An inventory of European data sources to support pharmacoepidemiologic research on neurodevelopmental outcomes in children following medication exposure in pregnancy: A contribution from the ConcePTION project

Joanne Given; Rebecca L. Bromley; Florence Coste; Sandra Lopez-Leon; Maria Loane

doi:10.1371/journal.pone.0275979

Peer Review History

Original SubmissionOctober 25, 2021
14 Mar 2022 Decision Letter - Maria Christine Magnus, Editor PONE-D-21-33083An inventory of European data sources to support pharmacoepidemiologic research on neurodevelopmental outcomes in children following medication exposure in pregnancy: A contribution from the ConcePTION projectPLOS ONE Dear Dr. Loane, 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 Apr 28 2022 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This review provided a very good overview of the European data sources available for researchers interested in studying neurodevelopmental outcomes related to medication use in pregnancy. I appreciated the way the outcomes were grouped in five broad categories. Main comments: 1. Material and methods, lines 175-176: It was not clear in the main manuscript what was meant by “prospective studies” that were to be excluded. Birth cohorts are also prospective studies, so it was clearer in the supplementary material (e.g., RCTs). Please explain this exclusion criteria in more detail in the main manuscript. 2. It was clear that diagnosis data would be most relevant for neurodevelopmental disorders (Table 5). However, ICD codes were mentioned once in Table 1 (Italy) and Table 3 (Sweden). Either these should be removed from Tables 1 and 3, or other sources would need to be added, e.g., Norwegian Patient Registry. Please clarify, and ideally, list or give examples of ICD codes relevant for Tables 1 (infant development) and 3 (cognitive outcomes). 3. It would be helpful for the reader to know the source(s) of information for maternal medication. It was reported (lines 400-401) the authors did not check if maternal medication information was available. It seems important to at least know that there is drug data available since this is the reason for compiling this list of data sources. I suggest that the authors add where maternal medication information comes from if it must be linked from another source. 4. Conclusions, line 416: Need to mention specificity. This is perhaps more important than sensitivity when it comes to diagnoses for obtaining an unbiased relative risks. 5. The link to descriptions of the abbreviations in the tables did not work. Therefore, I could not review them. Please make sure these are included in the next version. 6. Table 5: Should also mention ICPC codes for Finland and Norway primary care data 7. In some cases, too many abbreviations are used: e.g. in Table 5, remove LPR for Denmark, NRPHC for Norway, PAR for Sweden. I don’t think these are commonly used and you have the full name written so it seems unnecessary to include. 8. Can you comment on how you had enough information to include the data source in the paper, but not to know how the outcomes were assessed for those where the method to assess ND was unclear? Minor comments: 9. Table 1: Aarhus, not Aarhous 10. Lines 69, 302: Do not use the acronym CA. It is only mentioned one time after introducing it in the introduction, therefore it is not needed and clearer to write in full. 11. Line 310: add the word “brain” – brain regions is clearer 12. Line 373-4, blinding of the health care professionals: do you mean to the child to the exposure status of the child? 13. Line 414: add the word “potential” – associated with potential ND outcomes or potentially associated 14. Tables 2, 3: Not necessary to list every hospital name of the 10 from the Finnish study called PREDO. 15. Tables: Be consistent when you write ICD-10 or ICD 10 (with or without hyphen) 16. Table 5: Finland HILMO should include ICD-10 in recent years 17. Table 5: Sweden ABIS study – should say Southeast or Southwest in geographic coverage. There is a mismatch. Also, “diagnosis codes” is vague. Is it ICD-10 like other sources? 18. Table 5: Sweden Clinical database for child and adolescent psychiatry in Sweden should say DSM-IV (not DSV-IV) Reviewer #2: 1. The aim of this paper needs to be justified, given the project has been established. 2. The age of children would be important for the study of neurodevelopmental disorders. Thus, it would be very informative to list the start (end) year of the cohorts and registers to identify the children. 3. L371-379: The authors stated that detection bias is always possible when using health registries. To my knowledge, detection bias is less likely in registers since the prescribers and clinicians who see the children are often different. Moreover, as the author mentioned, a large proportion of women take medications during pregnancy. Therefore, medications do not necessarily influence the doctors’ diagnosis. For instance, clinicians may be more reluctant to prescribe the medication to pregnant women unless they have severe disorders when an association is established. It is difficult to know whether any associations are due to positively biased practice or indication for treatment. 4. There are still cohorts/registers missing from the ConcePTION project. Please clarify whether this project will be static, i.e., restricting to these 90 data sources, or be dynamic by identifying more relevant resources? ****** 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.] 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. Attachments Attachment Submitted filename: Reviews.docx https://doi.org/10.1371/journal.pone.0275979.r001
Revision 1
23 Aug 2022 Author Response Reviewer #1: This review provided a very good overview of the European data sources available for researchers interested in studying neurodevelopmental outcomes related to medication use in pregnancy. I appreciated the way the outcomes were grouped in five broad categories. Main comments: 1. Material and methods, lines 175-176: It was not clear in the main manuscript what was meant by “prospective studies” that were to be excluded. Birth cohorts are also prospective studies, so it was clearer in the supplementary material (e.g., RCTs). Please explain this exclusion criteria in more detail in the main manuscript. We have added more text in the manuscript (line 175) explaining the exclusion: Prospective Studies such as case reports, clinical studies, randomised controlled trials and adverse drug reaction databases were excluded as these have small sample sizes or selected populations. 2. It was clear that diagnosis data would be most relevant for neurodevelopmental disorders (Table 5). However, ICD codes were mentioned once in Table 1 (Italy) and Table 3 (Sweden). Either these should be removed from Tables 1 and 3, or other sources would need to be added, e.g., Norwegian Patient Registry. Please clarify, and ideally, list or give examples of ICD codes relevant for Tables 1 (infant development) and 3 (cognitive outcomes). We explained in lines 223-228 that there was overlap between the 5 domains of neurodevelopment. Tables 1 to 3 represent a variety of data sources including longitudinal cohorts, and databases which employ a variety of approaches to neurodevelopmental outcome measurement. The majority of sources reported in Tables 1-3 collect data on skill acquisition or functioning (e.g. data collected with the Bayley Scales of Infant and Toddler Development, or the Strengths and Difficulties Questionnaire) rather than the presence or absence of a particular set of symptoms and therefore ICD codes are not used by these sources to summarise their data. We have listed ICD codes, where the source provides them. We think a unique aspect of this manuscript is the provision of data sources which go beyond ICD codes which are a relatively underutilised resource which could be used for pharmacovigilance work in the future. .3. It would be helpful for the reader to know the source(s) of information for maternal medication. It was reported (lines 400-401) the authors did not check if maternal medication information was available. It seems important to at least know that there is drug data available since this is the reason for compiling this list of data sources. I suggest that the authors add where maternal medication information comes from if it must be linked from another source. The reviewer has misinterpreted the meaning of the sentence: “Data sources were not contacted to confirm the availability of medication exposure or ND outcome data for secondary research purposes.” We know the data are available, but we do not know if the data owners would allow their data to be used for secondary research. There are many reasons why data providers may not allow their data to be used in secondary research: • Data not collected for research purposes • Quality of the data • Potential risks of disclosure, especially if there are small numbers (i.e. rare exposures and rare outcomes) We have clarified this in the manuscript (line 402): “Data sources were not contacted to confirm if they would allow their data i.e. medication exposure records or ND outcome data to be used in secondary research.” 4. Conclusions, line 416: Need to mention specificity. This is perhaps more important than sensitivity when it comes to diagnoses for obtaining an unbiased relative risks. We agree with the reviewers and revised the sentence: “ Caution must be used when combining varied approaches to ND outcome measurement and consideration regarding the sensitivity and specificity of the outcome measure selected and the age of the child at review/follow up should be borne in mind.“ We have amended this throughout the paper 5. The link to descriptions of the abbreviations in the tables did not work. Therefore, I could not review them. Please make sure these are included in the next version. The list of abbreviations were uploaded as Supplementary File 3. We are sorry that the reviewer was unable to access this information, accessible by clicking on the Supplementary File link at the end of the document. 6. Table 5: Should also mention ICPC codes for Finland and Norway primary care data These have been added. 7. In some cases, too many abbreviations are used: e.g. in Table 5, remove LPR for Denmark, NRPHC for Norway, PAR for Sweden. I don’t think these are commonly used and you have the full name written so it seems unnecessary to include. We have deleted these abbreviations as suggested. 8. Can you comment on how you had enough information to include the data source in the paper, but not to know how the outcomes were assessed for those where the method to assess ND was unclear? These were five birth cohorts where the articles or websites describing the data list for example ‘questionnaires’ or measurement of ‘cognitive function, language, Autism or ADHD’ but no further detail on what measurement tools were used was available either via the website or in the papers published. Minor comments: 9. Table 1: Aarhus, not Aarhous This is now corrected in the manuscript. 10. Lines 69, 302: Do not use the acronym CA. It is only mentioned one time after introducing it in the introduction, therefore it is not needed and clearer to write in full. This is now corrected in the manuscript. 11. Line 310: add the word “brain” – brain regions is clearer This is now corrected in the manuscript. 12. Line 373-4, blinding of the health care professionals: do you mean to the child to the exposure status of the child? We have clarified this in the text: For example, it is not possible to blind a child’s exposure status from the health care professionals reviewing the child to rate the ND outcome 13. Line 414: add the word “potential” – associated with potential ND outcomes or potentially associated This is now corrected in the manuscript. 14. Tables 2, 3: Not necessary to list every hospital name of the 10 from the Finnish study called PREDO. We have deleted the hospital names 15. Tables: Be consistent when you write ICD-10 or ICD 10 (with or without hyphen) We have now corrected this to ICD-10 throughout the manuscript 16. Table 5: Finland HILMO should include ICD-10 in recent years We have now added this. 17. Table 5: Sweden ABIS study – should say Southeast or Southwest in geographic coverage. There is a mismatch. Also, “diagnosis codes” is vague. Is it ICD-10 like other sources? The correct geographical region is South East, and the study uses ICD-9 or ICD-10 codes. This is now corrected in the manuscript. 18. Table 5: Sweden Clinical database for child and adolescent psychiatry in Sweden should say DSM-IV (not DSV-IV) This is now corrected in the manuscript. Reviewer #2: 1. The aim of this paper needs to be justified, given the project has been established. 2. The age of children would be important for the study of neurodevelopmental disorders. Thus, it would be very informative to list the start (end) year of the cohorts and registers to identify the children. We agree with the comment that age at evaluation of development is very important, and many scales include an age range for use. The start/end dates of cohorts and registers would provide information about the generation rather than the age of subjects included. In some cases, the start year is included in the birth cohort name (such as Copenhagen Birth Cohort 2000). It would be a lot of work to include the start/end year for all data sources as some have closed enrolment, some have added waves of inclusion and others are still open. The purpose of our study was to identify those data sources with ND outcomes available, rather than the age of children included in these sources. 3. L371-379: The authors stated that detection bias is always possible when using health registries. To my knowledge, detection bias is less likely in registers since the prescribers and clinicians who see the children are often different. Moreover, as the author mentioned, a large proportion of women take medications during pregnancy. Therefore, medications do not necessarily influence the doctors’ diagnosis. For instance, clinicians may be more reluctant to prescribe the medication to pregnant women unless they have severe disorders when an association is established. It is difficult to know whether any associations are due to positively biased practice or indication for treatment. We acknowledge your comment and propose the following revision: “Finally, it should be considered that all data sources have potential for bias. In countries or regions with health registries, it may be comparatively cheap and fast to use diagnosis codes. However, detection bias cannot be fully ruled out. For example, it is not possible to blind a child’s exposure status from the health care professionals reviewing the child to rate the ND outcome. Whilst, this may be less of an influence early on, once an association between a medication exposure and a child ND outcome has been established this may positively bias practice, e. g. prescribing this medication only to clinically severe patients whose disease cannot be controlled with less toxic medications. Additional biases come from population health behaviour. For instance, it is suspected that women exposed to a suspected teratogen, or women with a history of mental illness, may be more likely to get health or developmental referrals for their children. “ 4. There are still cohorts/registers missing from the ConcePTION project. Please clarify whether this project will be static, i.e., restricting to these 90 data sources, or be dynamic by identifying more relevant resources? This study describes current electronic “linkable” data sources that can be used to assess neurodevelopmental outcomes in children. Other electronic data sources that have the potential to be linked to maternal and child outcomes will indeed be included in the catalogue developed within the CONCEPTION project. However, we cannot answer about the future updates and sustainability as these are not yet defined. We hope that we have addressed all comments satisfactorily. Attachments Attachment Submitted filename: Response to reviewer1.docx https://doi.org/10.1371/journal.pone.0275979.r002
27 Sep 2022 Decision Letter - Maria Christine Magnus, Editor An inventory of European data sources to support pharmacoepidemiologic research on neurodevelopmental outcomes in children following medication exposure in pregnancy: A contribution from the ConcePTION project PONE-D-21-33083R1 Dear Dr. Loane, 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, Maria Christine Magnus, PhD Academic Editor PLOS ONE 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: All comments have been addressed 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 #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A 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 #1: Yes 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 #1: Yes 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 #1: (No Response) 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 #1: No Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0275979.r003
Formally Accepted
7 Oct 2022 Acceptance Letter - Maria Christine Magnus, Editor PONE-D-21-33083R1 An inventory of European data sources to support pharmacoepidemiologic research on neurodevelopmental outcomes in children following medication exposure in pregnancy: A contribution from the ConcePTION project Dear Dr. Loane: 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. Maria Christine Magnus Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0275979.r004

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