Dear Dr. Abiri,

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: Please respond to all reviewers comments

Please submit your revised manuscript by Aug 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.

• 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'.

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,

Ahmed Mohamed Maged, MD

Academic Editor

PLOS ONE

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[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: No

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: Thank you for providing this opportunity to review this manuscript. Please see my comments as follows:

Background

1. Authors should start “Background” directly from cesarean section and its consequences such as wound infection.

2. LINES 66-71 are redundant as the focus of this study is noy\t why women choose cesarean. I recommend Combine redundant CS epidemiology paragraphs (lines 53-75 and 27-33).

3. Add quantitative data on AM's efficacy from recent meta-analyses (e.g., Zelen et al. 2020).

4. Clarify why autologous AM/AF may outperform processed products (cost/immunogenicity).

5. In my opinion the following are not advantages of cesarean section and they are disadvantages of C/S: shorter recovery, shorter length of hospitalization, more successful breastfeeding, and control over the birth process.

6. What is the meaning of “delicense” in line 78? I think it should have been “dehiscence”.

Methods

1. As the researchers are not blind, this study is not double blind, and this is single blind.

2. authors should explain the POSAS scale in more detail. How many questions does it have? Who validated this scale in Iran?

3. Are the patients hospitalizing until 36 hours after C/S, if not, how authors evaluate the pain of participants in this time?

4. Add screening flowchart (CONSORT-style) showing enrollment numbers at each stage.

5. Specify who conducts baseline assessments (trained nurses? residents?).

6. Line 159: Why authors consider gestational age of 36 weeks, that is not term pregnancy.

7. Line 160: Hb: 10g/dL is considered anemia and it can deteriorate wound healing.

8. A randomized list is generated using the sealed envelope is not correct and needs revision.

9. Line 220: the explanation of allocation concealment is not enough.

10. please explain Storage duration/temperature for AM/AF and standardized wound closure technique across groups.

11. Add Safety: Add protocol for adverse event reporting (e.g., allergic reactions).

Discussion

1. Comparative Context: Contrast with similar AM studies in non-CS wounds.

2. Implementation: Address feasibility of AM/AF use in low-resource settings.

3. Limitations: Acknowledge single-center design and short follow-up.

Reviewer #2: Dear Editor,

PLOS ONE

Thank you also for the opportunity to contribute to the peer review process for manuscript titled: “Effect of Autologous Amniotic Membrane and Fluid on Wound Healing and Complications of Cesarean Section: Study Protocol of A Factorial Randomized Controlled Trial”.

This is a well-written manuscript on an important topic. I commend the researchers and wish them success. I commend the researchers and wish them success. It is a valuable contribution to the existing literature and will undoubtedly stimulate further discussion and investigation. The methodology is sound I encourage the authors to continue their work in this area and look forward to seeing the future fruits of their labors.

Best regards

Reviewer #3: The protocol here is for a 2x2 factorial trial of two related interventions - autologous amniotic fluid, and amniotic membrane.

The assumption in the factorial design is that the tow treatments are basically additive (there is no interaction between them as measured when one performs analysis of one intervention stratified by another). This could usefully be justified here in light of the statements on lines 90-1 where it might be thought that similar biological characteristics lead to sub-additive properties (e.g. taking 2 doses of paracetamol instead of 1 does not double the headache cure rate). Additionally, if the wound healing properties are well-known there is presumably good randomised evidence already - so the precise need for this trial needs to be made clear - where is the uncertainty which underpins ethical randomisation?

It would be better to describe this as a 2x2 design and not a four arm study of 3 interventions and 1 control - there are two interventions each of which is given or withheld.

The interventions do not sound blinded - how are the sprays applied and should one not have a dummy spray - the preparation of the interventions seems to be different. How is one to avoid performacne bias in the period before the assessment by a blinded observer.

I think the statistician needs to be aware of allocation (line 211) to analyse the data.

There is insufficient guarding of allocation concealment given the use of blocking in a single centre. Closed envelopes do not provide good concealment (see the excellent example in Altman's book on medical statistics) so how will this be policed?

If the pain on a VAS is 8 with sd 1.7 it is not normally distributed - how was this taken into account in the sample size calculation.

To allow for 10% dropout one must inflate by 1/(0.9) - so the sample size would need to be slightly more than 56 - as it is 56 does not allow for 10% dropout but rather only about 9%. Also this is two 2-way comparisons - so if one wants to power each intervention on the differences seen you need only 104 patients in total in each comparison. In other words the sample size is out by a factor of two since every patient in a factoria ldesign counts double.

The analyses are not describedf in suffiicent detail or in a fashion appropriate to a factorially designed trial.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes:  Parvin Abedi

Reviewer #2: Yes:  Fereshteh Behmanesh

Reviewer #3: No

**********

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Dear Dr. Abiri,

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 Oct 16 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.

• 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'.

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,

Ahmed Mohamed Maged, MD

Academic Editor

PLOS ONE

Journal Requirements:

1. 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. 

Additional Editor Comments:

Please respond to all reviewer comments

[Note: HTML markup is below. Please do not edit.]

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #3: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #3: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #3: No

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #3: Yes

**********

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

Reviewer #3: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #3: Thank you for your response to my previous comments.

I note now that this is billed as a factorial design - so the power is different, and the calculation needs to show what the actual power is here for the design as chosen.

Please note also that you cannot analyse a factorial design given A vs B vs C vs D - it is okay not to know what is treatment and placebo (ie block blinding, not true blinding) but the two interventions need to be given separately to allow for the analyses proposed.

**********

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.

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Reviewer #3: No

**********

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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 . Please note that Supporting Information files do not need this step.

Dear Dr. Abiri,

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 Nov 14 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.

• 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'.

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,

Ahmed Mohamed Maged, MD

Academic Editor

PLOS ONE

Journal Requirements:

1. 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. 

Additional Editor Comments:

 Please respond to all reviewers comments .

[Note: HTML markup is below. Please do not edit.]

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

Reviewer #5: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

Reviewer #5: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: No

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

Reviewer #5: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: Thank you for inviting me to review this manuscript. Please see my comments as follows:

Abstract

1. Please mention the primary outcomes and how did you measure all outcomes? What are the statistical tests?

Introduction

1. All of benefits that authors mentioned about cesaean section in comparison to normal vaginal delivery, in fact are the hazards of this surgery such as: shorter hospitalization, shorter recovery, better breastfeeding. Please revise.

2. Lines 102-103 needs to be cited.

3. Line 95: please write the reference.

Methods

1. What was the minimum and maximum score of POSAS? Is there any cut-off?

2. Statistical analyses: did authors attempt to report effect size?

Line 335: why authors wrote that human ethics and consent to participate is NA?

Reviewer #2: I commented before and accept this manuscript for publication. I believe it offers a significant contribution to the field, presenting compelling evidence and a well-reasoned argument. The methodology is sound, the data is meticulously analyzed, and the conclusions are logically derived. Furthermore, the writing is clear and concise, making the complex subject matter accessible to a wider audience. I commend the author(s) for their thorough research and insightful presentation.

Reviewer #3: Thank you for your updated protocol - please note however, that given the breakdown that is given in the response it is possible to unblind the statistician as for ghroups A,B,C,D you are telling us precisely which comparison they are in. So please remove the statement at line 252 as it is not correct.

Reviewer #4: Thanks to the authors of the manuscript

The manuscript needs corrections, so it is recommended that the following items be corrected:

1. The references in the text need to be updated.

4. The manuscript should be re-edited.

Reviewer #5: 1. Line 54: The phrase “… CS increased by 12.4% (from 6.7% to 19.1%)” should be edited. First, CS should be spelled out. Second, increased by 12.4% implies a relative increase (RRI), whereas the authors mean an absolute increase (ARI).

2. Lines 59–61: The reference used for the sentence is out of date (2012), and I think some of the mentioned advantages (for example, shorter recovery, shorter length of hospitalization, more successful breastfeeding, and control over the birth process) are not correct.

3. The expected recruitment start date registered in the IRCT (2024-07-22) differs from what is reported in the manuscript as the recruitment start date (01/10/2024). Please describe the reason in the protocol.

4. Line 35: It is mentioned that the trial is double-blind, but the person performing the intervention could not be blinded. According to CONSORT, please specify in the abstract which groups are blinded.

5. It is better not to use uncommon abbreviations such as “PO.”

6. Table 1: It is suggested to use “×” for each assessment time point instead of the current symbol.

7. Please report which number was used for the numerator degrees of freedom. I used 3, and the calculated sample size was 141.

8. Most of the outcomes will be measured more than once. Please explain how time and the interaction of time × group will be assessed during analysis.

9. Please describe where all data underlying the findings will be made available when the study is complete.

**********

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: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: 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 . Please note that Supporting Information files do not need this step.

Effect of Autologous Amniotic Membrane and Fluid on Wound Healing and Complications of Cesarean Section: Study Protocol of A Factorial Randomized Controlled Trial

PONE-D-25-30795R3

Dear Dr. Abiri,

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,

Ahmed Mohamed Maged, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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

Reviewer #1: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: Thanks to authors as they provided comprehensive answers to my previous comments. In my opinion the protocol can be acceptable in the current version.

Reviewer #4: Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

I have no opinion on this.

Reviewer #5: The authors addressed all my previous comments. I have no other comment. Congratulation to the authors.

**********

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: No

Reviewer #4: No

Reviewer #5: Yes:  Sakineh Mohammad-Alizadeh-Charandabi

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