Dear Dr.  Narice,

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 Nov 08 2025 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.

• 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,

Nishel Mohan Shah, PhD

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. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following financial disclosure:

“BFN salary is partly covered by a National Institute for Health and Care Research Academic Clinical Lectureship. No other funding from the public, commercial or not-for-profit sectors was received for this work.”

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. Please note that funding information should not appear in any section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript.

5. We note that your Data Availability Statement is currently as follows:

“All relevant data are within the manuscript and its Supporting Information files.”

Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition).

For example, authors should submit the following data:

- The values behind the means, standard deviations and other measures reported;

- The values used to build graphs;

- The points extracted from images for analysis.

Authors do not need to submit their entire data set if only a portion of the data was used in the reported study.

If your submission does not contain these data, please either upload them as Supporting Information files or deposit them to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories.

If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) 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. If data are owned by a third party, please indicate how others may request data access.

6. Please amend your manuscript to include your abstract after the title page.

7. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

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

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: Thank you for inviting me to review this manuscript.

This retrospective case-control study investigates histopathological placental findings in non-anomalous stillbirth compared vs livebirths in a UK tertiary centre from 2018 to 2021.

The topic is relevant, especially considering that UK stillbirth rates remains among the highest of high-income countries, despite a good and continued efforts to reduce perinatal mortality as per The Saving Babies’ Lives Care Bundle’ (SBLCB) version 3. Please, do cite SVBCBv3.

Considering the UK stillbirth rate in 2024 was 4.1 per 1,000 births, a sample size of 83 stillbirths is relatively large, thus basic statistical analysis for binary and continuous variables is scientifically sound. Particularly, the association of stillbirths with social deprivation, histological maternal vascular malperfusion and high fetoplacental ratio when compared to livebirths has been effectively stressed, also in regard to MBRRACE-UK.

Although some major considerations need to be added.

- Can authors please specify the rate of stillbirth/births per year in Sheffield? This is to compare with current national rates (current stillbirth rate in UK is about 4,1 per 1000 births), especially because the sample size has been extracted from COVID pandemic period where stillbirth rates reportedly increased. Since the authors have discussed COVID extensively, including vaccinated controls only is a justified approach to mitigate potential bias.

- For preterm stillbirths, matching placentas by gestational age was not feasible due to limited sample availability of livebirths, although two-thirds of the stillbirths were preterm. However, for term births, matching by maternal age should have been attempted and this limitation should be acknowledged in the discussion as a potential source of bias, in view of the huge impact of advanced maternal age on stillbirth risk.

- I appreciate the effort to validate the FMF and NICE algorithms for predicting PET in a retrospective cohort of stillbirths versus matched controls. While MVM is present in all PET cases, MVM can also occur independently of PET, meaning that MVM can exist in non-hypertensive pregnancy disorders/placental dysfunction.

It would have been informative to examine placentas in livebirths of SGAs to explore whether MVM is present in these cases as well, particularly because approximately half of your stillbirths fetal weight is <10th centile. Although I appreciate it may not have been possible due to paucity of placentas, I believe authors should comment on literature findings of IUGR/SGAs placentas in regard to their findings.

- Twin and triplet pregnancies carry an increased risk of stillbirth per se, which may be further affected by chorionicity. Ideally, these cases should be analyzed separately; however, I understand that this may have been challenging. Please cite this as a potential source of bias and clarify whether "stillbirth" refers to the loss of one or both twins in the dataset.

Minor:

- Please state clearly it is a retrospective case-control study, both in abstract and in manuscript.

- The FMF algorithm outperformed NICE in predicting PET only when at least one continuous variable (e.g., MAP, UtA-PI, or PAPP-A) was included. In the absence of continuous variables, FMF and NICE are basically the same in terms of purely history-indicated PET screening. Please clarify both in abstract and manuscript.

-line 16, 'placental disorders' should be changed to placental histopathological lesions

Reviewer #2: This is a well-conducted retrospective cohort study that provides valuable insights into the role of placental pathology, particularly maternal vascular malperfusion (MVM) in stillbirths. The use of standardized Amsterdam criteria and the comparison between NICE and FMF risk assessment models are strengths. The study highlights the potential of early risk stratification to improve antenatal care and reduce stillbirth rates.

This study includes all eligible spontaneous stillbirths from a large tertiary center over a four-year period, making the findings representative of that specific population. The findings have direct implications for antenatal care, suggesting that improved risk assessment could lead to timely interventions (e.g., aspirin prophylaxis). The study accounted for confounding factors such as ethnicity, deprivation index, and COVID-19 vaccination status and the authors are also to be commended for their transparent and thorough discussion of the study's limitations, particularly concerning the control group and retrospective data collection.

The manuscript is clearly written, logically structured (Introduction–Methods–Results–Discussion–Conclusion), and well illustrated with figures and tables. It meets the standards of PLOS ONE.

Limitations and Areas for Improvement�

1.Inherent Limitations of Retrospective Design: The study is constrained by data completeness. As the authors note, the retrospective "reconstruction" of the FMF risk score was necessary due to missing first-trimester biophysical and biochemical markers in many cases, which may have impacted the accuracy of its calculated performance. Furthermore, clinical interventions during the study period (e.g., aspirin administration based on NICE criteria) could introduce a bias that is difficult to account for retrospectively

2.Challenges in Control Group Selection: The authors rightly identify control selection as a major challenge. A perfect "low-risk" control group for stillbirths is difficult to obtain, as placentas from uncomplicated pregnancies are not routinely sent for pathology.

3.Limited Sample Size: The total sample size of 83 stillbirths is relatively small for subgroup analyses, such as predicting PET (n=15) or specific MVM types. This can limit statistical power and leads to wide confidence intervals in some analyses, reducing the certainty of the findings.

**********

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:  Silvia L Spinillo

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.

Placental lesions in stillbirths: a  case-control study using the Amsterdam criteria and predictive models at a UK tertiary unit

PONE-D-25-32249R1

Dear Dr. Narice,

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. For questions related to billing, please contact billing support .

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,

Nishel Mohan Shah, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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??>

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: Thank you for your detailed response.

All the comments have been addressed. The revised manuscript has now expanded on potential sources of bias and has provided clarity on some specific issue.

Despite the retrospective nature and the limited size sample, the manuscript is scientifically sound and provides useful insight on histopathological lesions of stillbirth.

Reviewer #2: This is a well-designed and rigorously conducted retrospective case-control study. The study's core value lies in its dual focus: it not only identifies Maternal Vascular Malperfusion (MVM) as a dominant placental pathology in stillbirth using the standardized Amsterdam criteria, but also links this pathological finding to clinically relevant predictive tools (the FMF algorithm/Tommy's app). The findings strongly support a clinical shift from traditional NICE criteria to the more sensitive FMF algorithm for early-gestation risk identification, which could potentially lower stillbirth rates through interventions like aspirin the use of the standardized Amsterdam criteria for placental classification and the clinically relevant head-to-head comparison of the FMF and NICE predictive models.

The authors have provided excellent responses to editor and reviewer comments , thoroughly addressing limitations such as sample size, the retrospective design, and control group selection. While minor grammatical and formatting errors are present, the scientific core of the manuscript is solid and makes a valuable contribution to the field.

I recommend acceptance.

**********

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

**********