Effectiveness of Expressed Breast Milk Mouthwash for Infant Oral Hygiene

Round 1

Reviewer 1 Report (Previous Reviewer 3)

Comments and Suggestions for Authors

No more comments

Author Response

We sincerely thank the reviewer for the positive assessment and are pleased that the revised manuscript met expectations.

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

This manuscript presents a clinically meaningful and timely review, particularly relevant to neonatal and pediatric intensive care practice. The topic is of high importance for nursing protocols and infection prevention strategies.

Overall, the manuscript is well-structured and clearly written. However, some issues require clarification.

Major Concerns

While the findings are promising, several limitations should be more clearly reflected in the interpretation:

Most reported outcomes represent trends rather than robust or consistent effects

At times, the manuscript appears to overstate, for example, the reduction in ventilator-associated pneumonia (VAP)

I recommend that the authors be encouraged to adopt more cautious language throughout the manuscript, such as: “suggests” and “may be associated with.”

The manuscript tends to dismiss CHX based on limited pediatric evidence. However, CHX remains widely used in many intensive care settings.

The discussion should be more balanced by emphasizing that:

Lack of pediatric evidence does not equate to lack of efficacy.

Minor Comments

Clarify key acronyms earlier in the manuscript (e.g., MVT, LOS)

Improve the flow of the Discussion section, as some repetition is present.

The abstract is dense and would benefit from simplification.

Author Response

Dear Reviewer,

We sincerely thank you for your constructive and detailed feedback. We fully agree that the limitations of the evidence should be more clearly reflected and that the language should be appropriately cautious. We have revised the manuscript accordingly. Below is our point-by-point response:

1. Most reported outcomes represent trends rather than robust or consistent effects
   We have revised the Results, Discussion, and Conclusions sections to consistently describe outcomes as trends, associations, or potential effects, rather than definitive findings. Declarative language has been softened throughout.
2. At times, the manuscript appears to overstate, for example, the reduction in ventilator-associated pneumonia (VAP)

   We reviewed all statements related to VAP and revised them to avoid overinterpretation. Phrases such as “reduced VAP” were revised to “may be associated with lower VAP incidence” or “showed a potential trend toward reduction.”

3. I recommend that the authors be encouraged to adopt more cautious language throughout the manuscript, such as: “suggests” and “may be associated with.”

   We have systematically replaced stronger verbs and claims with cautious phrasing as recommended. Examples include: “EBM suggests potential benefits…” “EBM may be associated with…” “favorable associations were observed…”. These changes have been applied consistently in the Abstract, Results, Discussion, and Conclusions.

4. The manuscript tends to dismiss CHX based on limited pediatric evidence. However, CHX remains widely used in many intensive care settings.

   We have revised the Discussion section to present a more balanced perspective on CHX. We now explicitly state: “Despite these limitations, CHX continues to be widely used in many intensive care settings. The lack of high‑quality pediatric evidence does not imply inefficacy; rather, it highlights an important evidence gap and reinforces the need for further infant‑focused research.”

5. The discussion should be more balanced by emphasizing that: Lack of pediatric evidence does not equate to lack of efficacy.

   We have fully incorporated this point into the revised Discussion. The updated text now clearly acknowledges that the limited availability of pediatric evidence for CHX should not be interpreted as evidence of ineffectiveness. Instead, we emphasize that this gap highlights the need for more age‑specific research to better understand CHX performance in infant populations.   Minor Comments
6. Clarify key acronyms earlier (e.g., MVT, LOS)Response:                                                                                                   All acronyms (MVT, LOS, VAP, NEC, etc.) are now defined at their first mention in the Abstract, Introduction, and Methods sections.  
7. Improve the flow of the Discussion section (some repetition) :                                                                                  We have restructured the Discussion to remove repetitive statements, combine overlapping concepts, and improve logical flow and readability.
8. The abstract is dense and would benefit from simplification.                                                                                  We have simplified the Abstract by reducing technical density while retaining all essential information.     

We believe these revisions have produced a more balanced, cautious, and transparent manuscript while preserving its clinical relevance. Thank you once again for your insightful comments, which have significantly strengthened our work.

Sincerely,

Reda Elsahy

Corresponding Author

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1.Title: „Effectiveness of Expressed Breast Milk Versus Chlorhexidine

Mouthwash for Infant Oral Hygiene” should be changed because the authors do not compare EBM to chx.

2.This review does not compares EBM and CHX to identify the optimal infant oral hygiene approach because the authors did not present the results of chlorhexidine use in infants. Chlorhexidine is not recommended for children under 6 years of age, so perhaps that is why such studies were not found.

3. The conclusions are not supported by research by other authors.

4. How did the infant patients patients use CHX as a mouthwash if they can't rinse ?

5. The authors in Introduction should describe in more detail the action and mechanism of action of chlorhexidine.

6. The authors in the cited references presented the use of CHX in adults, not in infants.

7. What is the point of comparing the use of EBM to CHX if no other authors' works were found for comparison andCHX is not recommended for infants?

8.Conclusions do not correspond to the aim of the studdy.

Author Response

Reviewer 1 comments:

1. Title should be changed because the authors do not compare EBM to CHX.

Response: We have revised the title to “Effectiveness of Expressed Breast Milk Mouthwash for Infant Oral Hygiene: A Systematic Review” (page 1). (removing "Versus Chlorhexidine").

2. Review does not compare EBM and CHX; no CHX results in infants presented; CHX not recommended under 6 years.

Response: We now explicitly state throughout the manuscript that all EBM–CHX comparisons are indirect (Abstract, Introduction, Results, Discussion, and Conclusions). We also added a clear explanation of why CHX studies in infants are scarce and how it is applied in this population (via swab or gel, not traditional mouthwash rinsing) in the Introduction.

3. Conclusions not supported by other authors.

Response: We have moderated all conclusions and now use cautious language such as “trends toward,” “potentially beneficial,” and “preliminary” (Abstract, Discussion, Conclusions). All claims are directly supported by citations.

4. How infants use CHX as mouthwash if they can't rinse?

Response: Addressed in Introduction: "CHX is not recommended for children under 6 years of age due to their inability to rinse effectively and the risk of mucosal irritation" (with citation (6)).

5. Describe CHX action/mechanism in Introduction.

Response: We expanded the description of CHX’s mechanism (its broad antimicrobial activity by cationic antiseptic that disrupts bacterial cell membranes) and its limitations in infants.

6. Cited CHX references are adult, not infant.

Response: Acknowledged: we now distinguish adult evidence from the very limited paediatric data and explicitly note that robust infant-specific CHX studies are scarce (Results and Discussion).

7. Point of comparing EBM to CHX if no studies and CHX not recommended?

Response: We clarified the purpose in the Introduction and Conclusions: the review synthesizes EBM evidence and contextualizes it against the limited indirect CHX data to highlight evidence gaps and guide future research. No direct comparison claimed.

8. Conclusions do not correspond to aim.

Response: We revised the Conclusions to directly mirror the aim (indirect synthesis and identification of research gaps) and added explicit statements about the indirect nature of comparisons.

 

Reviewer 2comments:

1.    Moderate conclusions in Abstract; state indirect evidence/no head-to-head trials.

Response: Abstract revised and explicitly states “as no head-to-head trials exist” and uses moderated language (“trends toward,” “potentially beneficial”).

2.    Introduction: Clarify aim as indirect comparison.

Response: The final paragraph of the Introduction now clearly states the aim as an indirect comparison and synthesis of evidence.

3.    Methods: Summarize heterogeneity sources + overall RoB.

Response: We added a concise summary of heterogeneity sources and overall RoB (low to moderate) in the Methods section.

4.    Results: Distinguish VAP from pneumonia/sepsis/composites; reiterate indirect.

Response: We added “all comparisons are indirect” in the opening of Results and clearly distinguish VAP from sepsis/composite outcomes throughout.

5.    Discussion/Conclusions: Moderate superiority; frame recommendations preliminary; emphasize RCTs.

Response: We revised both sections with more cautious language and added “provisional” and “pending confirmation” for all recommendations.

