PONE-D-20-32227

HYPERTENSION INDUCED BY PREGNANCY AND NEONATAL OUTCOME: A RETROSPECTIVE COHORT STUDY

PLOS ONE

Dear Dr. ROCHA,

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 Jan 21 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:

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• 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'.
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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,

Antonio Simone Laganà, M.D., Ph.D.

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

The topic of the manuscript is interesting. Nevertheless, the reviewers raised several concerns: considering this point, I invite authors to perform the required major revisions.

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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

Reviewer #3: Partly

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

Reviewer #4: 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: Yes

Reviewer #3: No

Reviewer #4: 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: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: 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: I applaud the effort. You've amassed a fairly large cohort. There are many things however that need to be addressed. Some are described here, more in the attached PDF with comments/edits.

The writing is full of new abbreviations, some of which are not introduced, some are redundant or conflicting, and some are just unnecessary confusion. You use multiple different abbreviations to describe the 2 groups, when G1 & G2 would suffice. I've changed some, noted others, but this is very confusing to the reader and must be cleaned up. Other abbreviations appear without explanation (e.g., RN), or are explained & not used. You also interchange GHS & SHG?

I'm very confused about your exclusion/inclusion criteria. You exclude a large number of babies because of lack of Doppler (Table), but in the results you indicate that only ~ 70% of subjects had Doppler studies. I cannot understand this dichotomy; either it is an exclusion criteria, or it isn't.

There are substantial problems with your footnotes. I suspect during revisions you may have scrambled them up. I tried to correct a couple, but you need to go thru the paper and assure that the footnote numbers in it actually are to the appropriate references.

It appears that diastolic flow reversal is a critical contributor to the poor outcomes. I think you need to expand on & emphasize this. Perhaps even break G1 into DR/DZ vs normal Doppler patterns. Perhaps DR/DZ is the critical factor, not the maternal blood pressure. Did any G2 mother's have DR/DZ? Did this affect their fetuses?

Reviewer #2: I was pleased to revise the manuscript entitled “HYPERTENSION INDUCED BY PREGNANCY AND NEONATAL OUTCOME: A RETROSPECTIVE COHORT STUDY” (Manuscript Number: PONE-D-20-32227).

Study approval was viewed by the institutional review board.

I was particularly pleased to review this paper. In my honest opinion, the topic is interesting enough to attract the readers’ attention. Nevertheless, authors should clarify various points and improve the manuscript. Moreover, they should better discuss limitations of the study that are not evidenced in the discussion.

In general, the Manuscript may benefit from extensive revisions, as suggested below:

- All the text needs a language revision by a native English speaker person, in order to improve its readability, typos, and grammatical errors.

- I would suggest revising the manuscript, starting from the abstract, using more appropriate terms and definitions. Hypertensive pregnancy syndrome is not a term usually used to define the spectrum of hypertensive disorders of pregnancy. Low weight should be used as Low birth weight, small for gestational age, and low birth weight are not the same definition. Only one is reported in results.

- I would suggest checking the use of abbreviations.

- Introduction is not appropriate. It does not provide a clear overview of available pieces of evidence on the topic and does not clarify the gap in the literature that the current study aims to cover. Overall, it does not help to clarify the study aim, which answer is sought and why.

- The sample size calculation needs reporting the study hypothesis used to calculate the sample size. In other words, clarify what the calculated sample size was estimated.

- As a retrospective observational study, I would suggest providing details regarding the source of the list of patients, the source of data, how and who extracted data of patients.

- The “independent” variables are actually the dependent variables. The independent variable is the exposure or not exposure to the hypertensive disorder of pregnancy.

- Discussion should start referring to the study aim and providing an overall view of all results. Here it is reported only a secondary result.

- Overall, introduction and study aim, study methods, study results, and discussion does not appear consistent. The manuscript is hard to follow and, in some points, confusing. It cannot be accepted in the present form.

Reviewer #3: Issue 1: Firstly, with the introduction, clearly state what void this study is filling in the literature. In the discussion, try to avoid listing results over again. Instead focus on putting the research and most salient findings into the context of preexisting literature. I would focus on the outcomes that relate back to the AIM/hypothesis or illuminate an interesting contradiction with current published data. For example, the impact of chorioamnionitis on non-hypertensive preterm group should be emphasized as a distinct etiology of preterm birth, whereas it is less of the impetus for delivery in the hypertensive group. If available in your data set, please comment on the incidence of eclampsia within your population.

While the ability to have doppler data in a study that also has significant neonatal granularity is a strength of the study, I think it needs clarification. The inclusion of doppler information and the reasoning should be better stated in the introduction. In the discussion, this causal relationship should be clearer: are abnormal dopplers an effect modifier? What is the effect of abnormal dopplers in the setting without hypertensive disease? This needs to be clearly defined. Please be specific and use commonly accepted terminology for doppler findings (example: Umbilical artery dopplers may be normal, elevated, absent, or reversed diastolic flow).

Additionally, in the discussion the literature for administration of BMZ and magnesium is reviewed extensively. This could be summarized more succinctly as it is a well-accepted interventions and were not a main focus of the design and outcomes of your study. The authors should highlight the uniqueness of some of the study design: for example, having data on neonates 18 months out is rare. Even though maternal hypertension did not end up being a risk factor for poor growth at 18 months, this is clinically interesting as it implies a “catch up of growth” phenomenon (ie although born small they join an improved growth curve once delivered). Please expand on this.

Issue 2: Secondly, the methods section could benefit from additional clarification: how was chart abstraction done? Were people trained to ensure accurate collection? Were charts audited to check internal validity? The protocol used at their institution for deciding who gets umbilical artery dopplers and management should be clarified. Since small for gestational age was a major finding of their study, they should expand on their explanation of the criteria used (Are Lubchenco et al and Margotto population or customized curves? Is their population similar to those in this study?). For the statistical analysis, consideration should be made in adjusting for confounders like gestational age when looking at hospitalization, birth weight etc.

Issue 3: I would consider decreasing the strength of the language used to report the conclusions. Specifically, it was reported that with maternal hypertension, there was a decreased risk of survival. However, this association disappeared/was no longer significant when corrected for birth weight (CI crosses 1).

Issue 4: Lastly, the language is unclear and difficult to follow. In general, please utilize abbreviations accepted by international professional groups, such as ACOG. Please see some suggestions below for revisions. It may be helpful to work with an editor. Please use accepted nomenclature and abbreviations throughout your paper

Grammar/language:

- Results:

o When presenting data of odds ratios include the 95% CI and p value

o Paragraph 2: Zero diastole� change to absent diastole

o Paragraph 5: doesn’t really show morbidity and mortality or neonates

- Figures:

o Titles for table 1 and 2- GH and GNH are confusing, consider renaming to abbreviations consistent with for what they stand in English

o Consider simplifying numbers of words for table 1 and 2 titles

o Consider adding Doppler characteristics in table 1

o Table 1:

� P values could go out past two decimal points or rounded

� Consider adjusting the weights for GA

o Table 2:

� Consider putting your units in the title of the columns if they are all in precents

� Clarification of “resuscitation at sunrise” do you mean birth?

� Define your abbreviations (SGI, NB)

o Table 3:

� Please re-naming your title as this is more than just survival outcomes

� Clarify the meaning of “survival to high”

� It may improve the readability to have it in the format: OR (95% CI, p=…).

� Column IC 95% should be 95% CI

- Introduction:

o Second paragraph, last sentence: Consider rewording to say “White coat hypertension is an additional category…”

o Third paragraph: please add “accompanied by lab abnormalities indicative of end organ damage or by proteinuria” (reference ACOG Executive Summary 2013)

o Fourth paragraph: consider changing to “risk factors associated with development of pregnancy induced hypertension include: previous history of pre-eclampsia ….

o Paragraphs 6-8 could be combined into one as the subject is maternal and neonatal complications with hypertensive disease of pregnancy.

o Ninth paragraph: define SHG

- Materials and methods:

o First paragraph: could simplify this sentence and remove passive language

o Could move your exclusion criteria to the second paragraph to keep your inclusion/exclusion criteria together

- Discussion:

o Mode of delivery: Think about refining the way your frame this issue-I wouldn’t say it is “preferred” but the risk of cesarean section is increased due to worsening maternal disease or fetal distress

o Paragraph 12: 3rd sentence is difficult to understand. Where is the data from intrauterine growth restriction coming? Based on the birth weight, you can say they are SGA, but not IUGR

o Paragraph 8: You state “the low use of magnesium sulfate among normotensive women in this study is worrying”. This needs clarification as there are multiple indications for magnesium (tocolysis, neuroprotection and seizure prophylaxis). For example, many of the hypertensive patients likely received magnesium for seizure prophylaxis in the setting of severe pre-eclampsia. Whereas, in a normotensive group, the patients are more likely to receive it for other indications.

Reviewer #4: The authors report a meaningful analysis of a population that warrants further study, the neonatal outcomes associated with pregnancy induced hypertension in mothers of premature infants < 34 weeks. However, the translation into English is often awkward and thus needs significant editing. It will be confusing to use the Spanish abbreviations if the article is published in English, especially when the abbreviations are not used consistently. (GH, GHA, GN, GNH).

The title of the manuscript should reflect that the population being reported are premature infants < 34 weeks born to mothers with PIH. There are certainly many pregnant women with PIH who deliver from 34 weeks onward, and the outcomes for their infants may be very different from the population described.

In the Abstract Results and the Results sections, the CI95% for NEC is written incorrectly (should be 1.7 – 8.6)

The introduction section is too long. The discussion of terminating pregnancy seems unnecessary as this is rarely an option for the gestational ages of the study population.

Apgar scores (not “Apgars”) are categorical, not continuous and not normally distributed variables and need to be analyzed as such using non-parametric analysis.

Definition of pregnancy induced hypertension is not clear.

Not sure why mothers without Doppler evaluations were excluded.

Not sure why over 100 babies were referred elsewhere. If they belong predominantly to one study group (hypertensive or normotensive) this should be reported.

Not sure why authors used death defined at 28 days as opposed to survival to hospital discharge.

Don’t understand how mortality could be affected by PIH, but not survival at 18 months. It seems that the 18 months statistic is survival from NICU discharge to 18 months of age.

Unclear whether diagnosis of necrotizing enterocolitis requires at least one clinical sign and one radiological sign.

The phrase “head ultrasound” or “cranial ultrasound” should be used instead of “skull ultrasound”

There should be a more detailed description of the logistic regression analyses used. More results of the effect of umbilical flow should be presented in the Results section, or in another Table, but should not appear only in the Discussion section.

The Discussion section is far too long and overreaching in its scope. It is suggested that the authors focus on the findings of their study that might present new insights into outcomes of PIH in this population of premature infants, findings that are novel or else those that corroborate other studies that might impact the care of pregnant women with PIH and the outcomes of their infants when born prematurely.

In Table 3, don’t understand the meaning of “survival to high%”

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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: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: 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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Attachments

Attachment

Submitted filename: PONE-D-20-32227_reviewer.pdf

PONE-D-20-32227R1

Hypertension induced by pregnancy and neonatal outcome: Results from a retrospective cohort study in preterm under 34 weeks.

PLOS ONE

Dear Dr. ROCHA,

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 08 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,

Antonio Simone Laganà, M.D., 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):

Authors have performed the required changes, improving significantly the quality of the article.

Nevertheless, one of the Reviewers still has some minor concerns: for this reason, I invite the authors to perform these minor revision.

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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: (No Response)

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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 #1: Yes

**********

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

Reviewer #1: Yes

**********

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

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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 #1: Yes

**********

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: Thanks for your efforts to improve this paper, and it is much better now. I still had a few minor comments on the attached PDF. One concern was that your occasionally refer to hypertensive disorder as "present". Though you define pre-eclampsia, HELLP, etc., you do not define "present". I request that you do.

At least in USA, to "terminate" a pregnancy commonly means to Abort. I'd recommend alternative wording, e.g,. electively deliver, deliver prematurely, induce labor, etc.

Your data, especially reqarding PVL, suggests that more than 59.7% of the G1 moms might have benefited from Mag Sulfate; can you comment on that?

Also, contrary to ACOG recommendations, the Cesarean Section rate seems very high. Was there truly a "need", or was this a misperception among the OBs?

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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 #1: 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.

Attachments

Attachment

Submitted filename: PONE-D-20-32227_R1_reviewer.pdf

Hypertension induced by pregnancy and neonatal outcome: Results from a retrospective cohort study in preterm under 34 weeks.

PONE-D-20-32227R2

Dear Dr. ROCHA,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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,

Antonio Simone Laganà, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I carefully evaluated the revised version of this manuscript.

Authors have performed the required changes, improving significantly the quality of the paper.

Reviewers' comments: