Antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding: A population cohort analysis

Sue Jordan; Gareth I. Davies; Daniel S. Thayer; David Tucker; Ioan Humphreys

doi:10.1371/journal.pone.0225133

Peer Review History

Original SubmissionJune 19, 2019
17 Sep 2019 Decision Letter - Kenji Hashimoto, Editor PONE-D-19-17104 Antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding: a population cohort analysis PLOS ONE Dear Professor Jordan, 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. Two reviewers addressed several major and minor concerns about your manuscript. Please revise your manuscript carefully. We would appreciate receiving your revised manuscript by Nov 01 2019 11:59PM. When you are 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. 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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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: 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 ****** 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: Dear authors, This manuscript presents data based on a population cohort to study associations between exposure to antidepressants, their discontinuation, depression and preterm birth, small for gestational and breastfeeding at 6-8 weeks. The data presented are incredibly valuable and valid, however I would recommend to explain and demonstrate why these results are important? How they can contribute to the practice? what can be done regarding depression prevention? The manuscript lacks information, reflection and soundness. In addition, it seems that authors were just describing results (because data was available) and were not doing it for a specific propose. This feeling begins in introduction. A more reflective way on implications for practice would improve your manuscript. Please explain better how depression was measured, by whom? What manual/diagnosis system they used? can you guarantee they use the same methods? This need more detail since it is the main outcome. Reviewer #2: The authors investigated the associations between exposure to antidepressants, their discontinuation, depression and preterm birth, small for gestational age (SGA), breastfeeding at 6-8 weeks. They found that exclusive formula feeding at 6-8 weeks was associated with prescriptions in trimesters 2 or 3 for any antidepressants, SSRIs, particularly higher doses, discontinuation of antidepressants or SSRIs after trimester 1, diagnosis of depression, particularly if medicated, rather than unmedicated. Moreover, preterm birth at <37 and <32 weeks’ gestation was associated with diagnosis of depression, particularly if medicated; birth at <37 weeks was associated with antidepressants, SGA <3rd centile was associated with antidepressants, and SSRIs, particularly higher doses. They stated that both depression and antidepressants indicated increased risks of exclusive formula feeding at 6-8 weeks. These findings will be of interest to practitioners, as well as researchers in the field. I have the following concerns. 1.Abstract Line 59. Conclusions. What do the authors conclude from the results that intra-uterine exposure to antidepressants and maternal depression were associated with adverse perinatal outcomes? If possible, the authors should comment on the results. 2. The amount of the presented tables is very large, and this is confusing for readers. This aspect of the paper should be improved. Table 2a, 2b,and 2c show the infants excluded from the analysis. If possible, Table 2 could be transferred to the section of supplementary tables. 3. Discussion. Line 275. “To our knowledge, this is the first report that antidepressants, particularly high dose SSRIs, depression, particularly medicated depression, and discontinuation of antidepressants adversely affect breastfeeding rates at 6-8 weeks; the effects of high doses and discontinuation were not independent of depression.” The authors claim that this is the first report. But what do they mean by “first report”? Line 423, The authors also stated that “In Wales, the relationships between economic deprivation and breastfeeding, [55, 56] and SSRI prescription in pregnancy, adjusted for diagnosed depression are linear. [48]. This statement indicates that other researchers have also reported the relationships between breastfeeding, [55, 56] and SSRI prescription in pregnancy. The authors should clarify the new findings they found. In conclusion, I enjoyed reading this paper. This is a valuable paper that presents evidence of the associations between antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding. ****** 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 [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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0225133.r001
Revision 1
23 Oct 2019 Author Response Rebuttal letter PONE-D-19-17104 3.10.19 Dear Professor Hashimoto, Thank you for the return of our manuscript. We are very grateful for the reviewers’ support and suggestions. We have done our best to comply. We hope that readers will concur with reviewer 2: I enjoyed reading this paper. This is a valuable paper that presents evidence of the associations between antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding. Thank you for your time spent on this paper. Yours, Sue Jordan, on behalf of all authors Reviewer #1: Dear authors, This manuscript presents data based on a population cohort to study associations between exposure to antidepressants, their discontinuation, depression and preterm birth, small for gestational and breastfeeding at 6-8 weeks. The data presented are incredibly valuable and valid, however I would recommend to explain and demonstrate why these results are important? Thank you. We have added to lines 455-464: The concentration of prescribing and adverse outcomes amongst the economically disadvantaged should encourage pre-conception monitoring in tandem with review of antidepressants and non-pharmacological therapies. These data indicate that prescription of antidepressants is an important marker for adverse outcomes, easily identified in primary care records. This could, and should, be used to trigger additional monitoring, including third trimester scans or alternative continuous monitoring technology to detect SGA. Using prescriptions to target care before, during and after pregnancy How they can contribute to the practice? what can be done regarding depression prevention? We agree, it is essential to explain how the findings contribute to practice. We hope that the implications for practice derived from the study are set out clearly above. Prevention of depression is an important area, but outside the scope of the data presented. The manuscript lacks information, reflection and soundness. In addition, it seems that authors were just describing results (because data was available) and were not doing it for a specific propose. This feeling begins in introduction. A more reflective way on implications for practice would improve your manuscript. Thank you. To ensure the paper is of a manageable length, readers are referred to earlier work for methodological details at