 

Reviewer 3 comments

1.    The manuscript repeatedly concludes that EBM is superior to CHX; all comparisons are indirect.

Response: We removed any implication of superiority and repeatedly emphasize that “all comparisons between EBM and CHX are indirect” (Abstract, Results, Discussion, Conclusions)

2.    Heterogeneous populations and protocol variability not systematically analysed.

Response: We added structured subgroup summaries and effect directions in the Results section (under VAP, Bacterial Colonization, and Clinical Recovery Metrics) to improve transparency and reproducibility.

3.    Variability in EBM/colostrum protocols not systematically analysed.

Response: Methods/Results detail variability (dosage 0.1–2 mL, frequency every 3 h, duration up to 27 days, swabbing vs. rinsing); limits comparability/generalizability noted.

4.    CHX evidence limited (one RCT, bundles, adult data).

Response: We now explicitly highlight this limitation in the Results and Discussion. CHX limited to one RCT + bundles; adult data noted; conclusions cautious.

5.    Alternative quantitative synthesis approaches not explored.

Response: We incorporated structured subgroup summaries as alternative synthesis methods via demographics tables (RCTs/non-RCTs).

6.    RoB not integrated into key outcome interpretation.

Response: We now explicitly link RoB to specific outcomes (e.g., “high RoB in non-RCTs may overstate VAP reduction”) in the Results/Discussion subsections. (: "low to high risk... interpret cautiously"; "heterogeneity... limits generalizability").

7.    Outcome definitions vary; lack of harmonization.

Response: Results note variability ("heterogeneity in outcome definitions"); cautious interpretation.

8.    Geographic concentration (Asia).

Response: Results note geographic bias (Asia focus); generalizability restricted. Added to Limitations section.

9.    Caregiver acceptability limited/inconsistent.

Response: Added to Limitations section.

10. Recommendation premature; use cautious wording.

Response: We changed the wording to “may warrant consideration… such recommendations should remain provisional pending confirmation from large-scale head-to-head RCTs.”

Reviewer 2 Report

Comments and Suggestions for Authors

Review,

 

This manuscript addresses a relevant and timely topic in neonatal and pediatric nursing care and is generally well written. However, several clarifications are required to ensure that the conclusions are fully supported by the available evidence.

1. Abstract - Please moderate the conclusions and explicitly state that the comparison between EBM and chlorhexidine is based on indirect evidence, as no head-to-head trials were identified.
2. Introduction - Clarify in the final paragraph that the aim of the review is an indirect comparison of available evidence rather than a direct comparative effectiveness assessment.
3. Methods - Briefly summarize the main sources of heterogeneity that prevented meta-analysis and provide a clearer summary of the overall risk-of-bias findings (RoB 2 and ROBINS-I).
4. Results - Ensure consistent reporting of outcomes, clearly distinguishing VAP from pneumonia, sepsis, or composite infection outcomes, and reiterate that all EBM–CHX comparisons are indirect.
5. Discussion and Conclusions - Further moderate statements implying superiority of EBM over chlorhexidine and frame clinical recommendations as preliminary. Emphasize the need for well-designed head-to-head randomized controlled trials before firm practical recommendations can be made.

Author Response

Reviewer 2comments:

1.    Moderate conclusions in Abstract; state indirect evidence/no head-to-head trials.

Response: Abstract revised and explicitly states “as no head-to-head trials exist” and uses moderated language (“trends toward,” “potentially beneficial”).

2.    Introduction: Clarify aim as indirect comparison.

Response: The final paragraph of the Introduction now clearly states the aim as an indirect comparison and synthesis of evidence.

3.    Methods: Summarize heterogeneity sources + overall RoB.

Response: We added a concise summary of heterogeneity sources and overall RoB (low to moderate) in the Methods section.

4.    Results: Distinguish VAP from pneumonia/sepsis/composites; reiterate indirect.

Response: We added “all comparisons are indirect” in the opening of Results and clearly distinguish VAP from sepsis/composite outcomes throughout.

5.    Discussion/Conclusions: Moderate superiority; frame recommendations preliminary; emphasize RCTs.

Response: We revised both sections with more cautious language and added “provisional” and “pending confirmation” for all recommendations.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript repeatedly concludes that expressed breast milk is superior to chlorhexidine; however, the Results section clearly states that no direct head-to-head trials comparing EBM and CHX were identified. All comparisons are indirect, which substantially limits causal inference and should be more consistently emphasized across the Abstract, Discussion, and Conclusions. 

The included studies cover highly heterogeneous populations, including extremely preterm neonates, postoperative cardiac surgery infants, and mechanically ventilated PICU patients. These groups are synthesized together narratively without clear subgroup separation, which complicates interpretation of the clinical applicability of the findings.

There is considerable variability in EBM and colostrum administration protocols across studies in terms of dosage, frequency, duration, and delivery method. Although this heterogeneity is acknowledged, it is not systematically analyzed, limiting reproducibility and clinical translation.

Evidence regarding chlorhexidine effectiveness in infants relies largely on a single pediatric randomized controlled trial, while other CHX data are derived from bundled interventions or adult-focused studies. This imbalance weakens the strength of conclusions about CHX inefficacy in infant oral care.

Meta-analysis was deemed infeasible due to heterogeneity, yet alternative quantitative synthesis approaches, such as structured subgroup summaries or standardized effect direction analyses, were not explored and could have strengthened the evidence synthesis.

Risk-of-bias assessments using RoB 2 and ROBINS-I are reported, but the manuscript does not clearly integrate these assessments into the interpretation of key outcomes, such as ventilator-associated pneumonia reduction or length of stay, which may overstate the certainty of some findings.

Definitions of major outcomes, including ventilator-associated pneumonia, sepsis, and oral health indices, vary across included studies. The lack of harmonization or detailed discussion of these differences limits comparability across trials.

The evidence base is geographically concentrated, with most randomized trials conducted in Asia and relatively few studies from Western neonatal or pediatric intensive care settings, which restricts the generalizability of the conclusions.

Caregiver acceptability is listed as a secondary outcome, but supporting data are limited and inconsistently reported across studies, making this conclusion less robust than implied.

The recommendation to integrate EBM into standard ventilator-associated pneumonia prevention bundles may be premature given the indirect nature of the evidence, heterogeneous protocols, and absence of direct comparative trials with chlorhexidine, and would benefit from more cautious, conditional wording.

Comments on the Quality of English Language

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

Author Response

Reviewer 3 comments

1.    The manuscript repeatedly concludes that EBM is superior to CHX; all comparisons are indirect.

Response: We removed any implication of superiority and repeatedly emphasize that “all comparisons between EBM and CHX are indirect” (Abstract, Results, Discussion, Conclusions)

2.    Heterogeneous populations and protocol variability not systematically analysed.

Response: We added structured subgroup summaries and effect directions in the Results section (under VAP, Bacterial Colonization, and Clinical Recovery Metrics) to improve transparency and reproducibility.

3.    Variability in EBM/colostrum protocols not systematically analysed.

Response: Methods/Results detail variability (dosage 0.1–2 mL, frequency every 3 h, duration up to 27 days, swabbing vs. rinsing); limits comparability/generalizability noted.

4.    CHX evidence limited (one RCT, bundles, adult data).

Response: We now explicitly highlight this limitation in the Results and Discussion. CHX limited to one RCT + bundles; adult data noted; conclusions cautious.

5.    Alternative quantitative synthesis approaches not explored.

Response: We incorporated structured subgroup summaries as alternative synthesis methods via demographics tables (RCTs/non-RCTs).

6.    RoB not integrated into key outcome interpretation.

Response: We now explicitly link RoB to specific outcomes (e.g., “high RoB in non-RCTs may overstate VAP reduction”) in the Results/Discussion subsections. (: "low to high risk... interpret cautiously"; "heterogeneity... limits generalizability").

7.    Outcome definitions vary; lack of harmonization.

Response: Results note variability ("heterogeneity in outcome definitions"); cautious interpretation.

8.    Geographic concentration (Asia).

Response: Results note geographic bias (Asia focus); generalizability restricted. Added to Limitations section.

9.    Caregiver acceptability limited/inconsistent.

Response: Added to Limitations section.

10. Recommendation premature; use cautious wording.

Response: We changed the wording to “may warrant consideration… such recommendations should remain provisional pending confirmation from large-scale head-to-head RCTs.”