Seroprevalence analysis of SARS-CoV-2 in pregnant women along the first pandemic outbreak and perinatal outcome

Cecilia Villalaín; Ignacio Herraiz; Joanna Luczkowiak; Alfredo Pérez-Rivilla; María Dolores Folgueira; Inmaculada Mejía; Emma Batllori; Eva Felipe; Beatriz Risco; Alberto Galindo; Rafael Delgado

doi:10.1371/journal.pone.0243029

Peer Review History

Original SubmissionSeptember 9, 2020
27 Oct 2020 Decision Letter - Rogelio Cruz-Martinez, Editor PONE-D-20-28445 Seroprevalence analysis of SARS-CoV-2 in pregnant women along the pandemic outbreak PLOS ONE Dear Dr. Herraiz, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Dec 11 2020 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 We look forward to receiving your revised manuscript. Kind regards, Rogelio Cruz-Martinez, Ph.D. 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. Please amend your current ethics statement to address the following concerns: a) Did participants provide their written or verbal informed consent to participate in this study? b) If consent was verbal, please explain i) why written consent was not obtained, ii) how you documented participant consent, and iii) whether the ethics committees/IRB approved this consent procedure. 3. For more information on PLOS ONE's expectations for statistical reporting, please see https://journals.plos.org/plosone/s/submission-guidelines.#loc-statistical-reporting. Please update your Methods and Results sections accordingly. 4. Thank you for stating the following in the Funding Section of your manuscript: "This work was supported by grants to RD by the Instituto de Investigación Carlos III (grants FIS PI 1801007, by the European Union Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868. and by Fundación Caixa-Health Research (Project StopEbola). This work was supported by grant to MDF by the Instituto de Investigación Carlos III (FIS PI1800740). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. [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: Yes Reviewer #2: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: I Don't Know ****** 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 Reviewer #3: 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 Reviewer #3: 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: Overall, the results of this study are very timely and relevant. There are in my opinion a few of issues that need to be clarified/addressed. Is the highest number of preterm and cesarean births due to SARS-CoV2 positive RT-PCR? maternal respiratory impairment, obstetric or fetal cause? Can you discuss this point? Reviewer #2: The manuscript by Ignacio Herraiz et al. addressed the issue on Seroprevalence analysis of SARS-CoV-2 in pregnant women along the pandemic outbreak The article is interesting: it is well written, the methodology used is consistent and results are important. They provide information in the the seroprevalence of SARS-CoV-2 in the pregnant population of the south of Madrid during the outbreak and in the evaluation of maternal and perinatal outcomes. There is currently uncertainty regarding the impact of the infection caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS‐CoV‐2) in pregnancy . I consider that the information provided by the authors is useful and should be known by the scientific community TITLE: The title is clear and appropriate. "Seroprevalence analysis of SARS-CoV-2 in pregnant women along the 1 pandemic outbreak" However, it can be clarified more in the following way "Seroprevalence analysis of SARS-CoV-2 in pregnant women along the 1 pandemic outbreak and perinatal outcome." The abstract appropriately summarizes the manuscript without omitting important results. INTRODUCTION The topic is of clinical importance. Most of the previous work is adequately discussed and referenced. The rationale provided by the authors is sufficient and the purpose of the study is clearly defined. However line 54 " Regarding the impact of SARS-CoV-2 infection in pregnancy " It is important to clarify that the impact can be direct or indirect (psychological stress and problems with public health programs) please add these two references Ref - Miguel Parra-Saavedra et al, Attitudes and collateral psychological effects of COVID‐19 in pregnant women in Colombia ,International Journal of Gynecology and Obstetrics 2020 Ref - Roberton T, Carter ED, Chou VB, et al. Early estimates of the indirect effects of the coronavirus pandemic on maternal and child mortality in low‐ and middle‐income countries. Lancet Glob Health. 2020;8:e901–e908. METHODS The methodology is appropriate and sufficient for the stated purpose. Reviewer #3: Dr Herraiz et al made a good study of SARS-COV-2 seroprevalence, their results are in line with previous reports about the subject. The only comment about this manuscript is: how would you explain the relationship between higher BMI and seropositivity and symptomatology (groups G1 vs G4)? This is described also in non-obstetric population, and highlighting this finding would add interesting information about SARS-COV-2 and pregnancy. ****** 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: No Reviewer #3: 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.0243029.r001
Revision 1
8 Nov 2020 Author Response Journal 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 We have adjusted our manuscript to PLOS ONE´s style requirements. We have followed the instructions for file naming. 2. Please amend your current ethics statement to address the following concerns: a) Did participants provide their written or verbal informed consent to participate in this study? b) If consent was verbal, please explain i) why written consent was not obtained, ii) how you documented participant consent, and iii) whether the ethics committees/IRB approved this consent procedure. We have now amended the ethics statement to address these concerns: - We have included the following statement a at the beginning of the Methods section as requested by the editors: “This study was approved by the Institutional Review Board (Research Ethics Committee of the Hospital Universitario 12 de Octubre) and informed consent was obtained from all participants (Nº:20/241).” - We have included the following additional information in the Methods section, line 91: “The patients were informed of this seroprevalence study through telephone communication, to minimize the risk of contagion inherent in a hospital visit in a pandemic situation. It was explained to them that the study was carried out in the context of the public health need to understand the seroprevalence in our environment and to verify the efficacy of a new test recommended by the World Health Organization (WHO) in the network of seroprevalence studies Solidarity II. Their verbal consent was obtained for participation in the study and to be informed of the results, all being reflected in the clinical history. In the cases where the result was positive, a hospital visit was also arranged to provide additional information on recommendations and follow-up, and their written informed consent for their participation in the study was also obtained.” 3. For more information on PLOS ONE's expectations for statistical reporting, please see https://journals.plos.org/plosone/s/submission-guidelines.#loc-statistical-reporting. Please update your Methods and Results sections accordingly. We have now updated our Methods and Results sections according to the PLOS ONE´s requirements. 4. Thank you for stating the following in the Funding Section of your manuscript: "This work was supported by grants to RD by the Instituto de Investigación Carlos III (grants FIS PI 1801007, by the European Union Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868. and by Fundación Caixa-Health Research (Project StopEbola). This work was supported by grant to MDF by the Instituto de Investigación Carlos III (FIS PI1800740). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." Please include your amended statements within your cover letter; we will change the online submission form on your behalf. Yes, thank you for your support. We have now removed the funding-related text from the manuscript and included such statement in the cover letter. 5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. Thank you again for your support. We have now uploaded the minimal anonymized data set necessary to replicate our study findings as supporting information. Reviewer #1: Overall, the results of this study are very timely and relevant. There are in my opinion a few of issues that need to be clarified/addressed. Is the highest number of preterm and cesarean births due to SARS-CoV2 positive RT-PCR? maternal respiratory impairment, obstetric or fetal cause? Can you discuss this point? Yes, indeed. As stated in the discussion, several studies on pregnant women suffering from COVID-19 with positive RT-PCR have described an excess in the number of caesarean sections and preterm births. Unfortunately, our limited sample size of pregnant women with symptoms and positive RT-PCR (G4, n=14) prevent us to provide further evidence in this regard. Although we have certainly observed a higher rate of prematurity in G4, we had only 3 cases. We have examined our three cases of preterm birth in G4: one case was a monochorionic monoamniotic pregnancy in which a caesarean section was scheduled at 32 weeks and the other two were cases of preterm rupture of membranes in which labour induction was scheduled at 34 weeks according to local guidelines. In the case of caesarean sections, our results were not statistically significant, probably due to the small sample size. We have now included this detailed information in the results section (line 225). Therefore, we are unable to draw firm conclusions, as we have now discussed. Accordingly, we have replaced the following sentence in the discussion section (line 281): “These two outcomes had already been described in other cohorts of pregnant women with RT-PCR confirmed SARS-CoV-2 infection.” By: “Our small sample size is limited to draw conclusions about the implication of SARS-CoV-2 infection in these findings, although these two outcomes had already been described in other cohorts of pregnant women with RT-PCR confirmed SARS-CoV-2 infection [7].” Reviewer #2: The manuscript by Ignacio Herraiz et al. addressed the issue on Seroprevalence analysis of SARS-CoV-2 in pregnant women along the pandemic outbreak The article is interesting: it is well written, the methodology used is consistent and results are important. They provide information in the the seroprevalence of SARS-CoV-2 in the pregnant population of the south of Madrid during the outbreak and in the evaluation of maternal and perinatal outcomes. There is currently uncertainty regarding the impact of the infection caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS‐CoV‐2) in pregnancy. I consider that the information provided by the authors is useful and should be known by the scientific community. TITLE: The title is clear and appropriate. "Seroprevalence analysis of SARS-CoV-2 in pregnant women along the 1 pandemic outbreak" However, it can be clarified more in the following way "Seroprevalence analysis of SARS-CoV-2 in pregnant women along the 1 pandemic outbreak and perinatal outcome." Thank you for your suggestion. We have changed the title accordingly. The abstract appropriately summarizes the manuscript without omitting important results. INTRODUCTION: The topic is of clinical importance. Most of the previous work is adequately discussed and referenced. The rationale provided by the authors is sufficient and the purpose of the study is clearly defined. However line 54 " Regarding the impact of SARS-CoV-2 infection in pregnancy " It is important to clarify that the impact can be direct or indirect (psychological stress and problems with public health programs) please add these two references Ref - Miguel Parra-Saavedra et al, Attitudes and collateral psychological effects of COVID‐19 in pregnant women in Colombia ,International Journal of Gynecology and Obstetrics 2020 Ref - Roberton T, Carter ED, Chou VB, et al. Early estimates of the indirect effects of the coronavirus pandemic on maternal and child mortality in low‐ and middle‐income countries. Lancet Glob Health.2020; 8: e901–e908. Yes, indeed. We thank the reviewer for this important remark. We have incorporated the two references reflecting the indirect impact of COVID-19 in pregnant women. We have also replaced the sentence (Introduction, line 54): “Regarding the impact of SARS-CoV-2 infection in pregnancy, the current knowledge is…” By: “The SARS-CoV-2 infection in pregnancy has direct and indirect consequences (two new references inserted here). Focusing on the direct impact, current knowledge is…” METHODS. The methodology is appropriate and sufficient for the stated purpose. Reviewer #3: Dr Herraiz et al made a good study of SARS-COV-2 seroprevalence, their results are in line with previous reports about the subject. The only comment about this manuscript is: how would you explain the relationship between higher BMI and seropositivity and symptomatology (groups G1 vs G4)? This is described also in non-obstetric population, and highlighting this finding would add interesting information about SARS-COV-2 and pregnancy. Yes, thank you for arising this interesting point. We have highlighted this finding in the discussion section adding the following sentence (line 282): “Pregnant women with symptomatic COVID-19 had higher BMI than non-infected women as has been described in non-obstetric population (new reference: Azzolino D, Cesari M. Obesity and COVID-19. Front Endocrinol (Lausanne). 2020;11:581356.), and reflecting the importance of prevention in the specific subgroup of the obese gravida” Attachments Attachment Submitted filename: Response to reviewers_PONE-D-20-28445.docx https://doi.org/10.1371/journal.pone.0243029.r002
16 Nov 2020 Decision Letter - Rogelio Cruz-Martinez, Editor Seroprevalence analysis of SARS-CoV-2 in pregnant women along the first pandemic outbreak and perinatal outcome PONE-D-20-28445R1 Dear Dr. Herraiz, 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, Rogelio Cruz-Martinez, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): The authors should be congratulated for the effort to publish this very-well designed study during this Sars-Cov2 pandemia https://doi.org/10.1371/journal.pone.0243029.r003
Formally Accepted
18 Nov 2020 Acceptance Letter - Rogelio Cruz-Martinez, Editor PONE-D-20-28445R1 Seroprevalence analysis of SARS-CoV-2 in pregnant women along the first pandemic outbreak and perinatal outcome Dear Dr. Herraiz: 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 Rogelio Cruz-Martinez Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0243029.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .