Metformin exposure, maternal PCOS status and fetal venous liver circulation: A randomized, placebo-controlled study

Sindre Grindheim; Cathrine Ebbing; Henriette Odland Karlsen; Svein Magne Skulstad; Francisco Gómez Real; Marianne Lønnebotn; Tone Løvvik; Eszter Vanky; Jørg Kessler

doi:10.1371/journal.pone.0262987

Peer Review History

Original SubmissionJanuary 8, 2021
15 Jun 2021 Decision Letter - Stephen L Atkin, Editor PONE-D-20-40968 Metformin exposure, maternal PCOS status and fetal venous liver circulation: a randomized, placebo-controlled study PLOS ONE Dear Dr. Grindheim, 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. The reviewers have raised a number of issues and specifically on the statistical analysis that require addressing. Please submit your revised manuscript by Jul 30 2021 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: http://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, Stephen L Atkin, MD 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. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript entitled ‘Metformin exposure, maternal PCOS status and fetal venous liver circulation: a randomized, placebo-controlled study’ with the aims to compare 75 fetal venous liver blood flow in both metformin versus placebo-exposed fetuses of mothers with PCOS, and all fetuses of PCOS mothers to a low-risk reference population. This is quite an interesting study, however, the manuscript presentation can be further improved. Comments Material and Methods Line 129 and 161, Table 1 and Table 2 to be placed in the results section. Statistical analysis Line 208, proper citation for statistical software including publisher name to be included. Ensure all statistical tests mentioned in the statistical analysis section are clearly denoted in the results section table(s). 1 or 2-tailed test to be stated. Results Line 228-230, for the crude and adjusted analysis, the tables to be clearly indicated. The adjusted variables maternal blood pressure, BMI, and gestational weight gain to be denoted in the table footnote. Information on whether multicollinearity was assessed between the covariates to be stated. Line 128 Table 1, for some p values, technically p value cannot be zero (to use symbol p<) Symbol ¶ to be denoted in the table. Since the p value is written on the top of the table, individual ‘p=’ to be omitted. Likewise with Table 3. Line 161 Table 2, the decimal points for the p value to be standardized. Nonetheless, based on CONSORT statement, all statistical tests for baseline group comparison to be avoided (Table 1 & Table 2). Table 1 & 2, at least 1 decimal point for percentage figures. Line 243 Table 3, what the figures in bracket represents to be clearly denoted. More information on the GLM to be clearly highlighted/denoted e.g dependent variable(s), factors/covariates, multiple comparison correction (if any) etc, Adjusted variables to be indicated in the table footnote and 95%CI to be included for the p values. Line 253 Table 4, mean and sd to be clearly denoted. Figure 1 requires improvement by incorporating details of study design i.e. number of groups in the study. Reviewer #2: 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) (Limit 200 to 20000 Characters) please clarify the number of patients enrolled to this particular study in the abstract and put to the abstract that this paper is a part of larger study ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes:** Tomasz Milewicz M.D., Ph.D. [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. https://doi.org/10.1371/journal.pone.0262987.r001
Revision 1
24 Jul 2021 Author Response Dear Stephen L Atkin Thank you for the opportunity to improve our manuscript. We highly appreciate the meticulous work of the reviewers and have the following comments: Review Comments to the Author Reviewer #1: The manuscript entitled ‘Metformin exposure, maternal PCOS status and fetal venous liver circulation: a randomized, placebo-controlled study’ with the aims to compare 75 fetal venous liver blood flow in both metformin versus placebo-exposed fetuses of mothers with PCOS, and all fetuses of PCOS mothers to a low-risk reference population. This is quite an interesting study, however, the manuscript presentation can be further improved. Comments Material and Methods Line 129 and 161, Table 1 and Table 2 to be placed in the results section. Response: We chose to place these tables in the M&M section due to the nature of their content, as well as that is the place where they were first referred to. These tables show the baseline of the women included in the current study, as well as the reference group, in addition to maternal and fetal outcomes. Moving this information to the result section could indicate that the reference group was also recruited in parallel to this study, which was not the case. Also, PLOS-one manuscript formatting guidelines state that “Tables should be included directly after the paragraph in which they are first cited.” We do not mind moving these tables to the result section, but since the PLOS guidelines statement regarding tables are as such, we ask the editor for advice on where these tables should be placed. Statistical analysis Line 208, proper citation for statistical software including publisher name to be included. Response: The proper citation has been done according to publisher (https://www.ibm.com/support/pages/how-cite-ibm-spss-statistics-or-earlier-versions-spss) Ensure all statistical tests mentioned in the statistical analysis section are clearly denoted in the results section table(s). 1 or 2-tailed test to be stated. Response: The 2-tailed p-values have been stated in the M&M and relevant tests have been denoted in all tables. Results Line 228-230, for the crude and adjusted analysis, the tables to be clearly indicated. The adjusted variables maternal blood pressure, BMI, and gestational weight gain to be denoted in the table footnote. Response: We present the crude/unadjusted table since no changes were found after adjustment for these factors. This is now clarified in the table (table 3) and in the manuscript. We further decided to remove gestational weight gain from the adjustment since this was more likely to be an outcome of metformin treatment and not a baseline parameter. Since BMI at inclusion was border significant only, we ran the adjusted analyzes, however it had no impact on the results. Information on whether multicollinearity was assessed between the covariates to be stated. Response: We performed appropriate statistical analyses and found multicollinearity for systolic and diastolic blood pressure. We therefore adjusted for each of them separately as well as combined without finding any influence on the results (overlapping confidence intervals). We therefore chose not to present the adjusted numbers. Line 128 Table 1, for some p values, technically p value cannot be zero (to use symbol p<) Symbol ¶ to be denoted in the table. Since the p value is written on the top of the table, individual ‘p=’ to be omitted. Likewise with Table 3. Response: The duplications have been removed (p=) and correct values have been inserted (p<). Symbol ¶ has been denoted in table 1. Line 161 Table 2, the decimal points for the p value to be standardized. Response: Three decimals have been standardized in all analyzes Nonetheless, based on CONSORT statement, all statistical tests for baseline group comparison to be avoided (Table 1 & Table 2). Response: Since this study was a substudy of a larger RCT, we decided to run these analyses between the groups since the differences found do have a physiological potential to affect the fetal liver blood flow. These differences in baseline were not found in the main study thus indicating a slightly skewed inclusion. We therefore ask not to omit the statistical comparison. Table 1 & 2, at least 1 decimal point for percentage figures. Response: Adjustments have been performed accordingly. Line 243 Table 3, what the figures in bracket represents to be clearly denoted. More information on the GLM to be clearly highlighted/denoted e.g dependent variable(s), factors/covariates, multiple comparison correction (if any) etc, Adjusted variables to be indicated in the table footnote and 95%CI to be included for the p values. Response: We have clarified the content of the brackets. We used GLM using each flow measurement (z-score) as a dependent variable, randomization as fixed factor and BMI, systolic and diastolic blood pressure as covariates, first individually, then combined. This is further elaborated in the M&M section. Line 253 Table 4, mean and sd to be clearly denoted. Response: The denotation has been revised accordingly. Figure 1 requires improvement by incorporating details of study design i.e. number of groups in the study. Response: An updated consort diagram has been incorporated in the manuscript clarifying the randomization groups. Reviewer #2: 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) (Limit 200 to 20000 Characters) please clarify the number of patients enrolled to this particular study in the abstract and put to the abstract that this paper is a part of larger study Response: This request has been attended to and the text is revised accordingly. Attachments Attachment Submitted filename: Response to Reviews.docx https://doi.org/10.1371/journal.pone.0262987.r002
11 Aug 2021 Decision Letter - Stephen L Atkin, Editor PONE-D-20-40968R1 Metformin exposure, maternal PCOS status and fetal venous liver circulation: a randomized, placebo-controlled study PLOS ONE Dear Dr. Grindheim, 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 address the reviewers final comments ============================== Please submit your revised manuscript by Sep 25 2021 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: http://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, Stephen L Atkin, 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Minor comments Table 1 Parity & GDM, decimal points for percentage figures. It is best to present the findings in adjusted form even though it has no impact on the results. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: 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. https://doi.org/10.1371/journal.pone.0262987.r003
Revision 2
19 Aug 2021 Author Response Dear Stephen L Atkin Thank you for the important feedback we have received, especially from the reviewers, on our last revision. We have attended the last comments and submit now the latest version. Sincerely On behalf of the authors Sindre Grindheim Review Comments to the Author Reviewer #1: Minor comments Table 1 Parity & GDM, decimal points for percentage figures. Comment: This has been adjusted accordingly. It is best to present the findings in adjusted form even though it has no impact on the results. Comment: The adjusted results are now presented in the table and adjusted in the text. Attachments Attachment Submitted filename: Response to Reviewers 2nd review.docx https://doi.org/10.1371/journal.pone.0262987.r004
11 Jan 2022 Decision Letter - Stephen L Atkin, Editor Metformin exposure, maternal PCOS status and fetal venous liver circulation: a randomized, placebo-controlled study PONE-D-20-40968R2 Dear Dr. Grindheim, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to 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, Stephen L Atkin, MD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0262987.r005
Formally Accepted
20 Jan 2022 Acceptance Letter - Stephen L Atkin, Editor PONE-D-20-40968R2 Metformin exposure, maternal PCOS status and fetal venous liver circulation: a randomized, placebo-controlled study Dear Dr. Grindheim: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Stephen L Atkin Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0262987.r006

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