PONE-D-24-11287Neonatal outcomes and resuscitation practices following the addition of heart rate-guidance to basic resuscitationPLOS ONE

Dear Dr. Patterson,

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. The revised version of the manuscript needs to address the methodological limitations of the study and provide a detailed desription of the statistical methods were used for the analysis. 

Please submit your revised manuscript by Sep 23 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Dr. Ribka Amsalu

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include a complete copy of PLOS’ questionnaire on inclusivity in global research in your revised manuscript. Our policy for research in this area aims to improve transparency in the reporting of research performed outside of researchers’ own country or community. The policy applies to researchers who have travelled to a different country to conduct research, research with Indigenous populations or their lands, and research on cultural artefacts. The questionnaire can also be requested at the journal’s discretion for any other submissions, even if these conditions are not met.  Please find more information on the policy and a link to download a blank copy of the questionnaire here: https://journals.plos.org/plosone/s/best-practices-in-research-reporting. Please upload a completed version of your questionnaire as Supporting Information when you resubmit your manuscript.

3. Thank you for stating the following financial disclosure:

“This work was supported by a Saving Lives at Birth Grand Challenge Award, a Thrasher Early Career Award (PI: Jackie Patterson) and a Laerdal Foundation Award (PI: Sara Berkelhamer).”

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

4. Thank you for stating the following in the Competing Interests section:

“I have read the journal's policy and the authors of this manuscript have the following competing interests: Jackie K. Patterson is the recipient of a Laerdal Global Health gift and in-kind personnel support for an NIH-funded clinical trial in resuscitation in the DRC. Joar Eilevstjønn, Ingunn Haug and Helge Myklebust are all employed by Laerdal Medical, the company that developed NeoBeat. Beena Kamath-Rayne is an employee of the American Academy of Pediatrics, and was an Associate Editor for the Helping Babies Breathe, 2nd Edition. The other authors have no relevant conflicts of interest to disclose.”

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

5. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

6. We note that Figure 1 in your submission contain copyrighted images. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. For more information, see our copyright guidelines: http://journals.plos.org/plosone/s/licenses-and-copyright.

We require you to either (1) present written permission from the copyright holder to publish these figures specifically under the CC BY 4.0 license, or (2) remove the figures from your submission:

1. You may seek permission from the original copyright holder of Figure 1 to publish the content specifically under the CC BY 4.0 license.

We recommend that you contact the original copyright holder with the Content Permission Form (http://journals.plos.org/plosone/s/file?id=7c09/content-permission-form.pdf) and the following text:

“I request permission for the open-access journal PLOS ONE to publish XXX under the Creative Commons Attribution License (CCAL) CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/). Please be aware that this license allows unrestricted use and distribution, even commercially, by third parties. Please reply and provide explicit written permission to publish XXX under a CC BY license and complete the attached form.”

Please upload the completed Content Permission Form or other proof of granted permissions as an "Other" file with your submission.

In the figure caption of the copyrighted figure, please include the following text: “Reprinted from [ref] under a CC BY license, with permission from [name of publisher], original copyright [original copyright year].”

2. If you are unable to obtain permission from the original copyright holder to publish these figures under the CC BY 4.0 license or if the copyright holder’s requirements are incompatible with the CC BY 4.0 license, please either i) remove the figure or ii) supply a replacement figure that complies with the CC BY 4.0 license. Please check copyright information on all replacement figures and update the figure caption with source information. If applicable, please specify in the figure caption text when a figure is similar but not identical to the original image and is therefore for illustrative purposes only.

[Note: HTML markup is below. Please do not edit.]

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: Partly

Reviewer #2: No

**********

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

Reviewer #1: I Don't Know

Reviewer #2: No

**********

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

**********

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: Yes

**********

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: I congratulate and thank the authors on their important work in improving newborn outcomes. Their paper seeks to evaluate the impact of HR-guided basic resuscitation compared to HBB-alone on neonatal outcomes and resuscitation practices in the DRC. While the study found no significant difference in effective breathing at 3 minutes, it noted a significant reduction in time to bag-mask ventilation by over a minute in the post-intervention phase of the study. I believe the manuscript provides important preliminary data on the potential of HR in guiding newborn resuscitation, but I do have concerns about drawing any conclusions from these data given the complications with study design discussed below.

Title:

1. Clear and accurately reflects the study's content.

Abstract:

2. Concise and effectively summarizes the study's aim, methods, results, and conclusion.

Introduction:

3. Provides a thorough background on the importance of ventilation and HR monitoring during neonatal resuscitation, particularly in low-resource settings. There’s appropriate referencing of the key, relevant articles in the literature. The study’s objective is clearly stated as well as a well-defined primary outcome (effective breathing at 3 minutes after birth).

4. Line 91: The primary outcome measure (effective breathing at 3 minutes after birth) (Line 91) doesn’t seem to match the stated primary objective (evaluating impact on stillbirth misclassification) (Line 101). Wouldn’t it be best for the primary objective to focus on the primary outcome measure? The current primary outcome measure is more aligned with the stated secondary objective (Line 103). Would you like to switch the stated primary and secondary objectives so they better match the primary outcome measure?

Methods:

5. Strengths: Inclusion criteria (≥28 weeks gestation) are clearly defined. The description of the HR-guided resuscitation protocol and training is detailed. The use of observational data and medical records is appropriate, and the study employs rigorous training for data collectors.

6. Concerns: In this particular study, which included interim provider practice (~monthly) and additional training and simulation during the HR training, I have some concern with the pre-post study design being able to distinguish the impact from NeoBeat (discussed below). The lack of randomization may introduce biases. A cluster-randomized trial would strengthen the study's design and is proposed by the authors in their Conclusion. There is no mention of blinding, which could bias the outcomes assessed by the research staff. This could be mentioned in one’s Limitations paragraph.

7. Line 116: I understand it may be described in other publications, but it would likely be useful to readers if the authors provide a brief description of the NeoBeat device (e.g., reusable, hands-free device placed on the chest of the newborn, etc.).

8. Line 117: The authors mention the first phase of the trial included HBB training and that “no guidance on use of HR data to inform resuscitation steps was provided during this control phase.” While I agree that much of the focus of HBB is on newborn breathing rather than HR, the HBB training materials also mention HR evaluation repeatedly — and HR is the focus of the last part of the Action Plan, in particular, beginning on Page 38 of the HBB2 Provider Manual. I would suggest the authors please reword this sentence.

9. Line 132: As the article is written for an international audience, I would suggest the authors provide a reference for NRP and/or cite it as the training program of the AAP.

10. Line 171: Minor comment, but “data” is technically a plural noun so its verb (“was”) should be plural.

11. Line 188: Instead of including “total stillbirths,” shouldn’t the definition of perinatal mortality be “fresh stillbirths + death before discharge”? I don’t believe macerated stillbirths are included in perinatal mortality.

12. Line 196: The authors identify misclassification of a stillborn case includes the presence of a documented HR. However, shouldn’t they be including any sign of life (e.g., a respiratory gasp, any movement, etc.) and not just a documented HR?

Results

13. Strengths: Presented in a structured manner with appropriate use of tables and figures. The statistical methods used, including adjusted relative risk and general linear models, are suitable for the data.

14. Not essential, but additional subgroup analyses (e.g., based on gestational age) could provide deeper insights into which populations benefit most from HR-guided resuscitation.

15. Lines 217-218: Please clarify in the text that this is the *post* OSCE data, as you did in Table 1.

16. Line 219: As above, should be “Data were”

17. Table 2: Could the authors add an additional column that includes p-values comparing HBB to HR-guided basic resuscitation?

18. Table 3: Just a note that there appears to be a fair amount of missing data (e.g., 35.9% of HBB data). This could be briefly mentioned in the Limitations.

Discussion

19. Strengths: Appropriately contextualizes the findings within the broader literature on neonatal resuscitation.

20. Important: Lines 266-268: The authors report that, in addition to decreasing the time to BMV post-intervention, participants also reduced the time to some of the initial HBB steps. These initial resuscitation steps aren’t informed by HR, yet they improved, nonetheless. This suggests to me that these early resuscitation steps and, therefore, at least in part, BMV likely improved because of the interim provider practice and the additional training/practice during the HR training. It’s, therefore, unfortunately tough to say whether any of the improvements in the initial HBB steps or, more importantly, in BMV were attributable to the NeoBeat. I recognize that the authors may be tangentially alluding to this in their discussion of “time-dependent improvement in resuscitation practices” (Lines 313-319). However, I think the issue goes beyond just passive improvement with time; in the post-intervention period (i.e., HR-guidance phase), the providers not only had ~monthly HBB practice sessions but had also received additional HBB training and simulation during the HR training itself. (While I imagine the HR training had a particular focus on the HR portion of the HR-adapted HBB Action Plan, certainly providers were also refreshed to the other portions of the Action Plan, etc. during this HR training.) Therefore, I fear it is quite difficult to ascertain what role NeoBeat played in any improvements in provider skills, correct? Please correct me if I’m missing something. Otherwise, I think the Discussion, Conclusion, and Abstract need to be written in that light, and one couldn’t claim, for example, “HR-guided basic resuscitation resulted in earlier ventilation” (Lines 286-287), “Access to continuous HR data improved time to response…” (Lines 342-344), and other statements in the Discussion, Conclusion, and Abstract.

21. Lines 271-274: Just as a comment, and as the authors also mention, it is troubling that BMV post-intervention was not initiated until an average of 4:43 minutes after birth. In light of the Ersdal et al. statistic we all reference of 16% increased mortality for every 30-second delay in BMV, I am not even sure how much of an impact the one-minute decrease in time to BMV has on improving newborn outcomes after such a long delay. Although it is progress.

22. Lines 272-274: For the reasons cited by the them (in particular, stillborn misclassification and possibly improvement in data collection), I agree with the authors that an increase in death before discharge likely does not reflect less effective resuscitation post-intervention given improvements in other resuscitation parameters.

23. Line 298: Do the authors know whether the rates of delayed cord clamping were roughly similar during the pre vs post phases? DCC may play a role in ‘time to BMV’ if there’s a delay in initially recognizing a non-vigorous newborn and cutting the cord to facilitate BMV. However, if DCC rates were higher in the post-intervention period (which may have occurred with more recent newborn practices), the improvements in time to BMV may be even more noteworthy.

24. Limitations: In addition to the limitation comments above, several confounding variables could influence the results of this study and could be mentioned and/or discussed in the Limitations paragraph, including any pre/post differences in GA, BW, maternal factors, seasonality, concomitant changes in clinical practices, etc.

Conclusion

25. Lines 340-342: As discussed above, I have concern with concluding “Access to continuous HR data improved time to response…”

26. Lines 342-344: I agree with the authors’ proposal for additional studies (e.g., randomized trial), which may address my study-design concerns.

Acknowledgements

27. Minor point, but I believe “implement” should be “implemented”

Reviewer #2: PONE-D-24-11287: statistical review

SUMMARY. This study evaluates the impact of resuscitation training in the Helping-Babies-Breathe protocol (control group) compared to heart-rate-guided resuscitation protocol (intervention group) on effective breathing at three minutes after birth. Secondary outcomes are time to effective breathing, HR≥100 bpm at three minutes after birth, time to HR≥100 bpm, one and five minute APGARs and death before discharge. The statistical analysis seems to rely (not clear from text) on a battery of generalized linear models but statistical methods and materials are poorly presented: see my comments below.

MAJOR POINTS

1. Little is said about the statistical model that has been implemented for the analysis of the primary outcome and such little is also quite obscure. For example, the abstract says "using a method of least squares to fit general linear models". I guess the authors are dealing with generalized (not general) linear models, and these models are fitted by maximum likelihood methods (not least squares). Then lines 198-201 say "We used a method of least squares to fit general linear models using an identity link and binomial distribution assumption to evaluate whether HR-guided basic resuscitation results in an increased probability that infants breathe effectively within three minutes compared to HBB". An identity link function does not make sense under a binomial assumption. Maybe the authors are just misinterpreting statistical terminology, but correct teminology allows to know what exactly has been done, facilitating results reproducibility and interpretation.

2. Although it is not enterly clear (see major point no 1), I guess the authors are fitting a logistic regression model with a canonical logit link for the analysis of the primary outcome. The result are displayed in Table 4 (first row) but they are "adjusted for facility". What does it mean? Is this the "treatment" effect after removing facility-specific differences? In this case, the estimate of beta should be provided along with the facility differences (are they significant?). More generally, it looks like only facility was included as a confounder. What about all the other variables that are summarized in Table 2? Results can be severly biased if these confounders are significatly correlated with the response variable. The coefficient beta should be estimated along with all these confounders.

3. Nothing is said about the statistical models that have been estimated for the analysis of the secondary outcomes. Some of these outcomes are in the form of time up to an event (e.g. time to effective breathing or time to HR≥100 bpm), hence hazard-based regression models are appropriate. Other outcomes are in the form of a binary event (HR≥100 bpm at three minutes after birth or death before discharge) and hence logistic regression is appropriate. The Apgar index is an integer between 0 and 10 and requires a binomial regression or, less rigorously, a linear regression model if the index is approximately normally distributed. Without this information, the estimated treatment effect cannot be interpreted.

4. It seems that the confounders of Table 2 have been ignored in the analysis of the secondary outcomes. Results can be severly biased if these confounders are significatly correlated with the response variable. Relative risks and regression coefficients should be estimated along with all these confounders.

**********

6. 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 #1: Yes: Brett D. Nelson, MD, MPH

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Neonatal outcomes and resuscitation practices following the addition of heart rate-guidance to basic resuscitation

PONE-D-24-11287R1

Dear Dr. Patterson,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

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):

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 #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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 #1: Yes

Reviewer #2: (No Response)

**********

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

Reviewer #1: I Don't Know

Reviewer #2: (No Response)

**********

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 #1: Yes

Reviewer #2: (No Response)

**********

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 #1: Yes

Reviewer #2: (No Response)

**********

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 #1: Thank you to the authors for addressing my (Reviewer 1's) concerns -- particularly my significant concern over confounders being responsible for any changes in outcomes, instead of HR guidance. I defer to our statistician colleague whether all their statistical questions were adequately addressed. Otherwise, I'm comfortable with this revised paper being published.

Reviewer #2: (No Response)

**********

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 #1: Yes: Brett D. Nelson, MD, MPH, DTM&H

Reviewer #2: No

**********