PONE-D-20-39804

MEGACYSTIS IN THE FIRST TRIMESTER OF PREGNANCY: PROGNOSTIC FACTORS AND PERINATAL OUTCOMES

PLOS ONE

Dear Dr. Lesieur,

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.

Please submit your revised manuscript by Mar 25 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Rogelio Cruz-Martinez, Ph.D.

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. You indicated that you had ethical approval for your study.

In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study (if applicable) or whether the research ethics committee or IRB specifically waived the need for their consent.

3. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study.

Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent.

If patients provided informed written consent to have data/samples from their medical records used in research, please include this information.

Additional Editor Comments:

The authors included a large series of first trimester fetuses with megacystis and described the neonatal outcomes according to the bladder size.

I agree with one of the reviewers that this large series merits publication on this Journal but I also agree with the main criticism by the second reviewer that bladder size groups were arbitrarily selected and that fetal bladder size should be consider a continuous variable and therefore I strongly recommend to assess the clinical value of bladder size to predict neonatal outcome by a decision tree analysis, which allow an automatic classification using the predictive variable as a continuous variable allowing a sequential analysis to predict postnatal outcome. Since previous studies have demonstrated that the size of fetal bladder predicts adverse neonatal outcome, I think that assessing an automatic fetal bladder size cut-off may be of clinical interest and thus, deserving to be publish in this Journal

Please include the following references:

Fontanella et al. Antenatal Workup of Early Megacystis and Selection of Candidates for Fetal Therapy. Fetal Diagn Ther 2019;45(3):155-161.

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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: No

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

Reviewer #1: Yes

Reviewer #2: No

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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: No

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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 authors report a multicenter cohort study, which evaluates the prognosis associated with the bladder size at 1st trimester in case of megacystis.

This large and interesting series deserve to be published. However it should be more focus on its originality that lies in the analysis of outcomes based on bladder size. Moreover, data on evolution during pregnancies and renal function should be provided.

INTRODUCTION

L66-68: The sentence is a bit unclear. Do the authors mean ‘after’ rather ‘with’ checking of bladder emptying during the exam’ ?

L73-78: The authors should rather justify the interest of the present study by describing the lack of data regarding the prognosis associated with bladder size, so as the etiology depending on the bladder size.

L78-80: The main objective should be rephrased to: ‘…in case of megacystis at first trimester, whether bladder size is associated to unfavorable outcome’

L80-83: I suggest to focus only on etiology based on bladder size (rather than to also aiming to describe the whole series as an objective)

METHODS

L95-100 : The authors should justify further the choice of these thresholds.

L103-105: It would be very important to identify cases with or without normal renal function among live births if there is a one-year follow-up+++ Dead/Alive is not appropriate for a study on megacystis and renal function is of interest.

L109: ‘all patients’ rather than ‘all fetuses’

L116: There was no karyotypes performed in one of the centers???

L112-115: Authors should precisely describe the parameters related to the inclusion criteria. How was measured the bladder? Which axis? What if the measurement is different at two different time points during the US examination or between 2 US?

RESULTS

Again, reporting renal function would be really important.

L176-177: Authors introduce here the evolution of US findings at second US. Is it second trimester US? It would be of interest indeed to have follow-up data but it should be more detailed (including bladder aspect, gestational age,…) in a specific table.

L184-186: Mixing data from both US is a bit confusing. If inclusion so as tables based on first US, it should be clearly stated in the methods section so as in the results section.

L191-216: This section is too long, a bit hard to understand, and not necessary. First information is already provided in Table 3 and above all the article should focus on the outcome based on the bladder size.

DISCUSSION

Discussion is interesting and figure 2 is appropriate.

Reviewer #2: This appears to be a rather large series of a rare fetal condition.

However, megacystis was only transient in a large proportion with good outcomes as expected

The authors arbitrarily grouped cases by bladder size. There is no rationale for this and bladder size should therefore be considered a continuous variable

There are no information on standardized care pathway or on indications for TOPs

The etiologies for LUTO in this series are similar to those reported in previous studies

The conclusions are trivial and not substantiated by the data, as explained above.

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Reviewer #1: No

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.]

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PONE-D-20-39804R1

MEGACYSTIS IN THE FIRST TRIMESTER OF PREGNANCY: PROGNOSTIC FACTORS AND PERINATAL OUTCOMES

PLOS ONE

Dear Dr. Lesieur,

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 manuscript has been improved according to the reviewers' comments. However, a main concern persists throughout the manuscript, mainly due to the use of pre-defined bladder size groups instead to select an automatic bladder size cut-off to predict prognosis. 

Please submit your revised manuscript by May 14 2021 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: http://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,

Rogelio Cruz-Martinez, Ph.D.

Academic Editor

PLOS ONE

Editor comments:

The authors should grouped the prognostic category based in the analysis on bladder size and not in a pre-defined bladder size groups, i.e. to analyze bladder size as a continuous variable and selecting the best cut-off to predict adverse outcome. The mean bladder size was significantly higher in cases with adverse outcome, but it remains unknown which is the best cut-off to predict such adverse outcome.

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

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.

PONE-D-20-39804R2

MEGACYSTIS IN THE FIRST TRIMESTER OF PREGNANCY: PROGNOSTIC FACTORS AND PERINATAL OUTCOMES

PLOS ONE

Dear Dr. Lesieur,

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 manuscript has been improved according to the editor and reviewer's suggestions but I still consider it is not suitable for publication in its current form. 

Please submit your revised manuscript by Jul 05 2021 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: http://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,

Rogelio Cruz-Martinez, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

The manuscript has been improved according to the editor and reviewer's suggestions and I consider it is now suitable for publication in its current form

Minor comments:

The manuscript still require a gramatical correction.

Please rephrase the following sentence in the abstract in order to clarify the meaning "Pathological examination of the fetus was performed in 52 (82.5%)".

Please define "neonatal outcome" in the Abstract.

In the Methods section, neonatal outcome has been defined as a live birth with or without normal renal function. Such outcome should be defined as "neonatal survival"

The clinical algorithm should include prediction of neonatal survival as a primary outcome and prediction of renal failure as a secondary outcome

Please clarify the meaning of the following sentence "In the case of TPO; pathological examination of the fetus was suggested". Does it mean fetal autopsy?

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

[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.

PONE-D-20-39804R3

MEGACYSTIS IN THE FIRST TRIMESTER OF PREGNANCY: PROGNOSTIC FACTORS AND PERINATAL OUTCOMES

PLOS ONE

Dear Dr. Lesieur,

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.

Please submit your revised manuscript by Jul 30 2021 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: http://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,

Rogelio Cruz-Martinez, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

The manuscript has been improved accordingly. However, I strongly recommend to have a grammar correction by a native English speaker because there are still several typographical errors.

[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.

MEGACYSTIS IN THE FIRST TRIMESTER OF PREGNANCY: PROGNOSTIC FACTORS AND PERINATAL OUTCOMES

PONE-D-20-39804R4

Dear Dr. Lesieur,

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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Kind regards,

Rogelio Cruz-Martinez, Ph.D.

Academic Editor

PLOS ONE