Review Reports - Relationship Between Retinopathy of Prematurity and Anemia and Red Blood Cell Transfusions in Very Premature/Very-Low-Birth-Weight Neonates

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for this opportunity to review this article. The authors assessed the role of blood transfusion in developing retinopathy of prematurity.

Abstracts

Line 19. I guess not role of anemia but that of transfusion was analyzed?

Line 21. Please clarify inclusion criteria. Only GA or weight included in criteria?

Line 24. Is degree of ROP discussed? I think this sentence can be removed as authors write in the following paragraph.

Line 30. Please be consistent with main text. Is BW included as inclusion criteria?

Line 34. In line 27, authors describe as mechanical ventilation while respiratory distress syndrome in line35.

Introduction

Introduction part is well-organized, which starts from epidemiology and then describing factors of ROP, followed by pathology in preterm anomia. However, since it feels a bit wordy, I recommend adding subheadings. (eg. epidemiology, risk factors of ROP, pathology of ROP).

After describing these three sections, please explain why this study is necessary. This is because you have already stated in line 90 that blood transfusion is a risk factor for ROP, and the novelty of this study has not been highlighted.

Material and methods

Line 98, the number of participants should move to result section. Instead, please add recruiting period and inclusion criteria. (gestational week and weight, or only weight)

Also, I recommend to add subheadings to this section, too. Study design and participants for the first paragraph, Red blood cell transfusion for second paragraph.

The second paragraph discusses the importance of blood transfusions, but it remains at a general level. Since this is the “Methods” section, please add information regarding the indications and actual practices at your facility.

In definitions and clinical parameters section, spelling out EPI and VPI seems to be unnecessary as they appeared to line 95.

In line 127, apnea is defined, but is it analyzed as factor? Instead, please define respiratory distress syndrome or/and mechanical ventilation.

In ophthalmological screening section, general information is well-discribed, but please add the institutional practice.

In statistical analysis,

Results

Is table1, results of chi-square test? Then please specify in the text. Result described in line 176 seems to be that of chi-square test, while that of line 177 seems to be that of logistic regression. Please clarify the analysis procedure and describe in method section, too.

In Table2, there are several factors that are not defined in method section. Please define them in method section (eg. Severe respiratory syndrome, patent ductus arteiosus, bronchopulmonary dysplasia, early RBC transfusion)

It is a good idea to use symbols such as an asterisk (*) at the bottom of the table to clearly indicate which model was used for each variable.

Line 188, the result seems to be that of chi-square test.

In line 192, authors describe result with OR ratio, while that in Table 3 is written as Exp(B). It might be clearer to put “odds ratio” in parentheses here.

Discussion

Please add summary of your study in the very first part of discussion.

From line 222 to 247, association of anemia and ROP are discussed. Please add a discussion of how the findings of this study can be interpreted.

From line 248, known studies of RBC transfusion are described. Would you write what was added from the present study?

Line 264, mechanism of ROP is well-discribed.

Line 272, I agree with this opinion. It is a clinical dilemma whether to maintain low oxygen levels to prevent ROP or to maintain high oxygen levels to prevent complications such as cerebral palsy. Therefore, how about phrasing this to suggest that further research is needed regarding the indications for oxygen therapy and blood transfusions?

Line 281. Better to move to result part.

Research on retinopathy of prematurity has always been complicated by the fact that gestational age plays a role in whether or not the condition develops, making it very difficult to conduct comparative studies. Thank you for your hard work.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to the manuscript: Relationship of Retinopathy of Prematurity with Anemia and Red Blood Cell Transfusions in Very Premature / Very Low Birth Weight Neonates

I would like to thank the authors for their efforts.

This manuscript addresses an important and clinically relevant topic in neonatology that affects the quality of life. The association between anemia, RBC transfusions, and the development of retinopathy of prematurity (ROP). The study contributes to the ongoing debate about transfusion practices in preterm infants and their potential adverse effects. While the topic is significant and the findings are potentially valuable, several methodological, structural, and interpretative issues should be addressed to improve scientific rigor and clarity. The authors have to show what this work adds and was not known before. The significant methodological limitations, missing data, and clarity issues must be addressed before the manuscript can be considered for publication.

