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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Ammal Mokhtar Metwally, Ph.D (MD)

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PLOS ONE

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Additional Editor Comments:

The manuscript is interested meanwhile, the reviewers have raised a number of points which we believe would improve the manuscript and would allow a revised version to be published in PLOS one.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

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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Submitted filename: Descision of the reviewer 23-12-2022.docx

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Submitted filename: 20230131 Plos One.docx

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

Dear Dr. Gutema,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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'.
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• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ammal Mokhtar Metwally, Ph.D (MD)

Academic Editor

PLOS ONE

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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

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

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?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

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.

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."

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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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

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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Submitted filename: Reviewers decision after resubmission.docx

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.

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Kind regards,

Ammal Mokhtar Metwally, Ph.D (MD)

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: