revisions meet your expectations.

Reviewer #2:

We thank the reviewer for their very positive feedback and for their comments that helped us improve the manuscript.

I recommend the authors delete this sentence because it is irrelevant to the results, discussion, and study aim. Furthermore, the statement could be misunderstood as suggesting that a short duration of iron supplementation can be beneficial: "Targeting anemic children, and a more frequent supplementation for shorter duration showed promising results."

Response: The sentence has been dropped as recommended.

Reviewer #3:

I have reviewed the revised version of the manuscript from Gutema et al. I sincerely want to say thank you for the major improvements in the writings, especially in correcting for the typographical errors and other certain incorrect use of words in a sentence. The comments from other reviewer have also been addressed. However, I suggest to put the full form of abbreviated words as they first appeared on the text (e.g. RoB hasn't been explained until the end of the manuscript, the full word for RCPM hasn't been written) before this manuscript will be published.

Response: Corrected. We added the abbreviation Under 'Methods and design in subtitle ‘Assessment of risk of bias’ part. The risk of bias (RoB)…. Regarding RCPM, the abbreviation was only at one point. The others were written in full. So, we replaced abbreviation by the full word.

We thank you for the very positive evaluation.

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PLoS One. doi: 10.1371/journal.pone.0287703.r005

Decision Letter 2

Ammal Mokhtar Metwally

12 Jun 2023

Effects of iron supplementation on cognitive development in school-age children: Systematic review and Meta-analysis

PONE-D-22-28873R2

Dear Dr. Gutema,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ammal Mokhtar Metwally, Ph.D (MD)

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0287703.r006

Acceptance letter

Ammal Mokhtar Metwally

19 Jun 2023

PONE-D-22-28873R2

Effects of iron supplementation on cognitive development in school-age children: systematic review and meta-analysis

Dear Dr. Gutema:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Ammal Mokhtar Metwally

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

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S1 Table. Medline search strategy for the effects of iron supplementation on cognitive development in school-age children.

(DOCX)

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S2 Table. Embase search strategy for the effects of iron supplementation on cognitive development in school-age children.

(DOCX)

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S3 Table. Scopus search strategy for the effects of iron supplementation on cognitive development in school-age children.

(DOCX)

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S4 Table. Web of Science search strategy for the effects of iron supplementation on cognitive development in school-age children.

(DOCX)

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S5 Table. Cochrane Library search strategy for the effects of iron supplementation on cognitive development in school-age children.

(DOCX)

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S1 Fig. Frost plot, SMD analysis of the effect of iron supplementation on intelligence of school-age children (subgroup analysis for risk of bias of the study).

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S3 Fig. Frost plot, SMD analysis of the effect of iron supplementation on attention and concentration of school-age children (subgroup analysis for risk of bias of the study).

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S5 Fig. Frost plot, SMD analysis of the effect of iron supplementation on memory of school-age children (subgroup analysis for risk of bias of the study).

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S6 Fig. Sensitivity analysis: Forest plot, SMD analysis of the effect of iron supplementation on memory of school-age children by excluding studies supplemented iron with folic acid or vitamin C.

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S7 Fig. Frost plot, SMD analysis of the effect of iron supplementation on educational achievement of school-age children (subgroup analysis for risk of bias of the study).

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S8 Fig. Forest plot, SMD analysis of the effect of iron supplementation on hemoglobin level of the school-age children (all included studies).

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S9 Fig. Forest plot, SMD analysis of the effect of iron supplementation on hemoglobin level of the school-age children (categorized based on the cognitive domain).

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S10 Fig. Forest plot, SMD analysis of the effect of iron supplementation on ferritin level of the school-age children.

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S11 Fig. Forest plot, SMD analysis of the effect of iron supplementation on Serum transferrin level of the school-age children.

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Data Availability Statement

All relevant data are within the paper and its Supporting information files.

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PERMALINK

Effects of iron supplementation on cognitive development in school-age children: Systematic review and meta-analysis

Befikadu Tariku Gutema

Muluken Bekele Sorrie

Nega Degefa Megersa

Gesila Endashaw Yesera

Yordanos Gizachew Yeshitila

Nele S Pauwels

Stefaan De Henauw

Souheila Abbeddou

Roles

Abstract

Background

Method

Result

Conclusion

Introduction

Methods and design

Data sources and search strategy

Eligibility criteria

Outcome of the studies

Study selection

Data extraction

Assessment of risk of bias

Data synthesis

Analysis of subgroups

Results

Fig 1. PRISMA study flow diagram for the systematic review [34].

Study characteristics

Table 1. Descriptive summary of the studies included in the systematic review.

Risk of bias

Table 2. Risk of bias among the included studies using RoB 2 tool.

Effect of iron supplementation on cognitive development of school-age children

Effect of iron supplementation on general intelligence of the school-age children

Effect of iron supplementation on general intelligence of the school-age children—Meta-analysis

Fig 2. Forest plot, SMD analysis of the effect of iron supplementation on intelligence of school-age children (subgroup analysis for duration of intervention and frequency of supplementation).

Fig 3. Forest plot, SMD analysis of the effect of iron supplementation on intelligence of school-age children (subgroup analysis for anemia and iron status).

Effect of iron supplementation on attention and concentration of school-age children

Effect of iron supplementation on attention and concentration of school-age children—Meta-analysis

Fig 4. Forest plot, SMD analysis of the effect of iron supplementation on attention and concentration of school-age children.

Effect of iron supplementation on the memory of school-age children

Effect of iron supplementation on the memory of school-age children—Meta-analysis

Fig 5. Forest plot, SMD analysis of the effect of iron supplementation on memory of school-age children.

Effect of iron supplementation on educational achievement and school performance of school-age children

Effect of iron supplementation on educational achievement and school performance of school-age children—Meta-analysis

Fig 6. Forest plot, SMD analysis of the effect of iron supplementation on school achievement of school-age children.

Effect of iron supplementation on nutritional outcomes

Risk of iron supplementation on morbidity—Safety outcomes

Adherence to iron supplementation

Discussion

Concerns regarding possible side effects

Strengths and weaknesses of the systematic review and meta-analysis

Conclusion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Ammal Mokhtar Metwally

Roles

Author response to Decision Letter 0

Decision Letter 1

Ammal Mokhtar Metwally

Roles

Author response to Decision Letter 1

Decision Letter 2

Ammal Mokhtar Metwally

Roles

Acceptance letter

Ammal Mokhtar Metwally

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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