New Approaches in Motor Intervention for Infants Aged 0–2 Years with or at High Risk of Unilateral or Bilateral Cerebral Palsy: A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review this manuscript. Overall, this systematic review addresses an important and clinically relevant topic, offering a timely synthesis of early motor interventions for infants with or at high risk of cerebral palsy. The manuscript has several strengths, including its focus on early intervention and family-centered care; however, there are a number of methodological, reporting, and interpretive concerns that should be addressed before the manuscript is considered for publication. Please see my comments below:

Abstract:

Lines 39-40: The abstract states that “Four RCTs met the inclusion criteria,” which may be somewhat confusing since six manuscripts were included overall, with two representing secondary analyses of previously published RCTs. It would improve clarity to explicitly state that six articles representing four unique RCTs were included.

Lines 43-45: The phrase “clinically meaningful improvements” may overstate the findings, particularly given that superiority over control interventions was not consistently demonstrated. I recommend using more cautious language that emphasizes within-group improvements rather than suggesting definitive intervention efficacy.

Introduction:

Lines 84-91: The discussion of the Kennard Principle is informative but somewhat lengthy and may feel tangential to the primary objective of the review. Condensing this section and focusing more directly on its relevance to early intervention would improve flow and readability.

Lines 114-123: While the literature gap is introduced, it remains somewhat broad. It would strengthen the manuscript to more clearly explain what previous reviews, particularly Morgan et al. (2021), did not address and how this review meaningfully expands upon prior work.

Line 121: The phrase “between early, diagnosis-appropriate intervention” is awkwardly worded. Revising this to something like “between timely, diagnosis-appropriate intervention” would improve clarity.

Methods:

Lines 133-145: The review question and PICOS criteria appear somewhat broad, especially regarding what qualifies as a “motor intervention.” Providing a clearer operational definition would improve reproducibility and transparency.

Lines 206-207: The methods mention both ROBINS-I and RoB2, yet only RoB2 appears in the results. Please clarify whether ROBINS-I was unnecessary due to the exclusion of non-randomized studies or revise the methods accordingly for consistency.

Lines 209-211: Effect size calculations are described, but no quantitative synthesis or meta-analysis was ultimately conducted. This creates some methodological inconsistency and should either be clarified or removed.

Results:

Lines 218-219: The distinction between six included papers and four unique RCTs should be maintained consistently throughout the manuscript. Presenting primary RCTs separately from secondary analyses in both tables and narrative synthesis would improve clarity.

Lines 267-271: There appears to be contradictory wording where outcomes are described as showing greater improvement but not statistical significance. Revising this language would help avoid reader confusion.

Lines 327-340: The risk of bias discussion would benefit from stronger justification for ratings of “some concerns,” particularly regarding dropout rates and attrition thresholds, as some assessments currently appear somewhat subjective.

Discussion:

Lines 359-366: The interpretation that standard care is highly effective may be somewhat overstated given the heterogeneity of interventions and relatively small sample sizes. Reframing this discussion to acknowledge uncertainty would provide a more balanced interpretation.

Lines 377-406: The proposed “E-MELE” framework is a creative addition, but it currently appears somewhat speculative and may extend beyond the direct evidence presented in the included studies. It would be helpful to clearly frame this as an interpretive or conceptual model rather than an evidence-based consensus.

Lines 410-416: The discussion of excluded pilot studies and protocols, while informative, may distract from the primary review findings. This section may be better shortened, streamlined, or relocated.

Conclusions:

Lines 437-438: The conclusion that early motor interventions “appear to promote clinically relevant improvements” may overstate the certainty of the evidence. More cautious wording that acknowledges methodological limitations and lack of demonstrated superiority across interventions would strengthen the conclusion.

Author Response

Abstract:

Comments 1: Lines 39-40: The abstract states that “Four RCTs met the inclusion criteria,” which may be somewhat confusing since six manuscripts were included overall, with two representing secondary analyses of previously published RCTs. It would improve clarity to explicitly state that six articles representing four unique RCTs were included.

Response 1: Thanks for pointing this out, we agree with this comment, and we have replaced the sentence “Four RCTs met the inclusion criteria” with “Six articles, representing four RCTs, were included” to improve clarity and consistency.

Comments 2: Lines 43-45: The phrase “clinically meaningful improvements” may overstate the findings, particularly given that superiority over control interventions was not consistently demonstrated. I recommend using more cautious language that emphasizes within-group improvements rather than suggesting definitive intervention efficacy.

Response 2: Thanks for pointing this out, we agree with this comment, and we have replaced the sentence “however, all studies reported clinically meaningful improvements in motor and developmental domains in both arms” with “however, notable within-group improvements in motor and developmental domains were reported across both study arms.”

Introduction:

Comments 3: Lines 84-91: The discussion of the Kennard Principle is informative but somewhat lengthy and may feel tangential to the primary objective of the review. Condensing this section and focusing more directly on its relevance to early intervention would improve flow and readability.

Response 3: Thanks for pointing this out, we agree with this comment, and we have condensed this section by replacing with the following text: “Infants possess a significant, yet fragile, potential for neuroplasticity. Although early theories like the 'Kennard Principle' posited a linear advantage for younger patients, revised models recognize that functional outcomes depend on lesion characteristics and environmental factors [6, 7]. This reinforces the existence of a critical developmental window, making timely therapeutic intervention essential to leverage early brain potential.”

Comments 4: Lines 114-123: While the literature gap is introduced, it remains somewhat broad. It would strengthen the manuscript to more clearly explain what previous reviews, particularly Morgan et al. (2021), did not address and how this review meaningfully expands upon prior work.

Response 4: Thanks for pointing this out, we agree with this comment. We added text at line 120 “Notably, even the most recent international guidelines acknowledge that the quality of evidence across many intervention domains remains variable, with several recommendations being downgraded to 'conditional' due to a reliance on interpolated data from non-CP populations (9). This suggests a persistent operational gap regarding the precise technical protocols, dosages, and specific clinical potentials of emerging motor treatments”, and we added text at line 124 “to provide clinicians with more granular and evidence-based operational tools”

Comments 5: Line 121: The phrase “between early, diagnosis-appropriate intervention” is awkwardly worded. Revising this to something like “between timely, diagnosis-appropriate intervention” would improve clarity.

Response 5: Thanks for pointing this out, we agree with this comment, and we have revised the wording to “timely, diagnosis-appropriate intervention” to improve clarity and readability.

Methods:

Comments 6: Lines 133-145: The review question and PICOS criteria appear somewhat broad, especially regarding what qualifies as a “motor intervention.” Providing a clearer operational definition would improve reproducibility and transparency.

Response 6: Thank you for this comment. We did not include an overly detailed operational description of “motor intervention” within the PICOS statement because it is subsequently specified in the manuscript (Section 2.5.4, line 194).

Comments 7: Lines 206-207: The methods mention both ROBINS-I and RoB2, yet only RoB2 appears in the results. Please clarify whether ROBINS-I was unnecessary due to the exclusion of non-randomized studies or revise the methods accordingly for consistency.

Response 7: Thanks for pointing this out; we agree and revised the Methods for consistency. The text now reads: “The Risk of Bias for Randomized Controlled Trials (RCTs) was assessed using the RoB 2.0 tool. Although the use of the ROBINS-I tool had been pre-specified in the study protocol for the evaluation of non-randomized intervention studies, it was not ultimately applied as no such studies met the inclusion criteria.”

Comments 8: Lines 209-211: Effect size calculations are described, but no quantitative synthesis or meta-analysis was ultimately conducted. This creates some methodological inconsistency and should either be clarified or removed.

Response 8: Thank you for this observation; we agree. We have therefore revised the text in this paragraph as follows: “While the calculation of measures of change, specifically the between-group standardized mean difference (SD) for each outcome (post-intervention minus baseline) comparing the intervention group versus controls, was originally planned, this analysis was ultimately not feasible due to the high degree of heterogeneity found across the included literature.” We also note that this issue is acknowledged as a study limitation in Section 4.4.

Results:

Comments 9: Lines 218-219: The distinction between six included papers and four unique RCTs should be maintained consistently throughout the manuscript. Presenting primary RCTs separately from secondary analyses in both tables and narrative synthesis would improve clarity.

Response 9: Thank you for this comment. After discussion within the team, we felt it was more appropriate and clearer to keep publications arising from the same RCT presented together (i.e., grouped within the same narrative and table entries), while explicitly indicating when a paper reports primary trial results versus a secondary analysis. This approach preserves the distinction between four unique RCTs and six publications without fragmenting information across sections.

Comments 10: Lines 267-271: There appears to be contradictory wording where outcomes are described as showing greater improvement but not statistical significance. Revising this language would help avoid reader confusion.

Response 10: Thanks for pointing this out; we agree and have revised the text to avoid ambiguity by clearly distinguishing numerical trends from statistical significance. The paragraph now reads: “The intervention group demonstrated a numerical improvement in mean TSFI scores compared to the control group, although this difference did not reach statistical significance. No differences were observed in post-intervention AIMS scores between groups. While the addition of sensory integration to standard physiotherapy showed favorable trends in sensory processing for infants with CVI and CP, definitive superiority over standard care alone was not established.”

Comments 11: Lines 327-340: The risk of bias discussion would benefit from stronger justification for ratings of “some concerns,” particularly regarding dropout rates and attrition thresholds, as some assessments currently appear somewhat subjective.

Response 11: Thanks for pointing this out; we agree that the rationale should be stated more explicitly. Our RoB 2.0 judgments followed the RoB 2.0 flowchart for the “missing outcome data” domain. We have clarified added this text: “the rating of “some concerns” (moderate risk) for attrition in the “Start Play” and Benfer studies was based on the statistical consequences of dropout, as explicitly acknowledged by the authors themselves.” We added text at line 340 “ These author-reported consequences were used as an objective criterion for identifying potential bias.”

Discussion:

Comments 12: Lines 359-366: The interpretation that standard care is highly effective may be somewhat overstated given the heterogeneity of interventions and relatively small sample sizes. Reframing this discussion to acknowledge uncertainty would provide a more balanced interpretation.

Response 12: Thanks for pointing this out; we agree and have therefore rephrased this part of the Discussion as follows: “While none of the studies showed a significant difference between the experimental and standard care groups regarding primary motor function outcomes, significant improvements were observed across all cohorts. However, these results should be interpreted with caution; the lack of a statistically significant difference may not necessarily confirm the high efficacy of standard care but rather reflect the inherent challenges of these trials. Factors such as the high degree of clinical heterogeneity in the population and the relatively small sample sizes often confound between-group comparisons, making it difficult to isolate specific treatment effects or establish a clear superiority of one approach over another.”

Comments 13: Lines 377-406: The proposed “E-MELE” framework is a creative addition, but it currently appears somewhat speculative and may extend beyond the direct evidence presented in the included studies. It would be helpful to clearly frame this as an interpretive or conceptual model rather than an evidence-based consensus.

Response 13: Thanks for pointing this out, we agree with this comment, and we have revised the text to clearly present the proposed “E-MELE” framework as an interpretive/conceptual model derived from patterns across the included studies, rather than as an evidence-based consensus. In particular, we added the following sentence to introduce the framework: “Building upon the evidence identified in this review and integrating established neurodevelopmental principles, we propose the E-MELE framework. This conceptual model serves as an interpretive tool to help healthcare professionals translate clinical evidence into practice by focusing on five key pillars:”

Comments 14: Lines 410-416: The discussion of excluded pilot studies and protocols, while informative, may distract from the primary review findings. This section may be better shortened, streamlined, or relocated.

Response 14: Thank you for this comment. We agree that this section should not distract from the primary review findings. However, we feel that briefly commenting on study protocols remains relevant, as it helps readers appreciate why periodic updates of the literature are needed: a systematic review provides a snapshot of the evidence available today, while ongoing and forthcoming trials will soon shape the field and inform future syntheses.

Conclusions:

Comments 15: Lines 437-438: The conclusion that early motor interventions “appear to promote clinically relevant improvements” may overstate the certainty of the evidence. More cautious wording that acknowledges methodological limitations and lack of demonstrated superiority across interventions would strengthen the conclusion.

Response 15: Thanks for pointing this out, we agree with this comment, and we have revised the Conclusions to use more cautious language that reflects the limitations of the evidence base (methodological limitations, small samples, heterogeneity, and lack of consistent demonstrated superiority), while still summarizing the overall direction of findings. We have therefore rephrased this part of the Conclusions as follows:” While current evidence does not demonstrate the superiority of any specific intervention protocol, a trend toward improved motor and developmental outcomes was observed across the included studies. However, given the methodological heterogeneity and the lack of a clear advantage over standard care, these findings should be interpreted with caution, and the definitive efficacy of early motor interventions remains to be established through more rigorous research.”

Reviewer 2 Report

Comments and Suggestions for Authors

As the title suggests, the article addresses ‘early motor interventions for infants with or at high risk of cerebral palsy’ (CP). Given that the worldwide incidence of CP is 2 per 1,000 live births, the topic addressed by the authors is of significant medical and social importance. As is known, early diagnosis of CP is important for the effectiveness of treatment of this disorder. The authors conducted an extensive literature review based on strictly defined criteria. The process of selecting the literature that was the basis for the analysis is shown in Figure 1.

