Peer Review History

Original SubmissionAugust 13, 2020
Decision Letter - Artur Arikainen, Editor

Dear Dr Magnus,

Thank you for submitting your manuscript entitled "Risk of miscarriage in women with chronic diseases" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff as well as by an academic editor with relevant expertise and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Artur Arikainen,

Associate Editor

PLOS Medicine

Revision 1
Decision Letter - Emma Veitch, Editor

Dear Dr. Magnus,

Thank you very much for submitting your manuscript "Risk of miscarriage in women with chronic diseases" (PMEDICINE-D-20-03922R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to three independent reviewers, including a statistical reviewer (r#1). The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. 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 PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Dec 21 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***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 ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that 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/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of Artur Arikainen, PhD, Associate Editor,

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*Please revise your title according to PLOS Medicine's style - we'd suggest this includes an indication of the study design (eg, "registry linkage study) in the subtitle (ie, after a colon).

*In the paper the authors define the study as a prospective-registry-based study, however given the analysis uses routinely collected data (the medical birth registry, the Norwegian Patient Registry, and the general practitioner database), presumably the data existed in those registries before the plan to draw them together and analyse them for the purposes of this question, was developed? In which case it might be better to define it as retrospective (in the sense the data existed before the analysis plan)? More clarity on this would be helpful.

*We'd suggest using the RECORD guideline (developed to help reporting of analyses conducted using registry linkage/routinely collected data) - https://www.equator-network.org/reporting-guidelines/record/. In this case please include the completed RECORD checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the RECORD guideline (S1 Checklist)". When completing the checklist, please use section and paragraph numbers, rather than page numbers.

*In the last sentence of the Abstract Methods and Findings section, please include a brief note about any key limitation(s) of the study's methodology. Specifically, a reviewer notes that there are major limitations in terms of the ability to adjust for possible (likely) confounders in this study, and this certainly should be mentioned.

*Can the authors clarify at what point the analytical plan used in this paper was developed - please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

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Comments from the reviewers:

Reviewer #1: I confine my remarks to statistical aspects of this paper. These were well done. My only concern is about confidence intervals (I am glad the authors did not include p values). But, since the authors have the entire population, what are these CIs? Some people posit a "super-population" of some sort. I'm not a big fan of this, pregnancies in Norway are not a random sample of pregnancies world wide (for one thing, health care is much better there than in almost any other country). But this needs to be addressed.

I'd be fine with no CIs, but others might object.

Peter Flom

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Reviewer #2: This is a fairly straightforward analysis of whether chronic disease is associated miscarriage. Strengths of the paper are the large, population-based dataset, consistent coding, and careful consideration of analytic issues, such as competing risk due to induced abortion.

The authors discuss the possibility of missing diagnosis of chronic disease, but have less to say about missing diagnosis of miscarriage. Many early miscarriages are not clinically treated, many are probably not reported, and others are not even noticed. The authors discuss the overall incidence and how it compares to other populations, but not this issue. I also don't see discussion of the fact that women under treatment for some conditions may also be more aware of their bodies, or more likely to report to doctors if they do miscarry, particularly for a condition like endometriosis. An additional possible issue is competing risk from subfertility, which might be a cause for the lack of relationship with some outcomes (it is possible that some of the medications used to treat epilepsy could cause very early, i.e. undetectable, losses or infertility.)

The authors do consider the possibility of confounding, which they are able to address only to a limited extent. I would like to see this emphasized a bit more in the abstract.

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Reviewer #3: This study reports on the prospective risk of miscarriage in women with a preexisting chronic disease based on 6 years of all reported pregnancies in Norway (2010-2016). The study design ensures that the chronic disease is diagnosed prior to the pregnancy loss. The authors also undertake the task of estimating how many of the terminated pregnancies would have ended as a pregnancy loss if not the termination had been undertaken. The study is larger than previous studies, however no new information is given by the study.

Major issues.

Terminology: Miscarriage is per definition a loss of a confirmed intrauterine pregnancy. This requires that the pregnancy has been scanned, identification of villi or fetus in the expelled pregnancy or in the evacuate. The authors use miscarriage despite several of their included pregnancies are not confirmed intrauterine - please instead use pregnancy loss.

Definition: It is unclear why the authors included molar pregnancies in their definition of miscarriage. Please explain.

Selection of chronic diseases: On what basis was chronic diseases included in the analysis - why was Hashimoto thyroiditis not included? Known to be the most common autoimmune manifestation in women of reproductive age and previously found to be associated with the risk of pregnancy loss.

Validation of diagnosis: Please include information of diagnosis validation of the included diagnoses. It is surprising that only 1% of the included women suffer from PCOS. This is the most common endocrine disorder in reproductive aged women and supposed to be as high as 5-10%.

Why are numbers of pregnancy losses (the core of this manuscript) not mentioned in Table 1 as it is in supplementary table 2?

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Any attachments provided with reviews can be seen via the following link:

[LINK]

Revision 2

Attachments
Attachment
Submitted filename: 20201213_Response_letter.docx
Decision Letter - Artur Arikainen, Editor

Dear Dr. Magnus,

Thank you very much for re-submitting your manuscript "Risk of miscarriage in women with chronic diseases: a Norwegian registry linkage study" (PMEDICINE-D-20-03922R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by two reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***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.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Jan 26 2021 11:59PM.   

Sincerely,

Artur Arikainen

Associate Editor

PLOS Medicine

plosmedicine.org

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Requests from Editors:

1. Please address the reviewer #3’s comment on correct use of terminology – this has also been requested by the Academic Editor. Further consideration of your manuscript is contingent on this being addressed.

2. Title: Please amend to: “Risk of pregnancy loss in women with chronic diseases in Norway: A registry linkage study”

3. Short title: Please amend to: “Chronic diseases and pregnancy loss”

4. Please include line numbers in the margin throughout.

5. Abstract:

a. Please remove “prospectively” here and throughout, since your analysis itself is retrospective.

b. Please remove “retrospective” when describing the study here and throughout, since “registry-based” already implies a retrospective analysis.

c. Please include p values for your comparisons, alongside 95% CIs.

d. At the end of the ‘Methods and findings’ subsection, please state more clearly: “Limitations of this study were…”. You could also mention the rareness of some conditions as a further limitation, eg. Cushing’s syndrome.

e. Conclusions: Please begin with “In this registry study, we found that…”

6. Page 3: Delete keywords.

7. Author Summary: Amend to: “To our knowledge, none of the existing studies have…”

8. Please remove spaces from within citations, eg: “…environmental factors [5,6].”

9. Results: Please include p values for your comparisons, alongside 95% CIs.

10. Discussion: Please amend to: “Our study is, to our knowledge, unique in its…”

11. Pages 17-18: Please remove the Author Contributions, Data Availability Statement, Funding, and Competing interests sections – these are taken from the online submission form.

12. References:

a. Please remove city and country from journal names, eg. “(London, England)”.

b. Please delete this from reference 32: “at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.”

c. Please delete this from reference 36: “Copyright 2018, The Author(s).”

13. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and REporting of studies Conducted using Observational Routinely-collected Data (RECORD) guidelines (S1 Checklist)." (and rename the file accordingly)

14. When completing the STROBE/RECORD checklist, please use section and paragraph numbers, rather than page numbers.

---

Comments from Reviewers:

Reviewer #1: The authors have addressed my concerns and I now recommend publication

Peter Flom

Reviewer #3: I am highly surprised that this experienced and respected author group in their rebuttal to PLOS MEDICINE have not responded to a reviewer comment and therefore without any notice keep using miscarriage. To use miscarriage, they should be certain that the pregnancy had been confirmed intrauterine. In practical terms had been scanned, or villi had been identified or the fetus had been visible in the bleeding or the pregnancy material. Clinical researchers changed the terminology to pregnancy loss several years ago unless certain that the losses are intrauterine. I think women pregnant with a gestational age <12 and no prior ultrasound scans with a large bleeding prior to or on their way to hospital who present with an empty uterus at ultrasound and no evaluation of the bleeding will be included in this study.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Revision 3

Attachments
Attachment
Submitted filename: Response_letter.docx
Decision Letter - Artur Arikainen, Editor

Dear Dr. Magnus,

Thank you very much for re-submitting your manuscript "Risk of miscarriage in women with chronic diseases: a Norwegian registry linkage study" (PMEDICINE-D-20-03922R3) for review by PLOS Medicine.

I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining minor issues that need to be addressed are listed at the end of this email.

***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.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Feb 03 2021 11:59PM.   

Sincerely,

Artur Arikainen,

Associate Editor 

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1. Title: Thank you for your reply regarding the terminology – this is fine to leave as is, as we discussed. However, please nevertheless amend to the following to better fit our journal style: “Risk of miscarriage in women with chronic diseases in Norway: A registry linkage study”

2. Abstract: Please add some brief summary demographics for participants (eg. age).

3. Results/Figures and Abstract: Please present p values to 3 decimal places consistently, or “p<0.001”.

4. When completing the STROBE/RECORD checklist, please use section and paragraph numbers, rather than line or page numbers (these will change in the final published version).

Comments from Reviewers:

n/a

Any attachments provided with reviews can be seen via the following link:

[LINK]

Revision 4
Decision Letter - Richard Turner, Editor

Dear Dr. Magnus,

Thank you very much for re-submitting your manuscript "Risk of miscarriage in women with chronic diseases in Norway: A registry linkage study" (PMEDICINE-D-20-03922R4) for consideration at PLOS Medicine. We apologize for the delay in contacting you: Dr Arikainen has recently left the journal.

I have discussed the paper with editorial colleagues and I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Please take these into account before resubmitting your 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.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

Please let me know if you have any questions, and we look forward to receiving the revised manuscript shortly.   

Sincerely,

Richard Turner PhD

Senior Editor, PLOS Medicine

rturner@plos.org

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Requests from Editors:

Please amend your data statement to: "Study data are available on application via helsedata.no, subject to the necessary ethics approvals." or similar.

Please make that "risk of miscarriage" at line 57.

Please state early in the Methods section whether the study had a protocol or prespecified analysis plan. Please highlight analyses that were not prespecified.

Our Academic Editor has requested that you deal with referee 3's comment explicitly in your discussion section. We ask that you do this by amending the wording at line 322, and suggest: "Our study had important limitations. We acknowledge that the strict definition of miscarriage refers to uterine pregnancies. In our registry study, we defined the outcome as miscarriages or pregnancies that did not survive to 16 weeks; ectopic pregnancies were excluded." or similar.

***

Revision 5

Attachments
Attachment
Submitted filename: Response_Letter.docx
Decision Letter - Richard Turner, Editor

Dear Dr Magnus, 

On behalf of my colleagues and our Academic Editor Dr Myers, I am pleased to inform you that we have agreed to publish your manuscript "Risk of miscarriage in women with chronic diseases in Norway: A registry linkage study" (PMEDICINE-D-20-03922R5) in PLOS Medicine.

We ask you to address two further issues:

If available, please attach your study analysis plan as a supplementary document, referred to around line 106;

There is a sense of imbalance in the current presentation: around lines 50 and 66, for example, there is an emphasis on associations of miscarriage with cardiometabolic conditions, whereas in the Discussion (around lines 280 and 368) the emphasis is more on an absence of associations with chronic conditions, and we suggest amending the wording to harmonise the different parts of your paper.

Before your manuscript can be formally accepted you will also need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

PRESS

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To enhance the reproducibility of your results, we recommend that 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Richard Turner, PhD 

Senior Editor, PLOS Medicine

rturner@plos.org

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