Dear Dr Gilder,

Thank you for submitting your manuscript entitled "Adverse effects of submicroscopic malaria in pregnancy: a cohort study of 4,352 women on the Thailand-Myanmar border." for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff 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 Jul 17 2024 11:59PM.

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 me at lgaynor@plos.org if you have any queries relating to your submission.

Kind regards,

Louise Gaynor-Brook, MBBS PhD

Senior Editor

PLOS Medicine

Dear Dr Gilder,

Many thanks for submitting your manuscript "Adverse effects of submicroscopic malaria in pregnancy: a cohort study of 4,352 women on the Thailand-Myanmar border." (PMEDICINE-D-24-02236R1) to PLOS Medicine. The paper has been reviewed by subject experts and a statistician; their comments are included below and can also be accessed here: [LINK]

After discussing the paper with the editorial team and an academic editor with relevant expertise, I'm pleased to invite you to revise the paper in response to the reviewers' comments. We plan to send the revised paper to some or all of the original reviewers, and we cannot provide any guarantees at this stage regarding publication.

When you upload your revision, please include a point-by-point response that addresses all of the reviewer and editorial points, indicating the changes made in the manuscript and either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please also be sure to check the general editorial comments at the end of this letter and include these in your point-by-point response. When you resubmit your paper, please include a clean version of the paper as the main article file and a version with changes tracked as a marked-up manuscript. It may also be helpful to check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper.

We ask that you submit your revision by Sep 17 2024 11:59PM. However, if this deadline is not feasible, please contact me by email, and we can discuss a suitable alternative.

Don't hesitate to contact me directly with any questions (lgaynor@plos.org).

Best regards,

Louise

Louise Gaynor-Brook, MBBS PhD

Senior Editor

PLOS Medicine

lgaynor@plos.org

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

Comments from the reviewers:

Reviewer #1: This is a well written manuscript, with minimal grammatic/typo errors. In a case-cohort study, the report elegantly addresses the question if submicroscopic malaria affects inter-generational health outcomes during pregnancy.

Some points to clarify:

1) There are three groups derived from the case-cohort study, the last group regarded as "Control Group". Since the groups are derived based on outcomes, is it appropriate to designate the last group as "Control Group"? Why not just refer to it as "Group 3"?

2) For adjusting temporal changes in disease/infection prevalence, 8-time blocks were identified (lines 168-171). But the time blocks have not been characterized to show temporal trends, e.g., temporal trends of prevalence or parasitaemia. In lines 336-37, there is mention of primigravid women enrolled during early years of the case-cohort being at higher risk of getting a submicroscopic infection at their first ANC visit. This observation was not discussed considering the temporal variations.

3) Given that the uPCR has yielded parasitaemia ranges from 22 to 186,048p/ml, is there a high parasitaemic threshold above which parasitaemia is no more sMiP? In other words, is there uPCR threshold that precludes sMiP? In relation to this, can risk of developing mMiP be differentiated by parasitaemic groups: Q1, Q2, Q3, Q4? In line 250, the risk of developing mMiP, anemia and pre-term birth is given, but qualitatively based on presence or absence of sMiP.

4) In line 277: the given date and numbers that follow can confuse the reader. Re-writing using a combination of numbers and letters/words can help.

5) In lines 298-305, prevalence is given for the 3 groups: 36.1%, 5.1% and 3.8%. What was the mean parasitaemia for the 3 groups?

6) Given that the prevalence of mixed Pf/Pv malaria infection was only 1.8%, the analysis of data on risks (e.g., risk of anemia, lines 122/123) seems overly over-interpreted. This also seen in the tables showing HR and p-values.

7) In lines 132-135 (page 31), the fact that women were closely followed, screened for malaria and treated is discussed as a limitation of the study. It seems it should rather be a strength. Perhaps changing the context will help.

8) In table 3, Hb variants are classified as: Normal/mild, Moderate and Severe. This seems confusing as often Hb variants are mentioned in relation to abnormal structure of globulins and heme complex (Hg S, C, D, E). Maybe it is means to describe Hgb levels?

Reviewer #2: The authors present a large study examining submicroscopic malaria in pregnancy and the risk of microscopic infection, birthweight and preterm birth. They have used a pragmatic approach of a case-cohort design given the associated cost of PCR for all samples and utilised an appropriate Cox regression.

Minor comments:

� Postmenstrual age - should be estimated gestational age.

� Tables 1 is difficult to follow. Why are exclusions included in the table? This would be better suited to a flow diagram

� Table 1: Most data has been presented categorically including maternal age and BMI. Including a measure of central tendency (mean/median dependent on distribution of data) and spread for continuous data will provide the reader with a better understanding of the population.

� Table 1: Were all data complete? If not, include number of missing for each variable

� Table 1: Given the case-cohort is the population and not whole cohort, I suggest moving the column of the whole cohort (11,901) to the supplemental, this will improve the readability of the table. I understand it was included to show random sampling was effective but can be included as a supplement.

� Table 1: It is unclear why the authors have presented weighted values for maternal demographics when they have also presented adjusted analyses to account for the differences. Additionally, weighting does not appear to change proportions substantially.

� Birthweight; the authors state in the methods intergrowth and z-scores were used but this does not appear to be so in the results. Adjusted analyses should consider including a measure of SES. The 95% CI for birthweight at term is very narrow, is this correct? Would expect a larger spread.

� Was haematocrit nadir normally distributed?

Major comments

� A significant limitation of the study is the age of the cohort, with samples collected 2012 - 2015 (ie up to 12 years old). Given the change in the population since this time, the relevance of the findings to current practice and population needs to be clarified.

� Throughout the authors have used IPW models but have not provided any details of how the models were constructed. How was balance assessed and what difference was considered acceptable?

� The authors have included selected confounders based on a p-value of <0.2. Why was this value selected? More importantly, including confounders purely based on p-values is not recommended, this can introduce bias. The use of an IPW model should consider what variables would predict being in the exposure group as well as consider confounders - not based on p-values but the use of subject knowledge and ideally, direct acyclic graphs. Were new models constructed for each maternal baseline characteristic? It is unclear which variables are included for each outcome.

Reviewer #3: Overall this is a very interesting publication.

minor comments- throughout the paper, all instances of microscopy detected malaria should be replaced by microscopically detected.

Page 38, "From 2012 to 2015, approximately 1 in 22 women attending their first antenatal visit on the Thailand-Myanmar border had asymptomatic sMiP at their first antenatal care visits." - delete one of the "first antenatal care visit"

Did you assess preterm delivery as a potential cause of some LBW?

I'm not entirely clear why you excluded women negative at ANC1? this could be better explained in the methods.

Page 41- this needs a ref: "In areas of higher transmission, a higher proportion of infections are detectable by RDT or microscopy"

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

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

General editorial requests:

(Note: not all will apply to your paper, but please check each item carefully)

* 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. Please do not add or remove authors without first discussing this with the handling editor. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

* Please 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.

* 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 (web or email address) for obtaining the data. Please note that a study author cannot be the contact person for 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.

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* Please express the main results with 95% CIs as well as p values. When reporting p values please report as p<0.001 and where higher as the exact p value p=0.002, for example. Throughout, suggest reporting statistical information as follows to improve clarity for the reader "22% (95% CI [13%,28%]; p</=)". Please be sure to define all numerical values at first use.

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* For all observational studies, in the manuscript text, please indicate: (1) the specific hypotheses you intended to test, (2) the analytical methods by which you planned to test them, (3) the analyses you actually performed, and (4) when reported analyses differ from those that were planned, transparent explanations for differences that affect the reliability of the study's results. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data driven.

* Please state in the Methods section whether the study had a prospective protocol or analysis plan. 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 document(s) 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. 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. 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.

Dear Dr Gilder,

Many thanks for submitting your manuscript "Adverse effects of submicroscopic malaria in pregnancy: a cohort study of 4,352 women on the Thailand-Myanmar border." (PMEDICINE-D-24-02236R2) to PLOS Medicine. The paper has been reviewed by subject experts and a statistician; their comments are included below and can also be accessed here: [LINK]

As you will see, the statistical reviewer has requested further information regarding which variables have been included for each IPW model, and how covariate balance was checked between exposure groups. After discussing the paper with the editorial team, I'm pleased to invite you to revise the paper in response to the reviewer's comments. We plan to send the revised paper to some or all of the original reviewers, and we cannot provide any guarantees at this stage regarding publication.

When you upload your revision, please include a point-by-point response that addresses all of the reviewer and editorial points, indicating the changes made in the manuscript and either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please also be sure to check the general editorial comments at the end of this letter and include these in your point-by-point response. When you resubmit your paper, please include a clean version of the paper as the main article file and a version with changes tracked as a marked-up manuscript. It may also be helpful to check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper.

We ask that you submit your revision by Oct 25 2024 11:59PM. However, if this deadline is not feasible, please contact me by email, and we can discuss a suitable alternative.

Don't hesitate to contact me directly with any questions (lgaynor@plos.org).

Best regards,

Louise

Louise Gaynor-Brook, MBBS PhD

Senior Editor

PLOS Medicine

lgaynor@plos.org

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

Comments from the reviewers:

Reviewer #1: None

Reviewer #2: I thank the authors for their updates to the manuscript.

About the adjusted analyses, it is still not clear exactly which variables have been included for each IPW model. Can the authors include their models as a supplement? Removing variables that are considered theoretical confounders due to a p-value in their dataset is not recommended, which variables were removed based on p-values? Given you are using an IPW model the number of variables included in the model is less of a concern than in traditional adjusted regression. For these IPW cox regression models, how was covariate balance checked between exposure groups and what level determined acceptable?

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

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

General editorial requests:

(Note: not all will apply to your paper, but please check each item carefully)

* 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. Please do not add or remove authors without first discussing this with the handling editor. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

* Please 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.

* 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 (web or email address) for obtaining the data. Please note that a study author cannot be the contact person for 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 expect all researchers with submissions to PLOS in which author-generated code underpins the findings in the manuscript to make all author-generated code available without restrictions upon publication of the work. In cases where code is central to the manuscript, we may require the code to be made available as a condition of publication. Authors are responsible for ensuring that the code is reusable and well documented. Please make any custom code available, either as part of your data deposition or as a supplementary file. Please add a sentence to your data availability statement regarding any code used in the study, e.g. "The code used in the analysis is available from Github [URL] and archived in Zenodo [DOI link]" Please review our guidelines at https://journals.plos.org/plosmedicine/s/materials-software-and-code-sharing and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse. Because Github depositions can be readily changed or deleted, we encourage you to make a permanent DOI'd copy (e.g. in Zenodo) and provide the URL.

FORMATTING - GENERAL

* Abstract: Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions). Please combine the Methods and Findings sections into one section.

* At this stage, we ask that you include 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. Ideally each sub-heading should contain 2-3 single sentence, concise bullet points containing the most salient points from your study. In the final bullet point of 'What Do These Findings Mean?', please include the main limitations of the study in non-technical language. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary.

* Please express the main results with 95% CIs as well as p values. When reporting p values please report as p<0.001 and where higher as the exact p value p=0.002, for example. Throughout, suggest reporting statistical information as follows to improve clarity for the reader "22% (95% CI [13%,28%]; p</=)". Please be sure to define all numerical values at first use.

* Please include page numbers and line numbers in the manuscript file. Use continuous line numbers (do not restart the numbering on each page).

* Please cite the reference numbers in square brackets. Citations should precede punctuation.

FIGURES AND TABLES

* Please provide titles and legends for all figures and tables (including those in Supporting Information files).

* Please define all abbreviations used in each figure/table (including those in Supporting Information files).

* Please consider avoiding the use of red and green in order to make your figure more accessible to those with color blindness.

SUPPLEMENTARY MATERIAL

* Please note that supplementary material will be posted as supplied by the authors. Therefore, please amend it according to the relevant comments outlined here.

* Please cite your Supporting Information as outlined here: https://journals.plos.org/plosmedicine/s/supporting-information

REFERENCES

* PLOS uses the numbered citation (citation-sequence) method and first six authors, et al.

* Please ensure that journal name abbreviations match those found in the National Center for Biotechnology Information (NCBI) databases (http://www.ncbi.nlm.nih.gov/nlmcatalog/journals), and are appropriately formatted and capitalised.

* Where website addresses are cited, please include the complete URL and specify the date of access (e.g. [accessed: 12/06/2023]).

* Please also see https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references for further details on reference formatting.

OBSERVATIONAL STUDIES

* Abstract: Please include the study design, population and setting, number of participants, years during which the study took place (enrollment and follow up), length of follow up, and main outcome measures.

* Please ensure that the study is reported according to the STROBE (or appropriate STOBE extension) guideline (available from: https://www.equator-network.org/reporting-guidelines/strobe) and include the completed STROBE (or STROBE extension) checklist as Supporting Information. 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) guideline (S1 Checklist)." When completing the checklist, please use section and paragraph numbers, rather than page numbers.

* For all observational studies, in the manuscript text, please indicate: (1) the specific hypotheses you intended to test, (2) the analytical methods by which you planned to test them, (3) the analyses you actually performed, and (4) when reported analyses differ from those that were planned, transparent explanations for differences that affect the reliability of the study's results. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data driven.

* Please state in the Methods section whether the study had a prospective protocol or analysis plan. 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 document(s) 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. 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. 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.

Dear Dr. Gilder,

Thank you very much for re-submitting your manuscript "Adverse effects of submicroscopic malaria in pregnancy: a cohort study of 4,352 women on the Thailand-Myanmar border." (PMEDICINE-D-24-02236R3) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by one reviewer. 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 the next few weeks. 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.

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 02 2025 11:59PM.   

Sincerely,

Rebecca Kirk

On behalf of:

Louise Gaynor-Brook, MBBS PhD

Senior Editor 

PLOS Medicine

plosmedicine.org

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

Requests from Editors:

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* At this stage, we ask that you include 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. Ideally each sub-heading should contain 2-3 single sentence, concise bullet points containing the most salient points from your study. In the final bullet point of ‘What Do These Findings Mean?’ Please include the main limitations of the study in non-technical language.

Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary.

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* Your study is observational and therefore causality cannot be inferred. Please remove language that implies causality and refer to associations instead.

Comments from Reviewers:

Reviewer #2: I thank the authors for their reply and updated manuscript/regression following further thought given to potential confounders. Although I believe the adjustment is sufficient the DAGs have not been constructed correctly, with multiple variables included as one, variables adjusted for but not in DAG (such as sex), adjusted variables shown rather than the total model and interactions between variables not entirely considered. However, these updates are unlikely to change the adjusted models and I therefore suggest the DAGs are removed from the figures.

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

[LINK]

Dear Dr Gilder, 

On behalf of my colleagues and the Academic Editor, James Beeson, I am pleased to inform you that we have agreed to publish your manuscript "Submicroscopic malaria in pregnancy and associated adverse pregnancy events: a case-cohort study of 4,352 women on the Thailand-Myanmar border." (PMEDICINE-D-24-02236R4) in PLOS Medicine.

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Rebecca Kirk

On behalf of:

Louise Gaynor-Brook, MBBS PhD 

Senior Editor 

PLOS Medicine