I assess the structure of the manuscript as appropriate (clear) for this type of article. The references selected by the authors are relevant to the topic. However, I would suggest supplementing the References section with at least two publications: 1. Ryder S., Kerner-Rossi M. et al. Standardizing early cerebral palsy detection in high-risk infants: reducing age at diagnosis through a quality improvement initiative. Journal of Perinatology; 2025, https://doi.org/10.1038/s41372-025-02412-z. 2. Hadders-Algra M., Boxum A., Hielkema T., Hamer E. Effect of early intervention in infants at very high risk of cerebral palsy: a systematic review. Developmental Medicine & Child Neurology 2017, 59: 246–258. The first of these should be included in the Introduction section. The second approach could be used for appropriate comparisons in the Discussion section.

A strength of the reviewed text is its reliance on relatively recent publications presenting the current state of medical knowledge on the topic. Furthermore, the graphic materials presented by the authors facilitate understanding and interpretation of the manuscript's content. The final conclusions are also consistent with the evidence and arguments presented by the authors.

The authors are aware of the limitations of their study, which speaks positively about their scientific approach. Overall, I believe the reviewed manuscript is clear, relevant to the field, and presented in a well-structured form, thus meeting the basic requirements for scientific texts.

In the context I have presented above, I positively assess the publication of this manuscript after incorporating my proposed changes.

Author Response

Comments 1: As the title suggests, the article addresses ‘early motor interventions for infants with or at high risk of cerebral palsy’ (CP). Given that the worldwide incidence of CP is 2 per 1,000 live births, the topic addressed by the authors is of significant medical and social importance. As is known, early diagnosis of CP is important for the effectiveness of treatment of this disorder. The authors conducted an extensive literature review based on strictly defined criteria. The process of selecting the literature that was the basis for the analysis is shown in Figure 1.

Response 1: We sincerely thank the Reviewer for this positive evaluation of the manuscript’s topic, rationale, and methodological approach. We appreciate the recognition of the medical and social relevance of early motor interventions in infants with or at high risk of cerebral palsy, as well as the acknowledgment of the rigor of our literature selection process and the clarity of Figure 1.

Comments 2: I assess the structure of the manuscript as appropriate (clear) for this type of article. The references selected by the authors are relevant to the topic. However, I would suggest supplementing the References section with at least two publications: 1. Ryder S., Kerner-Rossi M. et al. Standardizing early cerebral palsy detection in high-risk infants: reducing age at diagnosis through a quality improvement initiative. Journal of Perinatology; 2025, https://doi.org/10.1038/s41372-025-02412-z. 2. Hadders-Algra M., Boxum A., Hielkema T., Hamer E. Effect of early intervention in infants at very high risk of cerebral palsy: a systematic review. Developmental Medicine & Child Neurology 2017, 59: 246–258. The first of these should be included in the Introduction section. The second approach could be used for appropriate comparisons in the Discussion section.

Response 2: We are grateful to the Reviewer for appreciating the structure of the manuscript and the relevance of the selected references. We also thank the Reviewer for recommending these two valuable publications. We carefully considered both suggestions. However, after discussion among the authors, we decided not to include them in the revised manuscript in order to preserve the specific clinical focus and methodological homogeneity of our review. Regarding Ryder et al. (2025), we fully agree on the importance of early detection and diagnosis of cerebral palsy; however, since our review is specifically focused on the clinical efficacy of active motor rehabilitation interventions once high risk for cerebral palsy has already been established, we believe that this paper, which mainly addresses implementation of a quality-improvement pathway for earlier diagnosis, falls somewhat outside the direct scope of our therapeutic question. Regarding Hadders-Algra et al. (2017), we recognize its importance as a landmark review; however, because it summarizes studies published up to 2016, we chose to keep our Discussion centered on the most recent and methodologically comparable trials in order to provide a more contemporary clinical perspective. We hope the Reviewer will understand this choice, which was made to maintain the coherence, specificity, and timeliness of the manuscript.

Comments 3: A strength of the reviewed text is its reliance on relatively recent publications presenting the current state of medical knowledge on the topic. Furthermore, the graphic materials presented by the authors facilitate understanding and interpretation of the manuscript's content. The final conclusions are also consistent with the evidence and arguments presented by the authors.

Response 3: We thank the Reviewer for highlighting these strengths of our manuscript. We especially appreciate the acknowledgment of our effort to rely on recent literature, to provide clear graphic support, and to formulate conclusions that are consistent with the evidence presented.

Comments 4: The authors are aware of the limitations of their study, which speaks positively about their scientific approach. Overall, I believe the reviewed manuscript is clear, relevant to the field, and presented in a well-structured form, thus meeting the basic requirements for scientific texts.

Response 4: We are grateful to the Reviewer for this encouraging assessment. We appreciate the recognition of our attention to the limitations of the study and of the overall clarity, relevance, and organization of the manuscript.

Comments 5: In the context I have presented above, I positively assess the publication of this manuscript after incorporating my proposed changes.

Response 5: We sincerely thank the Reviewer for the positive overall recommendation and for the constructive comments provided. We carefully considered all observations and revised the manuscript accordingly where appropriate.

Reviewer 3 Report

Comments and Suggestions for Authors

I have read this paper with great interest, and with a background on perinatal and pediatric clinical research, including on aspects related to CP.

Are findings similar in cases with proven CP versus a high risk, or are the simply not sufficient data and granularity to explore both ‘sub’groups?

While I understand your approach to restrict the publications on year, 2020-2024 is perhaps a somewhat too stringent decision ? would you consider this as a potential shortage ?

If I understood your results well, none of the additional interventions were of add on value. If so, should this not be added to the abstract and the conclusion section of the paper. How congruent is this with other systematic reviews on this topic, if present (considering also the ‘high risk’ concept versus ‘confirmed’ cp).

Abstract: why not put the registration comments in the methods section of your abstract.

Can you add some ‘numbers’ to the abstract, like number of patients included in the 4 RCT, verifying your table 1, the overall number is limited.

Line 61-62: perhaps add that the CP clinical picture will still evolve of age, despite the non-progressive disturbances.

I had problems to retrieve your protocol, but finally retrieved this, perhaps adapt your number to facilitate retrieval, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024506784

The ‘core principles’ approach has value, but seems not to be the explicit initial intention of the systematic review. You may also provide some additional context on this aspect ?

Supplemental materials

Please check the figure A on editing in the supplement, in the full version, it seems ok (so why report twice).  Similar reflection for other supplemental materials, that are also in the full document.

 

Author Response

Comments 1: Are findings similar in cases with proven CP versus a high risk, or are the simply not sufficient data and granularity to explore both ‘sub’groups?

Response 1: Thanks for pointing this out, we agree with this comment, we thank the Reviewer for this important observation. We chose to consider children with confirmed CP and those at high risk of CP within the same framework because current international recommendations support the initiation of early intervention as soon as a high risk is identified, rather than waiting for a formal diagnosis (Novak et al., 2017; Morgan et al., 2021). In addition, the studies included in our review did not provide sufficient detail to allow a reliable subgroup analysis between these two populations.

Comments 2: While I understand your approach to restrict the publications on year, 2020-2024 is perhaps a somewhat too stringent decision? would you consider this as a potential shortage?

Response 2 Thanks for pointing this out, we agree with this comment, and we thank the Reviewer for this thoughtful comment. We agree that the review by Morgan et al. addressed a closely related question and represents an important reference in this field. At the same time, as also acknowledged in that work, further literature appraisal is still needed to better identify which rehabilitation approaches may be the most effective. For this reason, we considered it important to extend the work initiated by Morgan et al., using the same search strings to map the literature published since that review and to provide an updated overview of the available evidence as we declare at lines 147 Eligibility criteria 2.1.

Comments 3: If I understood your results well, none of the additional interventions were of add on value. If so, should this not be added to the abstract and the conclusion section of the paper. How congruent is this with other systematic reviews on this topic, if present (considering also the ‘high risk’ concept versus ‘confirmed’ cp).