Comments , points covered adequately in the manuscripts

The introduction showed clinical relevance and the importance of ROP.
Clear research objective, aim, and research question
The study population included very preterm and extremely preterm infants, which is appropriate as it reflects the population at highest risk.
ROP classification follows the International Classification of ROP, enhancing comparability. Screening protocols and diagnostic criteria are clearly described, too.
Appropriate statistical approach; use of bivariate analysis and logistic regression tests.
Results demonstrated that RBC transfusion is associated with increased ROP risk (OR ≈ 4.8), and a higher number of transfusions correlates with greater risk. These were reported by existing literature,

The study has several major areas that need to be clarified and or improved before publishing

The introduction could be more concise and focused on the knowledge gap and study rationale
Retrospective, single-center design carries a high risk of selection bias and missing data and limits generalizability to other settings. Moreover, causality cannot be established; only association. This has to be emphasized all over the results, discussion, and conclusion.
Small sample size; total sample: 124 infants, that was divided into subgroups (e.g., severe ROP, >3 transfusions), is very small; this reduces statistical power and increases risk of type II and type I errors. How would authors explain this serious point?

Authors need to review sample size as there are some inconsistencies in sample sizes (e.g., Table 2: ROP N=41 vs earlier N=48 line 168).

A major limitation, too, is missing critical transfusion data. No data on: timing of transfusion (early vs late, clearly quantified), volume per transfusion, and transfusion thresholds.

These are key variables in ROP pathogenesis and interpretation.

Although regression was performed, residual confounding remains significant: Confounding is not fully addressed, and need to relate to the elaborate, we know that sicker infants have more transfusions and have higher ROP risk. Also important covariates missing in the regression:

Oxygen exposure (dose/duration)
Mechanical ventilation duration
Nutritional status
Iron therapy / EPO use

I suggest including: Hemoglobin levels analysis and transfusion timing, and volumes (if available), and strengthening the regression model with additional confounders.

The manuscript focuses heavily on transfusion, but anemia itself is not quantitatively analyzed. There is NO: Hemoglobin thresholds, duration, or severity of anemia were taken in consideration; it is important to be shown in the manuscript, as it weakens the interpretation of anemia vs transfusion effects.
Some issues in tables and data consistency; there is discrepancies related to ROP sample size between the text and tables. Some variables lack clarity; required RBC transfusion n=72” vs earlier total transfused 79 / please explain or correct. Units and formatting inconsistencies are present.
Overinterpretation of results as in the conclusion, RBC transfusions increase the risk of ROP. Although the observational retrospective design does not confirm causality. Association may reflect illness severity.
Language and writing; several issues include grammatical errors, repetition, and long, sometimes unclear sentences. Some paragraphs need restructuring for clarity.
Discussion: Critical interpretation is limited.Does not fully explore alternative explanations and reverse causation (illness severity bias)
Minor Comments :

Clarify the definition of “early transfusion” and the criteria for severe ROP vs any ROP
Improve the table labeling and formatting, and consistent sample numbers throughout the manuscript
Add a flowchart of patient selection and a missing data handling explanation

I suggest including hemoglobin levels analysis and transfusion timing and volumes (if available). Strengthen the regression model with additional confounders.

I suggest reporting correct inconsistencies in tables and numbers and improving the clarity and structure of the results section.

I suggest interpreting tone down causal language and emphasizing the observational nature.

Language needs professional editing for grammar and clarity.

References need to follow the J style

Comments on the Quality of English Language

Need professional editing for grammar and clarity

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

My original comment ”I guess not role of anemia but that of transfusion was analyzed？”　was meant to suggest that while this paper analyzes blood transfusions, it doesn’t seem to address anemia. However, after reading the new section starting on line 241, I see that anemia is also thoroughly analyzed, so please disregard my earlier comment.

Research on retinopathy of prematurity is truly challenging because gestational age and birth weight have such a significant impact; I struggle with this myself on a daily basis. I commend the authors for their hard work. Thank you for giving me the opportunity to review this paper. I look forward to its publication.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The authors responded clearly to the majority of the comments. Comment number 5.Still, the risk factors related to ROP: Oxygen exposure (dose/duration) •Mechanical ventilation duration• Nutritional status•Iron therapy / EPO use to be clarified.