points (references 33 and 17). The information from the study is contained in 9 tables, 5 with 8 multivariate models. Thank you. We have added to the statement of purpose / aim, line 63 et seq: … the key question for women and clinicians - the harm to benefit balance of starting, stopping or continuing antidepressant pharmacotherapy [5] - remains unanswered. Accordingly, the aim of this study is to investigate … The implications for practice are summarised in the ‘Conclusion and Implications’ section, to which we have added, lines 455-464, above. We feel that some caution is needed before drawing causal inferences from observation data, and our main implication for practice is the need to target groups identified for additional care. We have added, line 446: Drawing causal inferences from observation data may be imprudent. Please explain better how depression was measured, by whom? What manual/diagnosis system they used? can you guarantee they use the same methods? This need more detail since it is the main outcome. Thank you, we have added, line 114-5: Depression was defined as any diagnosis of depression in the woman’s record before the end of trimester 1 [91 days after 1st day of LMP], recorded by the GP using Read codes, version 2 [17, 36, 37] We acknowledge the limitations of using the diagnoses of GPs, lines 598-. We acknowledge the risks of under-ascertainment or inconsistency between individual GPs, and the limitations of taking the absence of records as ‘no problems’. Thank you. We have added, line 408: We acknowledge the risks of under-ascertainment or inconsistency between individual GPs, and the limitations of taking the absence of records as ‘no problems’. We agree that more detail will improve the value of the paper. Therefore, we have added the S1 file, to give full details of the codes GPs used to record depression. Reviewer #2: The authors investigated the associations between exposure to antidepressants, their discontinuation, depression and preterm birth, small for gestational age (SGA), breastfeeding at 6-8 weeks. They found that exclusive formula feeding at 6-8 weeks was associated with prescriptions in trimesters 2 or 3 for any antidepressants, SSRIs, particularly higher doses, discontinuation of antidepressants or SSRIs after trimester 1, diagnosis of depression, particularly if medicated, rather than unmedicated. Moreover, preterm birth at <37 and <32 weeks’ gestation was associated with diagnosis of depression, particularly if medicated; birth at <37 weeks was associated with antidepressants, SGA <3rd centile was associated with antidepressants, and SSRIs, particularly higher doses. They stated that both depression and antidepressants indicated increased risks of exclusive formula feeding at 6-8 weeks. Thank you These findings will be of interest to practitioners, as well as researchers in the field. Thank you I have the following concerns. 1.Abstract Line 59. Conclusions. What do the authors conclude from the results that intra-uterine exposure to antidepressants and maternal depression were associated with adverse perinatal outcomes? If possible, the authors should comment on the results. Thank you. Our comment has been modified, and the section retitled ‘implications’: Implications: Exposure to antidepressants or depression increased risks of exclusive formula feeding at 6-8 weeks, and prescription of antidepressants was associated with SGA <3rd centile. Prescription of antidepressants offers a useful marker to target additional support and additional care before and during pregnancy and lactation. We feel that some caution is needed before drawing causal inferences from observation data, and our main implication for practice is the need to target groups identified for additional care. This is now stated under ‘limitations’. We have added, line 446: Drawing causal inferences from observation data may be imprudent. 2. The amount of the presented tables is very large, and this is confusing for readers. This aspect of the paper should be improved. Table 2a, 2b,and 2c show the infants excluded from the analysis. If possible, Table 2 could be transferred to the section of supplementary tables. This is very helpful. Done. 3. Discussion. Line 275. “To our knowledge, this is the first report that antidepressants, particularly high dose SSRIs, depression, particularly medicated depression, and discontinuation of antidepressants adversely affect breastfeeding rates at 6-8 weeks; the effects of high doses and discontinuation were not independent of depression.” The authors claim that this is the first report. But what do they mean by “first report”? Thank you. We have clarified by adding ‘in the published literature’. Line 278: To our knowledge, this is the first report, in the published literature, Line 423, The authors also stated that “In Wales, the relationships between economic deprivation and breastfeeding, [55, 56] and SSRI prescription in pregnancy, adjusted for diagnosed depression are linear. [48]. This statement indicates that other researchers have also reported the relationships between breastfeeding, [55, 56] and SSRI prescription in pregnancy. The authors should clarify the new findings they found. Thank you, we have clarified, lines 361-3. In Wales, linear relationships between economic deprivation and breastfeeding, [58, 59] and economic deprivation and SSRI prescription in pregnancy, adjusted for diagnosed depression, have been identified. [50] These studies were authored by our group. In conclusion, I enjoyed reading this paper. This is a valuable paper that presents evidence of the associations between antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding. Thank you. We hope that others will concur, and modify practice to help prevent some of these adverse outcomes in future. Attachments Attachment Submitted filename: Rebuttal letter PONE.docx https://doi.org/10.1371/journal.pone.0225133.r002
30 Oct 2019 Decision Letter - Kenji Hashimoto, Editor Antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding: a population cohort analysis PONE-D-19-17104R1 Dear Dr. Jordan, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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. With kind regards, Kenji Hashimoto, PhD Section Editor PLOS ONE Additional Editor Comments (optional): 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 #2: All comments have been addressed ******** 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ****** 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 #2: 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 #2: 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 #2: (No Response) ****** 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 #2: No https://doi.org/10.1371/journal.pone.0225133.r003
Formally Accepted
7 Nov 2019 Acceptance Letter - Kenji Hashimoto, Editor PONE-D-19-17104R1 Antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding: a population cohort analysis Dear Dr. Jordan: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Kenji Hashimoto Section Editor PLOS ONE https://doi.org/10.1371/journal.pone.0225133.r004

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