Pharmacologic neuroprotective agents for the treatment of perinatal asphyxia in low-income and lower-middle-income countries: A systematic review and meta-analysis of randomised controlled trials

Victor Ayodeji Ayeni; Aisha Adam Abdullahi; Abdulmuminu Isah; Love Bukola Ayamolowo; Timothy Adeyemi; Motunrayo Adebukunola Oladimeji; Ufuoma Shalom Ahwinahwi; Vitalis Ikenna Chukwuike; Oluchukwu Perpetual Okeke; Olunike Rebecca Abodunrin; Folahanmi Tomiwa Akinsolu; Olajide Odunayo Sobande

doi:10.1371/journal.pone.0337798

Peer Review History

Original SubmissionApril 16, 2025
15 Oct 2025 Decision Letter - Stefan Grosek, Editor Dear Dr. Ayeni, 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. ============================== ACADEMIC EDITOR: Statistical part should be clarified whether a staticians was a part of the the team. ============================== Please submit your revised manuscript by Nov 29 2025 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. 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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, Stefan Grosek, Ph.D., M.D., Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf . 2 Thank you for stating the following financial disclosure: “VAA, AAA, AI, LBA, TA, MAO, USA, VIC got a grant from Nigerian Institute of Medical Research Foundation for the work. Grant Number: NF-GMTP-24-152809” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 5. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 6. 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. Additional Editor Comments (if provided): Dear Authors Positive comments came out from both reviewers, however on of them wants to know if statistical approach is appropriate. Therefore I would like to ask you to explain whay this statistics was used and if statistician is part of of teams who prepared this paper. Kind regards [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: I congratulate the authors for a well and meticulously conducted research. I have the following points to make: 1. better keywords can be selected which are not a part of the title. 2. forest plot for different outcomes have not been provided. 3. Conclusion heading does not have complete text. Reviewer #2: The paper by Victor Ayodeji Ayeni et al is a systematic review and metanalysis of eligible randomised controlled trials (RCTs) published between 2000 and 2024 on various pharmacologic neuroprotective agents for the treatment of perinatal asphyxia compared with placebo or standard care, excluding therapeutic hypothermia, in LILMICs. Data on survival and neurodevelopmental outcomes are analysed. The article fulfils some of the criteria for publication: the authors claim it is an original work and the results reported have not been published elsewhere. In the aspect of statistical analysis, I would very much appreciate if the article could be subjected to an expert on the field. The conclusions are presented in an understandable and appropriate fashion and are supported by the given data. The article is is written in good intelligible English. The research meets the applicable standards for the ethics of experimentation and research integrity. The article adheres to appropriate reporting guidelines and community standards for data availability. Minor suggestions: why are there two different abbreviations used since I believe there could be only one: LMIC and LILMIC? In the materials the Table 6 seems not in the appropriate form, it is not possible to read the text. Also, the references are missing, there is only minor part appearing at the end of the available materials. ****** what does this mean? ). If published, this will include your full peer review and any attached files. 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: Dr Ruchi Rai Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org Attachments Attachment Submitted filename: Review of Manuscript Number PONE.docx https://doi.org/10.1371/journal.pone.0337798.r001
Revision 1
17 Oct 2025 Author Response 1. Statistical part should be clarified whether a statistician was a part of the team. Yes, one of the authors is indeed a Statistician and she was involved with the process of the systematic review from the beginning, through the meta-analysis and up till submission: Olunike Rebecca Abodunrin. The appropriate statistical methods were used and verified by the statistician on the team. 2. Why are there two different abbreviations used since I believe there could be only one: LMIC and LILMIC? The review focused on low-income and lower middle-income countries (LILMICs) rather than low- and middle-income countries (LMIC). We decided to focus on LILMICs for better homogeneity of the included countries, as it was known that upper middle-income countries (which are part of LMIC but not part of LILMIC) have distinctive qualities, which may not be shared by pure LILMIC. However, LMICs were mentioned in the Background aspects of the Manuscript at points where we were referring to previous work and publications, which focused on LMIC (which included our subject area of LILMIC). The appearances of LMICs from referenced texts were found on pages 2-4. 3. In the materials the Table 6 seems not in the appropriate form, it is not possible to read the text. Also, the references are missing, there is only minor part appearing at the end of the available materials. The font has been increased in size for both Tables 5 and 6, shown on pages 24-27 4. Line 33 on page 1, the spelling of “Biostatistics” was corrected. 5. Please state what role the funders took in the study. "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. The captions for the Supporting Information files are now included at the end of the manuscript, and supplementary files 1-6 (S1 – S6) have been re-submitted. 7. Reviewer 2: Has the statistical analysis been performed appropriately and rigorously? Yes, one of the authors is indeed a Statistician and she was involved with the process of the systematic review from the beginning, through the meta-analysis and up till submission: Olunike Rebecca Abodunrin. The appropriate statistical methods were used and verified by the statistician on the team. 8. Reviewer 1: better keywords can be selected which are not a part of the title The keywords section has now been updated as follows: perinatal asphyxia, neonatal encephalopathy, pharmacologic neuroprotective agents, magnesium sulphate, neurodevelopmental outcomes, low-income and lower-middle-income countries 9. Reviewer1: forest plot for different outcomes have not been provided. These are shown in Figures 2 – 12. 10. Reviewer 1: Conclusion heading does not have complete text. This has been checked. 11. I have confirmed the following: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 12. I have included the following: "All data are in the manuscript and/or supporting information files". 12. The identifying information has been removed from the S3_Data extraction, and it has been resubmitted, along with S1, S2 and S4, because it was noted that the previous submission before review was retained because of similarity in names. Attachments Attachment Submitted filename: Response to Reviewers.pdf https://doi.org/10.1371/journal.pone.0337798.r002
14 Nov 2025 Decision Letter - Stefan Grosek, Editor Pharmacologic neuroprotective agents for the treatment of perinatal asphyxia in low-income and lower-middle-income countries: a systematic review and meta-analysis of randomised controlled trials PONE-D-25-16916R1 Dear Dr. Ayeni, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . 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, Stefan Grosek, Ph.D., M.D., Academic Editor PLOS ONE Additional Editor Comments (optional): Dear Authors Both reviewers found that all issuess have been addressed and implented in the paper. Therefore I suggest for acceptance of the paper. Kind regards Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: (No Response) Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: (No Response) Reviewer #2: (No Response) ****** what does this mean? ). If published, this will include your full peer review and any attached files. 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: Ruchi RaiNone Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0337798.r003
Formally Accepted
Acceptance Letter - Stefan Grosek, Editor PONE-D-25-16916R1 PLOS ONE Dear Dr. Ayeni, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@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 Stefan Grosek Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0337798.r004

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