Response 3: Thank you for pointing this out. We agree that the absence of clear additional benefit from add-on interventions is an important take-home message. Therefore, we have revised both the Abstract (lines 44 “however, notable within-group improvements in motor and developmental domains were reported across both study arms.”) the Discussion (lines 359-366 “While none of the studies showed a significant difference between the experimental and standard care groups regarding primary motor function outcomes, significant improvements were observed across all cohorts. However, these results should be interpreted with caution; the lack of a statistically significant difference may not necessarily confirm the high efficacy of standard care but rather reflect the inherent challenges of these trials. Factors such as the high degree of clinical heterogeneity in the population and the relatively small sample sizes often confound between-group comparisons, making it difficult to isolate specific treatment effects or establish a clear superiority of one approach over another. Our findings regarding the lack of clear 'add-on' value are highly consistent with recent high-level evidence syntheses in the field [9, 29].”) and the Conclusions (lines 437-438:” While current evidence does not demonstrate the superiority of any specific intervention protocol, a trend toward improved motor and developmental outcomes was observed across the included studies. However, given the methodological heterogeneity and the lack of a clear advantage over standard care, these findings should be interpreted with caution, and the definitive efficacy of early motor interventions remains to be established through more rigorous research.”) to reflect this finding more explicitly.

Comments 4: Abstract: why not put the registration comments in the methods section of your abstract.

Response 4: Thank you for this helpful suggestion. We agree that registration information should be reported as clearly as possible. After consideration, we decided to retain the PROSPERO registration ID in the Abstract, as this allows immediate identification of the review registration. We then provided the full web address to access the protocol document in the Methods section, in order to facilitate retrieval and consultation of the complete record.                                                                                 Lines 213: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024506784

Comments 5: Can you add some ‘numbers’ to the abstract, like number of patients included in the 4 RCT, verifying your table 1, the overall number is limited.

Response 5: Thank you for pointing this out. We agree that including quantitative information in the Abstract can improve interpretability. However, in the present review, we considered it more appropriate not to provide a cumulative numerical synthesis of the results, because the included studies were highly heterogeneous in terms of outcomes, measurement tools, and types of intervention. This methodological heterogeneity also prevented us from performing a meta-analysis so we have therefore revised the text al lines 209-211 as follows: “While the calculation of measures of change, specifically the between-group standardized mean difference (SD) for each outcome (post-intervention minus baseline) comparing the intervention group versus controls, was originally planned, this analysis was ultimately not feasible due to the high degree of heterogeneity found across the included literature.” We also note that this issue is acknowledged as a study limitation in Section 4.4. We have therefore chosen to present the findings narratively, in order to provide a more accurate and methodologically appropriate summary of the available evidence lines 240 Table 1.

Comments 6: Line 61-62: perhaps add that the CP clinical picture will still evolve of age, despite the non-progressive disturbances.

xResponse 6: Thank you for pointing this out, we agree with this comment, and we have added at line 62: “The resulting clinical picture is 'persistent but not immutable';  as the child grows, the interaction between the static brain injury, the maturation of the central nervous system, and environmental factors leads to a continuous evolution of posture and movement patterns [2].

Comments 7: I had problems to retrieve your protocol, but finally retrieved this, perhaps adapt your number to facilitate retrieval, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024506784

Response 7: Thank you for pointing this out. We agree that the protocol should be easily retrievable. Therefore, we have checked and corrected the PROSPERO registration number and ensured that it is consistently reported throughout the manuscript at lines 213.

Comments 8: The ‘core principles’ approach has value, but seems not to be the explicit initial intention of the systematic review. You may also provide some additional context on this aspect ?

Response 8: Thank you for pointing this out. We agree that the “core principles” framing requires additional context, we added at Lines 377-406 the following sentence to introduce the framework: “Building upon the evidence identified in this review and integrating established neurodevelopmental principles, we propose the E-MELE framework. This conceptual model serves as an interpretive tool to help healthcare professionals translate clinical evidence into practice by focusing on five key pillars:”

Supplemental materials

Comments 9: Please check the figure A on editing in the supplement, in the full version, it seems ok (so why report twice).  Similar reflection for other supplemental materials, that are also in the full document.

Response 9: Thank you for this helpful comment. If we understood correctly, Figure A refers to Figure 1, the PRISMA flow diagram, which was included in the main manuscript and also uploaded separately as requested by the journal. The supplementary files were intended to include only Appendix A.1 Search strategies, Appendix B.1 PRISMA Checklist, Appendix B.2 PRISMA Abstract Checklist, and Appendix C Reports excluded. If any duplication resulted from the submission process, we would be grateful for further clarification so that we can correct it accordingly.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for addressing all my comments thoroughly and revising the manuscript. I feel the manuscript is now much stronger and has improved the rigor.  

Author Response

We sincerely thank the reviewer for the careful and constructive evaluation of our manuscript. We truly appreciate the positive feedback provided and are pleased that the revisions have improved the overall quality and methodological rigor of the manuscript.