PONE-D-22-07025Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trialPLOS ONE

Dear Dr. Diguisto,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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ACADEMIC EDITOR:

As highlighted by Reviewer 3, although this trial was interrupted prematurely, the results of this study are interesting. However, this manuscript needs major modifications. Therefore, responses to reviewers' comments should be done carefully, especially Reviewer 2 comments.

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Please submit your revised manuscript by Jul 16 2022 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Patrick Rozenberg, MD

Academic Editor

PLOS ONE

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Additional Editor Comments::

As highlighted by Reviewer 3, although this trial was interrupted prematurely, the results of this study are interesting. However, this manuscript needs major modifications. Therefore, responses to reviewers' comments should be done carefully, especially Reviewer 2 comments

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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: A randomized controlled clinical trial was conducted which aimed to evaluate whether daily low-dose aspirin reduces preeclampsia and growth restriction in nulliparous women at high risk for the condition. The proportion of women who developed preeclampsia was not significantly different in the two randomization arms.

Minor revisions:

1- Line 190: Provide a measure of dispersion for age.

2- Table 1: It is customary to report means and standard deviations for normally distributed variables and median, first and third quartiles for non-normally distributed variables.

3- Table 2: Provide a p-value comparing the association of anesthesia and arm. Perhaps this p-value is 0.94. If so, move the p-value to the line labeled “Anesthesia (n=539 vs 537).”

4- Table 3: Provide p-values comparing the proportions with adverse events.

5- Indicate if adverse events were collected according to a standardized method such as the Common Terminology Criteria for Adverse Events (CTCAE).

Reviewer #2: Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trial; by Diguisto C et al.

This study addresses a very interesting question: the usefulness of low-dose aspirin (LDA) to prevent preeclampsia and growth restriction in high risk nulliparous women identified by early uterine artery Doppler. The article is well-written and easy to read.

I have some major comments:

In the introduction section the rational of the study in insufficiently detailed:

- Line 82-86, the authors discuss the use of algorithms involving biological, maternal and ultrasound parameters to select high risk women. This is off-topic in the introduction and the authors should mention the articles they are relying on to carry out the study. In addition, in their rational they refer to articles published after the start of the trial, which is illogical (ref 9,11,12)), and they use a reference in which uterine doppler was performed in the second trimester (ref 11)

- Amazingly, I did not find any reference in the introduction section supporting the use of early uterine Doppler alone to select high risk nulliparous women. This is essential for the calculation of the number of patients to be included in the study

- Instead of citing general articles concerning the rate of PE (line 74, ref 1 and 2) the authors are lucky to have French publications on the subject, with a risk of PE in nulliparous women of 1.7% (Subtil et Al, ERASME trial Part 1, BJOG. 2003;110:475-484), and in general population of 0.7% (Goffinet et al. BJOG. 2001;108:510-8.)

- In addition, do the authors have any idea on the performance of early uterine Doppler to select high risk nulliparous women in a french cohort (pilot study for instance)

In the Screening for participants section (line 101) the authors should mention how many women were approached before randomization, the reasons of refusals, and put all these informations in the flow-chart.

In sample size section, I do not understand how the authors calculated the number of patients to recruit. They must provide the articles they rely on because the two references cited by the authors (ref 18 and 19) do not address prediction of SGA < 5th centile. The authors should discuss and may be use the findings of Pilalis et al ( Acta Obstetrica et Gynecologica. 2007; 86:530-34.) where these authors found the same composite outcome of 14%. This article might have helped the author to calculate the number needed to recruit.

In Analysis section, the authors should present the data of an RCT as RR and absolute risk reduction. In addition, they should mention when they did the unblinding compared to the analysis of complications

In the results section:

Table 2, the authors must separate primary outcome from secondary outcomes, add two columns ( one for RR and one for ARR)

They must add a specific par for side effects. In addition, Table 3 is not clear: serious events are different from those of Table 2?, for instance, rates of preterm delivery are different ?; What are the maternal hypertensive complications? Why the numbers are not similar for perinatal death? I encourage the authors to detail serious events.

In the discussion section:

Line 271, add after was not “statistically”…

You must discuss in first why you have such difference of primary outcome (21.2% expected and 14.4% observed), almost 32%.

