PONE-D-19-18526

Early and late onset pre-eclampsia and small for gestational age risk in subsequent pregnancies.

PLOS ONE

Dear Authors,

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.

We would appreciate receiving your revised manuscript by 1st October. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Salvatore Andrea Mastrolia, M.D.

Academic Editor

PLOS ONE

Journal requirements:

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

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

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

1. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: No

Reviewer #2: Yes

**********

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: Early and late onset preeclampsia and small for gestational age risk in subsequent pregnancy

The study aims to evaluate whether delivery of an SGA infant affected the risk of early and late onset pre-eclampsia in a subsequent pregnancy, and conversely, if occurrence of early and late onset pre-eclampsia in the previous pregnancy increases SGA risk.

Overall, this study touches upon an important topic and, together with previous studies describes the association between a history of preeclampsia and subsequent delivery of an SGA infant.

However, this topic has been extensively described in the North American and European literature and there is no reason to suspect different outcomes in same population.

The following problems are most troubling when considering this article for publication:

1. Alternating the care between the Dutch perinatal caregivers, general practitioners and midwives cannot be ruled out. Moreover, is it possible that the higher risk population's care will be provided by the perinatal caregivers as opposed to midwifery care, for example?

2. Data regarding other related factors such as BMI and other important risk factors for preeclampsia such as vascular, kidney of autoimmune disease was not provided and not controlled for.

3. Pre-gestational diabetes is a potential confounder and an important risk factor for preeclampsia and was not controlled for in the multivariable logistic regression model.

4. No description of those lost to follow up between consecutive pregnancies was provided.

The importance of this manuscript to the medical literature-

Many studies have investigated and described the common pathophysiological features that favor parallel occurrence of preeclampsia and growth restriction. Moreover, it is well established that women with pre-eclampsia or SGA in a previous pregnancy have high risk of recurrence. Therefore, one should consider whether this study presents an important addition to the medical literature that has faced many studies dealing with the same topic in different populations in the world.

Reviewer #2: Well written and methodologically correct manuscript on association between pre-eclampsia and SGA.

In figure 1, the increased risk of SGA (both <p5 as="" p5-10="">p10 in the first pregnancy? Or is the increased risk of SGA in the subsequent pregnancy merely the result of recurrence of SGA in these groups? This should be explained more clearly or added in the analysis.

Hereby, it should also be taken into account that birthweight charts are influenced by the association between placental pathology and preterm delivery. Consequently the amount of SGA infants tends to be underestimated in the preterm period.

Also I suggest that for clinical use, some findings should/could be highlighted more clearly.

For both patients and clinicians absolute risks are more useful than relative risks or odds ratios.

For example: the odds ratios for both early onset and late onset pre-eclampsia in the second pregnancy in women with a previous pregnancy complicated by SGA <p5 and="" pre-eclampsia=""> --> This could be done with a flow chart that can be used in national guidelines and local protocols. (first pregnancy hypertension Yes/no --> first pregnancy pre-eclampsia yes/no --> first pregnancy SGA <p5 --="" no="" yes=""> and subsequent risks of 2nd pregnancy Pre-eclampsia and SGA.

Other comments/sugggestions:

- Abstract:

conclusion "Women with 1st pregnancy early onset pre-eclampsia have increased risk of SGA <5th percentile

45 in the 2nd pregnancy." is not complete/correct. This should be something like: "Women with 1st pregnancy early onset hypertension, pre-eclampsia or delivery <34 weeks have increased risk of SGA (<5th and 5th-10th percentile) in the 2nd pregnancy."

conclusion: "SGA in the 1st pregnancy increases pre-eclampsia risk in the 2nd pregnancy even in the absence of hypertensive disorders in the 1st pregnancy" should in my oppinion be adjusted: "SGA in the 1st pregnancy increases pre-eclampsia risk in the 2nd pregnancy even in the absence of hypertensive disorders in the 1st pregnancy the is an increased risk of pre-eclampsia in the 2nd pregnancy if the first born had a birthweight below the 5th percentile... however, absolute risks are very low (<0.1% for early onset pre-eclampsia, and <0.7% for late onset pre-eclampsia)"

- Introduction

Line 51: "The severity of adverse outcomes has strong association..." ==> consider changing to: "The severity of adverse outcomes has a strong association..."

 </p5></p5></p5>

**********

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: 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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Early and late onset pre-eclampsia and small for gestational age risk in subsequent pregnancies.

PONE-D-19-18526R1

Dear Authors,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With kind regards,

Salvatore Andrea Mastrolia, M.D.

Academic Editor

PLOS ONE

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: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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

Reviewer #2: Yes

**********

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: 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: (No Response)

Reviewer #2: All comments have been addressed. In my opinion the manuscript is methodologically sound and well written.

However some point need attention or adjustment:

Figures:

figure1 and figure2 should be adjusted in such a way that it is more obvious which factors concern the first pregnancy, and which concern the second pregnancy. Especially the vertical "Late onset pre-eclampsia" and "early onset pre-eclampsia" on the left in the figure are confusing ==>

The figure could be separated into.

Figure 1a => "influence of first pregnancy outcomes on late onset pre-eclampsia risk in the second pregnancy"

Figure 1b => "influence of first pregnancy outcomes on early onset pre-eclampsia risk in the second pregnancy"

The same applies to figure 2.

Conclusion:

"SGA in the 1st pregnancy increases pre-eclampsia risk in the 2nd pregnancy even in the absence of hypertensive disorders in the 1st pregnancy, although absolute risks remain low."

Although statistically siginificant. The clinical relevance of this finding remains very doubtful (absolute risk of 0.09% and 0.64%). The finding could also merely be a result of stricter monitoring of pregnant women who delivered a (unexpected) SGA baby in their first pregnancy.

Example: Mother with Diastolic BP of 88mmHg and proteinuria (that wasn't tested because BP was <90 and no symptoms) delivers an SGA baby in her first pregnancy. She is monitored more strictly in her second pregnancy and proteinuria is diagnosed and diastolic BP measured at 90mmHg. This should be addressed in the discussion and the conclusion should be adjusted, either by removing this complete sentence, or by adding absolute risks.

**********

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: Pariente G, Department of Obstetrics and Gynecology, Soroka University Medical Center, Beer - Sheva, Israel

Reviewer #2: No