Tranexamic Acid for Postpartum Haemorrhage in Low-, Middle-, and High-Income Countries: An Integrative Review Aligned with the WHO PPH Roadmap (2023–2030)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article entitled "Tranexamic Acid for the Management of Postpartum Haemorrhage in Low- and Middle-Income Countries: Aligning Efficacy, Safety, and Implementation Strategies with the WHO PPH Roadmap (2023–2030)" presents quite interesting topic among scientific literature. The Authors focused on postpartum hemorrhage (PPH) which remains a significant cause of maternal mortality and disproportionately affects low- and middle-income countries. The Results of the study revealed that tranexamic acid (TXA) significantly reduced PPH-related mortality by 31% when administered within three hours of delivery. The Authors have included few of the studies. However, The Reviewer has some issues and special comments regarding manuscript.

1. Methodology section. The Reviewer would advise to revise this section. It should be clearly stated e.g. in which article how many participants were eligible to the study, were there the exclusion criteria, age, health and socioeconomic status. 

2. The name of the countries in which study were evaluated should also be specified. The Authors have only stated that there are low- and middle-income countries. 

3. Moreover, the Reviewer should also suggest to add the information concerning the dosage of the TXA and route of administration in all of the described studies - including toxic and side effects. There is only one small chapter entitled Adverse effects. "These adverse effects underscore the importance of careful patient selection, appropriate dosing, and close monitoring during TXA administration." How about the treated patients during gestation and postpartum? 20000 participants and none side effects?

Author Response

Thank you for the useful feedbacks on our paper. WE have now revised below

Reviewer #1’s Overall Comments

1. Methodology section. The Reviewer would advise to revise this section. It should be clearly stated e.g. in which article how many participants were eligible to the study, were there the exclusion criteria, age, health and socioeconomic status.
2. The name of the countries in which study were evaluated should also be specified. The Authors have only stated that there are low- and middle-income countries.
3. Moreover, the Reviewer should also suggest to add the information concerning the dosage of the TXA and route of administration in all of the described studies - including toxic and side effects. There is only one small chapter entitled Adverse effects. “These adverse effects underscore the importance of careful patient selection, appropriate dosing, and close monitoring during TXA administration.” How about the treated patients during gestation and postpartum? 20000 participants and none side effects?

Reviewer #1’s Comment	Response / Action Taken	Location in Revised Article
1. Methodology: Clearly detail participants in each study, exclusion criteria, age, health status, etc.	- We revised the Methods to clarify how many participants each major trial included, typical maternal risk factors, and broad demographics (age, high-risk conditions, etc.).We also clarified the approach to including/excluding studies.	Methods section (“Inclusion and Exclusion Criteria,” “Screening and Identification”)
2. Name of Countries: Must specify which countries were involved, not just “LMIC.”	- We updated Table 1 to include a “Country/Region” column explicitly (e.g., “Nigeria & Pakistan,” “Zimbabwe,” “France”). In the text, we also note sub-Saharan Africa, South Asia, etc. explicitly where relevant.	Table 1 (“Country/Region” column) and Results: Overview of Studies
3. Dosage & Route + Side Effects: Add info on TXA dosing and side effects. “20000 participants and no side effects?”	- We expanded the “Route & Dose of TXA” column in Table 1 to show prophylactic vs. therapeutic doses (e.g., 1 g, 2 g, 4 g infusion). We emphasized in the text that major trials (WOMAN) reported few serious events, but mild side effects did occur.	Table 1 (new columns) and “TXA Efficacy in Acute PPH Treatment” + “Discussion”

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

Comments for Women-3422043

Entitled “Tranexamic Acid for the Management of Postpartum Hemorrhage in Low- and Middle-Income Countries: Aligning Efficacy, Safety, and Implementation Strategies with the WHO PPH Roadmap (2023–2030)”

General Comments:

This is an ancient topic. Apart from the different research areas, it does not attract readers' attention. But there's still something to be done. If acceptance is under consideration, many places need to be revised.

Specific Comments:

1.      Abstract:

a.      Full length must be streamlined.

b.      The background must mention the main aim of this research. This study’s aim should be as the topic, such as

c.      Method: The statistical method used in this study needs to be mentioned.

d.      Do your results meet the primary purpose of your research on this paper?

e.      Please condense your results and remove any irrelevant findings affecting your research goals.

2.      In the Introduction:

Your introduction does not have clear boundaries. Except for the conclusion, is almost the entire text covered?

3.      In the methods:

Where are your study methods? What are the enrolled criteria? Where are the inclusion criteria and exclusion criteria? Does the study belong to a prospective or retrospective study?

4.      In the results:

 

There are no clear paragraph separations, making reviewing this article hard, and I cannot know the main result.

Comments on the Quality of English Language

Minor revision in the English language is better.

Author Response

Thanks for the useful feedbacks on our paper. We have now revised below: 

Reviewer #2’s Overall Comments

General Comments:
This is an ancient topic... many places need to be revised if acceptance is under consideration.

Specific Comments:

1. Abstract:
   a. Must be streamlined
   b. The background must mention the main aim of this research
   c. Method: The statistical method used must be stated.
   d. Clarify if results meet research objectives.
   e. Condense results / remove irrelevant findings.
2. Introduction: The introduction boundaries are unclear; entire text is near conclusion?
3. Methods: Where are the criteria? Is it prospective or retrospective?
4. Results: No clear paragraph separation, so the main result is obscured. Also minor English revision.

Reviewer #2’s Comment	Response / Action Taken	Location in Revised Article
1(a)-(e) Streamlined Abstract: Must highlight aim, mention methods, keep it shorter, ensure results match objectives.	- We shortened the abstract to ~350 words and highlighted the main aim (efficacy/safety/cost-effectiveness). Mentioned that it is an “integrative review” involving RCTs, observational data, etc. We trimmed extraneous detail.	Abstract (updated to emphasize methods, aim, key results)
2. Introduction: Must define boundaries more clearly.	- We reorganized the introduction into discrete paragraphs covering (a) the global burden, (b) mechanism of TXA (c) shift in guidelines, and (d) current evidence gaps, so it has clearer boundaries.	Introduction section
3. Methods: State if prospective/retrospective, inclusion/exclusion criteria.	- We labelled the article an “integrative review” and clarified that we used both prospective RCTs & retrospective cohorts, explicitly describing “Inclusion & Exclusion Criteria” and search details.	Methods section
4. Results: Clear paragraph breaks, highlight main results.	- We broke down results under five subheadings (Efficacy, Prophylaxis, Cost-Effectiveness, Routes, Implementation).We also refined paragraphs to ensure each section states findings concisely.	Results section with sub-headers + new paragraphing
Minor English revision	- We rechecked grammar/wording throughout (particularly in Abstract, Introduction, and Discussion) to ensure clarity and correctness.	Throughout the revised manuscript

 

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you to the authors for addressing this interesting topic.

The abstract is overall well-written but should be shorter and. Its primary role is to provide an overview of the study, clearly highlighting the aim. 

The manuscript as a whole is not well-organized and requires a clearer structure.

• Type of review: The type of review conducted is not specified. The authors should explicitly describe the methodological approach used, as this is currently absent from the text.

• Articles included: It is unclear which types and how many articles were included in the review. Additionally, the inclusion and exclusion criteria are not stated. A resuming table could be useful.

• Results: The results section is unclear and not well-defined in the text. The authors must better organize the manuscript, ensuring clearly defined sections, such as Introduction, Methodology, Results, Discussion, and Conclusion.

A reorganization of the manuscript and more detailed explanations regarding the methods and results are strongly recommended

Author Response

Thanks for the useful comments and feedbacks on our paper. We have nw revised below in line with the suggestions:

Reviewer #3’s Overall Comments

1. Abstract: good but shorter, clearly highlight the aim.
2. Manuscript structure: must be better organized.
3. Type of review not stated (methodological approach missing).
4. Articles included: unclear which types, how many. No mention of inclusion/exclusion.
5. Results: not well-defined or well-structured.
   Strongly recommends reorganizing manuscript + more detail on methods/results.

Reviewer #3’s Comment	Response / Action Taken	Location in Revised Article
1. Abstract: Should be shorter and show the aim clearly.	- We streamlined the abstract (~350 words) and explicitly stated the main aim (“to integrate evidence on TXA efficacy, prophylaxis, cost, alternative routes, and implementation barriers/facilitators”).	Abstract
2. Manuscript Structure: Not well organized; must clarify.	- We introduced a clearer structure: Introduction, Methods, Results (subdivided into five themes), Discussion, Conclusion.	Throughout the revised manuscript
3. Type of Review: Must be explicitly stated.	- We labelled it an “integrative review” in the abstract and methods, clarified our multi-source approach to RCTs, observational studies, policy documents, and cost evaluations.	Abstract & Methods section
4. Articles Included: Hard to see how many or which types, no mention of inclusion/exclusion.	- We listed ~40 included studies in a “Summary Table.” We detailed in “Inclusion & Exclusion Criteria” how we screened for relevant outcomes (mortality, transfusion, cost, etc.) and omitted smaller case reports.	Table 1 + Methods (“Inclusion and Exclusion Criteria”)
5. Results: Not well-defined. Recommends reorganizing with distinct headings.	- We presented results under five headings: (1) TXA Efficacy in acute PPH, (2) Contradictory prophylactic data, (3) Cost-effectiveness, (4) Alternative routes, (5) Implementation. This clarifies the main outcome findings.	Results section with subheadings + “Overview of Studies” portion
Reorganization & “More Detail on methods/results.”	- We expanded the methods to describe search strategy, risk populations, TXA dose/route. We structured results to highlight key findings (blood loss, mortality, cost, route) within discrete paragraphs.	Methods + Results sections

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The Authors have responded to all comments and remarks. The article has gained in coherence. It is more readable and logical.All inconsistencies have been clarified.

The Reviewer recommend to accept the article in present form.

Author Response

Dear Reviewer,

We sincerely appreciate your thorough review and positive feedback on our manuscript. We are grateful for your recommendation to accept the article in its present form.

Thank you for your time and effort in reviewing our work.

Best regards,
Victor Adepoju, on behalf of all authors

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to Women-3422043

1.      The abstract is too lengthy, so please shorten it, especially the results and conclusions. Please explain the primary purpose of this research in the Introduction.

2.      In Figure 1:

A.     In Identification, the total numbers are incorrect.

B.     The boxes in the screening need to be revised (the number is incorrect).

C.    In Eligibility, the box (Full-text articles excluded) needs to be revised.

3.      In Table 1:

A.     In-country/region: Please note the number in multiple countries.

B.     In Sample Size/design: Please list sample sizes/what kind of study design in each column.

C.    In Route & Dose of TXA: Please indicate the route and dosage in each column.

D.     The main findings should be consistent with the primary purpose of this research; please revise them. Please also remove references that are irrelevant to this article.

E.      If your classification items can compare the effectiveness of Tranexamic Acid for treating Postpartum Hemorrhage in Low-, Middle-, And High-Income Countries, that would be better and easier to understand your study.

F.      The classification in Table 1 should be more streamlined, enhance induction ability, and eliminate the unnecessary while retaining the essential.

G.    What statistical method did you use to compare the effectiveness of medications in treating postpartum hemorrhage? Please add an explanation in Materials and Methods.

 

4.      What are the advantages and disadvantages of this study? Add a paragraph before the discussion.

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Response to Reviewer 2

Dear Reviewer,

We appreciate your constructive feedback, which has greatly improved the quality and clarity of our manuscript. Below, we address each of your comments point by point:

1. The abstract is too lengthy; please shorten it, especially the results and conclusions. Please explain the primary purpose of this research in the Introduction.

Response: We have revised the abstract to meet the word limit requirements of MDPI Women Journal. The results and conclusions have been streamlined for brevity. Additionally, we have explicitly stated the primary purpose of the research in the Introduction.

2. In Figure 1 (PRISMA Flowchart):
3. In Identification, the total numbers are incorrect.
   Response: We have revised the PRISMA flowchart to ensure accuracy in the total numbers at the Identification stage.
4. The boxes in Screening need to be revised (the number is incorrect).
   Response: We have corrected the numbers in the Screening section to ensure consistency with the data presented in the text.
5. In Eligibility, the box (Full-text articles excluded) needs to be revised.
   Response: We have revised the text in the Eligibility box to clarify exclusion criteria and ensure coherence with the PRISMA methodology.
6. In Table 1:
7. In Country/Region: Please note the number in multiple countries.
   Response: We have clarified the country/region column, ensuring that studies covering multiple countries are properly labeled as “Global/Multicountry.”
8. In Sample Size/Design: Please list sample sizes/what kind of study design in each column.
   Response: We have separated the sample size and study design into distinct columns for better clarity and readability.
9. In Route & Dose of TXA: Please indicate the route and dosage in each column.
   Response: We have revised and updated this column to clearly specify the route of administration and TXA dosage used in each study.
10. The main findings should be consistent with the primary purpose of this research; please revise them. Please also remove references that are irrelevant to this article.
    Response: We have ensured that the main findings align with the study objectives and have removed four irrelevant references (original references 41, 47, 52, and 54), reducing the final number of included studies from 40 to 36.
11. If your classification items can compare the effectiveness of Tranexamic Acid for treating Postpartum Haemorrhage in Low-, Middle-, and High-Income Countries, that would be better and easier to understand your study.
    Response: While we did not separate studies explicitly into Low-, Middle-, and High-Income Countries due to differences in study design (some are secondary reviews, and some span multiple economic classifications), we have clearly indicated the countries in the Country/Region column. Studies covering multiple income classifications have been labelled as “Global/Multi-country.”
12. The classification in Table 1 should be more streamlined, enhance induction ability, and eliminate the unnecessary while retaining the essential.
    Response: We have streamlined Table 1, removed redundant information and improving clarity while maintaining key details necessary for understanding the study outcomes.
13. What statistical method did you use to compare the effectiveness of medications in treating postpartum haemorrhage? Please add an explanation in Materials and Methods.
    Response: Since this study is a narrative review rather than a meta-analysis, we did not use statistical methods to compare effectiveness quantitatively. We have clarified this in the Materials and Methods section.
14. What are the advantages and disadvantages of this study? Add a paragraph before the Discussion.

Response: We have added the following paragraph before the Discussion section:

"This review systematically consolidates evidence on TXA for PPH and aligns findings with the WHO PPH Roadmap to inform clinical and policy decisions. Its strength lies in its broad scope, consolidating 36 studies and providing practical insights spanning clinical efficacy, cost-effectiveness, route of administration, and implementation barriers and facilitators. However, study limitations include potential publication bias, heterogeneity of included studies, and varying outcome definitions, TXA dosages, and timings, as well as mode of delivery (vaginal versus cesarean section), which may affect comparability."

Comments on the Quality of English Language

Response: We have revised the manuscript for clarity and readability, addressing areas where the language could be improved.

We appreciate your detailed feedback, which has helped us refine and strengthen our study.

Best regards,
Victor Adepoju, on behalf of all authors

 

Reviewer 3 Report

Comments and Suggestions for Authors

Thanks to the authors for accepting suggestion and revising the manuscript. 

Author Response

Response to Reviewer 3

Dear Reviewer,

Thank you for your positive feedback and for recognizing the revisions we made to improve the manuscript. We are grateful for your thoughtful review and support.

Best regards,
Victor Adepoju, on Behalf of authors

 

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to Women-3422043 (3^rd)

1. In Figure 1:

The total numbers are still incorrect!

After unrelated titles were excluded (n=30) From Articles reached for title screening (n=225) to Records screened for abstract review (n=225), why did the total number not change?  

 

2. In Table 1:
3. Not only did the author not shorten the content at all, but they increased the content of Table 1, indeed increasing the content from page 5 to page 14. What’s wrong with the authors?
4. 4, the sample size should be [144], not [Randomized, controlled, multi-centered, open-label trial].
5. It is recommended that Table 1 be regarded as a supplementary table and does not need to appear in this article.

Author Response

Comments to Women-3422043 (3^rd)

1. In Figure 1:

The total numbers are still incorrect!

After unrelated titles were excluded (n=30) From Articles reached for title screening (n=225) to Records screened for abstract review (n=225), why did the total number not change?  

Response: Thanks for the observation. This has now been corrected. 10 articles were initially excluded for duplicate and additional 30 for unrelated titles.

 

1. In Table 1:

Thanks for this suggestion. We have now moved the table from the body of the manuscript and included it in a separate supplementary material and reference the table accordingly as supplementary material in the body of the manuscript

1. Not only did the author not shorten the content at all, but they increased the content of Table 1, indeed increasing the content from page 5 to page 14. What’s wrong with the authors?

Apologies for this. We have now moved the table to supplementary materials. We just wanted to be as detailed as possible to improve clarity of each study findings for our readers

1. 4, the sample size should be [144], not [Randomized, controlled, multi-centered, open-label trial].

We have corrected this and included the sample size and study design in relevant section

1. It is recommended that Table 1 be regarded as a supplementary table and does not need to appear in this article.

This has been actioned accordingly