PONE-D-23-19394AN OBSERVATIONAL, MULTICENTER, REGISTRY-BASED COHORT STUDY OF TURKISH NEONATAL SOCIETY IN NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHYPLOS ONE

Dear Dr. Okulu,

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.

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ACADEMIC EDITOR: Please go through all reviewers' comments and reply to point by point. We believe that your study is very interesting comparing data pre and post invention of therapeutic hypothermia.

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We look forward to receiving your revised manuscript.

Kind regards,

Stefan Grosek, Ph.D., M.D.,

Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Authors

Two reviewers reviewed your article as myself and we found it interesting and well presenting. Please go through all comments and reply point by point.

Kind regards

Academic Editor

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The current study explains the prevalence of HIE in their own nation, where they found decline death rate as compare to the prior report. They concluded that early TH would be preferable because it was not linked to brain damage. They also came to the conclusion that the incidence of HIE stayed the same throughout time with previously published reports but the death rate decreased.

Please find the few Suggestions for improvement of the study

1- Please improve the quality of the figures. It's hard to read the figures.

2- In these HIE instances, were there any sex differences?

3- For more thorough information, also provide the sex details and their results should be supplied. Please discuss any outcome if available.

4-The long-term neurodevelopmental effects of newborns, which may be crucial to discuss before drawing any conclusions about when TH should start, are important aspects. Please modify the conclusion and discuss this in details.

Reviewer #2: The manuscript, which is under evaluation, is designed to deal with data from the multicentre,

observational, nationally based Register of Hypoxic Ischemic Encephalopathy (HIE).

The main strength of this study is to determine the incidence and progression of perinatal newborn

care during the analysed years based on a nationwide data set from a database registry of your country.

The added value of this study is to compare the treatment of newborns before and after the introduction of the national registry and, based on the finding’s improvement of treatment.

Congratulations to the authors for the introduced registry of newborns with HIE and the evaluation of their national data.

While reviewing this manuscript, I have a few comments, questions, and requests for minor corrections:

1. Minor corrections:

- line 366: number missing - value: "mild HIE: ......median"; please added.

- Line 508: need to be rewritten; a new term for HI "trauma" is needed?

2. Questions:

-- It is interesting that a postpartum event (probably in the first hours after birth), most likely defined

as Apparent Life-Threatening Event, occurred in 10.3% of newborns treated with hypothermia.

Do you have an explanation for this percentage of postpartum events underlying HIE?

- How can you explain findings in your study that only severe HIE is associated with

dysfunction of one organ system, when, we know that even mild and moderate hypoxia

is accompanied by impairment of organ systems; including the bone marrow.

- Before drawing conclusions about the differences between groups based on MRI and aEEG,

would it make sense to analyse their neurodevelopmental outcomes at 24 months of age?

Because HI is also a long-term process; when analysing the effectiveness of hypothermia,

we do not take into account the tertiary phase of HE brain damage,

which continues for a long time after the acute event. Do you have any data about

neurodevelopmental outcome of children treated with TH in newborn period?

- The same applies to the interpretation of TH in late preterm infants, please.

- Perhaps, a higher predictive value when comparing groups would be achieved if the

brain magnetic resonance imaging will be assessed based on

MRI scoring systems for HIE brain injury designed by Weeke and co-authors. I will suggest to use

Weekes MRI scoring system as a validated and standardized tool for defining HI brain injury

and as a marker for the analysis of two groups in your study.

- Your study highlights that the overall incidence of severe HIE has decreased; which is consistent

with the results of other studies. Given the fact that your study includes only inborn patients,

would the results be the same if you also included outborn neonates?

-With the introduction of the national registry of newborns with HIE, did you also notice a difference

in the treatment of such newborns before and after the introduction of the registry, such as achieving

the same cooling temperature between different centres; unified neuromonitoring,

unified imaging diagnostics and unified follow up?

Thank you,

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Reviewer #1: Yes: Preeti Singh Chauhan

Reviewer #2: No

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AN OBSERVATIONAL, MULTICENTER, REGISTRY-BASED COHORT STUDY OF TURKISH NEONATAL SOCIETY IN NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY

PONE-D-23-19394R1

Dear Dr. Okulu,

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.

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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,

Stefan Grosek, Ph.D., M.D.,

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors

I found that you addressed all issues I'll recommend to the Editor to accept your article for publication

Kind regards

Academic Editor

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Thank you for your answers and corrections.

The manuscript is processed for acceptance and publication in PLOS ONE journal.

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7. PLOS authors have the option to publish the peer review history of their article (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 #2: No

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