In the conclusion section, you must add that your results are uncertain because of lack of power related to insufficient number of patients recruited in the study.

Reviewer #3: This is a randomized, blinded, placebo-controlled, parallel-group trial assessing whether daily low-dose aspirin initiated before 16 weeks of gestation can reduce preeclampsia and growth restriction in nulliparous women identified by first-trimester uterine artery Dopplers as at high risk of preeclampsia. Aspirin was administered at the appropriated doe of 160 mg/day. Preeclampsia or a birthweight ≤ 5th percentile occurred in 88 (16.0%) women in the low-dose aspirin group and in 79 (14.4%) in the placebo group (proportion difference 1.6 [-2.6 ; 5.9] p=0.45). The two groups did not differ significantly for the secondary outcomes.

The manuscript by Diguisto et al. is well written. The methodology is clear and clearly explained. Although, the trial was interrupted after including 44% of the expected number of patients (1104 of the 2486 planned), the results of this study are interesting and need to be published.

In the introduction, please mention the prevalence of preeclampsia (PE) in France in the general population and in nulliparous women. This will allow to show that the patients of the placebo group are at higher risk of PE.

The result section is very limited. Please describe the results in this section. Gestational age at delivery should be added.

In the discussion, please present the results of the previous studies evaluating first trimester uterine Doppler (such The Great Obstetrical Syndrome Study) and show how the outcomes of the placebo group are comparable to these studies. Please also discuss the previous studies assessing the effect of low dose aspirin in patients first trimester uterine Doppler and show how the outcomes of the placebo (Acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery Doppler: a systematic review and meta-analysis; Usefulness of aspirin therapy in high-risk pregnant women with abnormal uterine artery Doppler ultrasound at 14-16 weeks pregnancy: randomized controlled clinical trial).

Please also discuss that 2/3 of preeclampsia cases occurred after 37WG. This is normal but may contribute to the results of the trial.

Line 121 : the sentence is not clear. Did the patients receive Kardegic sachets or a reconditioned for of aspirin? If patients received Kardegic sachets please explain how the patients and the investigators were blinded to the treatment?

Lines 301-303: The sentence is not clear. Please who was more successful in identifying women at risk.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PONE-D-22-07025R1Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trialPLOS ONE

Dear Dr. Diguisto,

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.

ACADEMIC EDITOR:

You made appropriate changes following the Reviewers comments. However, an edit shown in the response to Reviewer #3 was overlooked and not inserted into the edited text: "We have added in the discussion section that 2/3 of preeclampsia occurred after 37 WG in our study. Those late/term preeclampsie are not particularly prevented by low dose aspirin which could explain why our trial is negative. This paragraph has been added to the discussion: “Bujold et al’s meta-analysis which evaluated acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery doppler found that this treatment, when initiated early, could reduce the incidence of preeclampsia and in particular severe preeclampsia. It turns out that most of the observed cases of term preeclampsia and was mild which may explain partly the lack effect of the treatment in our trial.” Please correct this oversight and modify the text accordingly before final acceptance.

Please submit your revised manuscript by Sep 15 2022 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,

Patrick Rozenberg, MD

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:

The authors made appropriate changes following the Reviewers comments.

However, an edit shown in the response to Reviewer #3 was overlooked and not inserted into the edited text:

"We have added in the discussion section that 2/3 of preeclampsia occurred after 37 WG in our study. Those late/term preeclampsie are not particularly prevented by low dose aspirin which could explain why our trial is negative. This paragraph has been added to the discussion: “Bujold et al’s meta-analysis which evaluated acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery doppler found that this treatment, when initiated early, could reduce the incidence of preeclampsia and in particular severe preeclampsia. It turns out that most of the observed cases of term preeclampsia and was mild which may explain partly the lack effect of the treatment in our trial.”

The authors should correct this oversight and modify the text accordingly before final acceptance.

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

Reviewers' comments:

[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.

Low-dose aspirin to prevent preeclampsia and growth restriction in nulliparous women identified by uterine artery Doppler as at high risk of preeclampsia: a double blinded randomized placebo-controlled trial

PONE-D-22-07025R2

Dear Dr. Diguisto,

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.

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Kind regards,

Patrick Rozenberg, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

This manuscript have been appropriately corrected and can be published

Reviewers' comments: