Characterization of neonatal opioid withdrawal syndrome in Arizona from 2010-2017

Emery R. Eaves; Jarrett Barber; Ryann Whealy; Sara A. Clancey; Rita Wright; Jill Hager Cocking; Joseph Spadafino; Crystal M. Hepp

doi:10.1371/journal.pone.0248476

Peer Review History

Original SubmissionJune 10, 2020
14 Oct 2020 Decision Letter - Barbara Wilson Engelhardt, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-20-17306 Characterization of Neonatal Abstinence Syndrome in Arizona from 2010-2017 PLOS ONE Dear Dr. Hepp, 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 12/31/2020. 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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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. 5. Please ensure that you refer to Figures 6 and 7 in your text as, if accepted, production will need this reference to link the reader to the figure. 6. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 3 in your text; if accepted, production will need this reference to link the reader to the Table. [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: Yes 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: RE: Review of PONE-D-20-17306; Characterization of Neonatal Abstinence Syndrome in Arizona from 2010-2017 DATE: August 21, 2020 Thank you for the opportunity to review this manuscript, which summarizes the occurrence of NAS over 8 years in Arizona. The data are unique in that the they span before and after the installation of a NAS surveillance system. The data also end in 2017, the year that the AZ governor declared that opioid use disorder had reached epidemic levels. I believe there is great potential for this paper, but have recommendations that may enhance its quality. I will review these in the order that they appear. ABSTRACT The structure of the abstract should be revisited so that the lit review is completed prior to stating the purpose of the study. Following the research justification and purpose, the data description and results would follow. Currently, after the research purpose, the authors revisit literature justification prior to moving into the results. This is an awkward sequencing. INTRODUCTION Line 56: Treatment protocol for NAS does not seem relevant for this paper unless you wish to link the procedure to length of stay. Clarify the importance of treatment in relation to the study or delete. Line 69-76: It is unclear how the discussion of prevention, screening for NAS, and standardization of care for infants with NAS is relevant to this manuscript. These issues may be worked into the discussion perhaps but they do not assist in justifying the importance of the study. I recommend the deletion of this paragraph. More attention could be given to what we know about the demographics of mothers with infants with NAS, and their comorbidities, nationally or in other states. Line 75: Note, the early identification of NAS cases can be challenging as some infants do not exhibit signs of withdrawal until days after their birth. Line 93: Clarify why the initiation of the surveillance system would lead to a hypothesized increase in NAS cases. Given that NAS is determined based on the medical codes, the codes should remain consistent for billing purposes – both before and after the surveillance system. Based on existing data, it seems this increase was typical, until greater efforts to intervene were implemented. METHODS Line 142: The study includes only non-tribal PCAs. In attempts to better understand the state of AZ, the exclusion of the tribal areas diminishes the ability to address the study purpose. The possible impact of not including tribal areas should be explored further in the Discussion, based on what is understood about NAS in the tribal communities. RESULTS and DISCUSSION Line 164: The cases of NAS are not clearly laid out to test whether there was an increase in cases after the surveillance system was implemented. As a proposed hypothesis this should be explicitly tested. (e.g., in relation to Figure 1). Line 191: The race, ethnicity, marriage status, and insurance coverage are very comparable to the data across the US. Ideally such data from earlier studies would be reflected in the Introduction. Length of stay can vary greatly in whether infants are released earlier to complete weaning at home, use of rescue dosing, and the inclusion or exclusion of complementary treatment approaches. The variability of the AZ treatment approaches should be discussed in the Discussion. Line 262: This is an example of the Discussion lurking into the Results. This is not in keeping with manuscript sections. Please keep the Results in the first section and the Discussion points would then follow. Line 296: Given the variability of the comorbid conditions, it seems that this may contribute to challenges related to standardization of care. This needs to be revisited and better clarified. In sum, I believe these data have much to contribute to our understanding of NAS in relation to both infants and their mothers. However, opportunities to strengthen this contribution remain. Toward this end, I hope these comments are beneficial Reviewer #2: Comments to author Excellent study that contributes to the evidence. Minor revisions are outlined for your consideration. Recommend consideration of replacing infants with neonates. There were inconsistencies in formatting regarding indention of new paragraphs, I pointed these out initially. Page 8 Abstract Line 38 & 41 suggest separating ethnic/racial with a comma as ethnic, racial, and/or.. Line 44 consider rephrasing to best outline the withdrawal of substances such as “infants opioid exposed in utero who experience withdrawal following birth.” Line 45 rephrase the portion of this sentence “less well understood” consider “there remains a gap in regional trends.” Line 46 rephrase portion of the sentence “we find that..” consider “Our findings suggest…” Line 48 delete “we find that” Line 50 consider rephrasing “we report…” to “we identified comorbidities associated with … not previously reported Introduction Line 57 in discussing treatment of NAS, consider mentioning non-pharmacologic interventions as the first line therapy Line 61 Consider rewording “identify” and discuss diagnostic criteria Line 65 rephrase the sentence “we found..” I had to read this a few times to understand the message and it is a vital message Line 67 “improving understanding in these areas..” state what you are referring to for the reader – comorbid conditions? Line 70 “changes in the prescribing of opioid drugs” could be rephrased such as “opioid medication modifications and routine screening for substance use.” Line 71 ..and the American.. consider adding period in that prior sentence and start a new sentence stating AAP recommendations Line 74 consider rephrasing “Better and …” such as “In an effort to improve and standardized NAS treatment, there is a need for xxx.” Page 10 Line 123 consider replacing newborn infants with neonates Line 157 delete “very small” Page 11 Results and Discussion consider separating these two sections out Line 164 indent, consider rephrasing this sentence such as “The incidence of NAS in Arizona continues to rise..” Line 166 consider rephrasing your sentence on “the large number of infants… “ recommend separating this point from the sentence and highlight the incidence of NAS is a sequela/consequence from the opioid epidemic 172 Indent, again consider neonate rather than “newborn infant” and rephrase this sentence for clarity. 181 Indent. Curious are these rates including infants treated in the intensive care, meaning are these NAS neonates of all gestational ages compared to all conditions/neonates. Would be a great point to highlight if so.. 191 Indent. 205 Rephrase “past studies,” consider “Previous studies reported…” Page 12 207 delete duplicate that 232 consider rephrasing “we are planning..” consider “future studies may investigate..” Page 13 264 Discussion/Conclusions – Consider deleting discussion ****** 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: PLOS One NAS Aug21 2020.docx https://doi.org/10.1371/journal.pone.0248476.r001
Revision 1
6 Jan 2021 Author Response 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 AUTHORS’ RESPONSE: We have carefully reformatted according to PLOS ONE’s formatting requirements as shown in the linked documents. 2. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. AUTHORS’ RESPONSE: This effort was deemed to be public health surveillance and epidemiological activity, and not research, by both the Arizona Department of Health Services Human Subjects Research Board and Northern Arizona University Institutional Review Board. Because it is not research, the limited dataset, which was deidentified to the federal standards of a limited dataset associated with a data use agreement (between the Arizona Department of Health Services and Northern Arizona University) prior to us receiving it, did not require participant consent. 3. In your Methods section, please provide additional information about the methodology used, for example by listing the comorbidities analysed, and describing how variables were defined and categorised. AUTHORS’ RESPONSE: We added language in the METHODS – Associated Comorbid Conditions section to highlight that all possible diagnosis codes (~13,000 IDC-9-CM and ~70,000 ICD-10-CM possible codes) from each patient record are assessed for their potential to be a comorbid condition. 4. 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. AUTHORS’ RESPONSE: The limited data set that was accessed by our team was made available to us because the effort was classified as public health surveillance and not research. We are unsure of how the Arizona Department of Health Services would choose to classify an identical data request, as the classification of research versus public health surveillance depends on a researcher’s motivation as well as whether the researcher is collaborating with the public health agency for a public health purpose. Additionally, the data set that we received was considered to be fully deidentified due to the data use agreement that Northern Arizona University has with the Arizona Department of Health Services. However, it was provided to us as a limited use, rather than public use, data set. As part of our data request, we are only to report data in aggregate format (as in Table S1). Researchers wishing to reproduce or build on this study will need to submit a data request to the Arizona Department of Health Services to be approved: https://www.azdhs.gov/documents/director/administrative-counsel-rules/HSRB_NewProductSubmission.pdf We have also added our response to the revised cover letter as requested. 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. AUTHORS’ RESPONSE: Response is provided under 4a (directly above). We will update your Data Availability statement on your behalf to reflect the information you provide. 5. Please ensure that you refer to Figures 6 and 7 in your text as, if accepted, production will need this reference to link the reader to the figure. AUTHORS’ RESPONSE: We have added references to Figures 6 and 7 to the text. 6. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 3 in your text; if accepted, production will need this reference to link the reader to the Table. AUTHORS’ RESPONSE: We have corrected this omission and Table 3 is now listed appropriately in the text. [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: Yes 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: RE: Review of PONE-D-20-17306; Characterization of Neonatal Abstinence Syndrome in Arizona from 2010-2017 DATE: August 21, 2020 Thank you for the opportunity to review this manuscript, which summarizes the occurrence of NAS over 8 years in Arizona. The data are unique in that the they span before and after the installation of a NAS surveillance system. The data also end in 2017, the year that the AZ governor declared that opioid use disorder had reached epidemic levels. I believe there is great potential for this paper, but have recommendations that may enhance its quality. I will review these in the order that they appear. AUTHORS’ RESPONSE: We appreciate the reviewers’ careful review and helpful suggestions. We have detailed edits and how we addressed each comment below. ABSTRACT The structure of the abstract should be revisited so that the lit review is completed prior to stating the purpose of the study. Following the research justification and purpose, the data description and results would follow. Currently, after the research purpose, the authors revisit literature justification prior to moving into the results. This is an awkward sequencing. AUTHORS’ RESPONSE: We have restructured the abstract based on the reviewers’ suggestions. INTRODUCTION Line 56: Treatment protocol for NAS does not seem relevant for this paper unless you wish to link the procedure to length of stay. Clarify the importance of treatment in relation to the study or delete. Line 69-76: It is unclear how the discussion of prevention, screening for NAS, and standardization of care for infants with NAS is relevant to this manuscript. These issues may be worked into the discussion perhaps but they do not assist in justifying the importance of the study. I recommend the deletion of this paragraph. More attention could be given to what we know about the demographics of mothers with infants with NAS, and their comorbidities, nationally or in other states. AUTHORS’ RESPONSE: We have deleted the sentence about treatment protocols and moved the lines about standardization in screening to the discussion (page 10). We hope this change addresses both of the reviewers’ above comments. Line 75: Note, the early identification of NAS cases can be challenging as some infants do not exhibit signs of withdrawal until days after their birth. AUTHORS’ RESPONSE: We have deleted this paragraph from the introduction and clarified how early identification relates to the purpose of this paper in the discussion (page 10). Line 93: Clarify why the initiation of the surveillance system would lead to a hypothesized increase in NAS cases. Given that NAS is determined based on the medical codes, the codes should remain consistent for billing purposes – both before and after the surveillance system. Based on existing data, it seems this increase was typical, until greater efforts to intervene were implemented. AUTHORS’ RESPONSE: We have changed this in response to the reviewers’ comment and the text now reflects the more descriptive nature of this analysis in the context of increased surveillance (Page 2). METHODS Line 142: The study includes only non-tribal PCAs. In attempts to better understand the state of AZ, the exclusion of the tribal areas diminishes the ability to address the study purpose. The possible impact of not including tribal areas should be explored further in the Discussion, based on what is understood about NAS in the tribal communities. AUTHORS’ RESPONSE: We have added a discussion of this in the limitation sections that we added after the newly created discussion question and linked it to what is known nationwide. RESULTS and DISCUSSION Line 164: The cases of NAS are not clearly laid out to test whether there was an increase in cases after the surveillance system was implemented. As a proposed hypothesis this should be explicitly tested. (e.g., in relation to Figure 1). AUTHORS’ RESPONSE: Based on the reviewers’ comment, we removed the hypothesis that there would be an increase in cases. Line 191: The race, ethnicity, marriage status, and insurance coverage are very comparable to the data across the US. Ideally such data from earlier studies would be reflected in the Introduction. Length of stay can vary greatly in whether infants are released earlier to complete weaning at home, use of rescue dosing, and the inclusion or exclusion of complementary treatment approaches. The variability of the AZ treatment approaches should be discussed in the Discussion. AUTHORS’ RESPONSE: We have added more literature review to reflect data from earlier studies in the introduction (page 2). The variability of Arizona treatment approaches is outside the scope of this analysis because we are focused on hospital discharge records, which report diagnoses. We have added a section on limitations to note that this is a limitation. Line 262: This is an example of the Discussion lurking into the Results. This is not in keeping with manuscript sections. Please keep the Results in the first section and the Discussion points would then follow. AUTHORS’ RESPONSE: We have separated out these instances of discussion into a separate discussion section in response to the reviewers’ comment. Line 296: Given the variability of the comorbid conditions, it seems that this may contribute to challenges related to standardization of care. This needs to be revisited and better clarified. AUTHORS’ RESPONSE: We have revisited this and attempted to clarify in the conclusion (page 11). In sum, I believe these data have much to contribute to our understanding of NAS in relation to both infants and their mothers. However, opportunities to strengthen this contribution remain. Toward this end, I hope these comments are beneficial AUTHORS’ RESPONSE: Thank you for this thorough review. We have attempted to address each comment carefully. Reviewer #2: Comments to author Excellent study that contributes to the evidence. Minor revisions are outlined for your consideration. Recommend consideration of replacing infants with neonates. There were inconsistencies in formatting regarding indention of new paragraphs, I pointed these out initially. AUTHORS’ RESPONSE: We have changed “infant” to “neonate” throughout and corrected formatting issues per PLoS One’s guidelines. Page 8 Abstract Line 38 & 41 suggest separating ethnic/racial with a comma as ethnic, racial, and/or.. Line 44 consider rephrasing to best outline the withdrawal of substances such as “infants opioid exposed in utero who experience withdrawal following birth.” Line 45 rephrase the portion of this sentence “less well understood” consider “there remains a gap in regional trends.” Line 46 rephrase portion of the sentence “we find that..” consider “Our findings suggest…” Line 48 delete “we find that” Line 50 consider rephrasing “we report…” to “we identified comorbidities associated with … not previously reported AUTHORS’ RESPONSE: We have made all of the suggested edits about to the abstract. We appreciate the reviewers’ attention to detail and suggestions that we hope have increased clarity. Introduction Line 57 in discussing treatment of NAS, consider mentioning non-pharmacologic interventions as the first line therapy Line 61 Consider rewording “identify” and discuss diagnostic criteria Line 65 rephrase the sentence “we found..” I had to read this a few times to understand the message and it is a vital message Line 67 “improving understanding in these areas..” state what you are referring to for the reader – comorbid conditions? Line 70 “changes in the prescribing of opioid drugs” could be rephrased such as “opioid medication modifications and routine screening for substance use.” Line 71 ..and the American.. consider adding period in that prior sentence and start a new sentence stating AAP recommendations Line 74 consider rephrasing “Better and …” such as “In an effort to improve and standardized NAS treatment, there is a need for xxx.” AUTHORS’ RESPONSE: We have made all edits to the introduction as suggested by the reviewer. Page 10 Line 123 consider replacing newborn infants with neonates Line 157 delete “very small” AUTHORS’ RESPONSE: We have replaced “newborn infants” with “neonates” throughout, per suggestions from both reviewers. Page 11 Results and Discussion consider separating these two sections out AUTHORS’ RESPONSE: We have separated out the results and discussion sections based on comments from both reviewers. Line 164 indent, consider rephrasing this sentence such as “The incidence of NAS in Arizona continues to rise..” Line 166 consider rephrasing your sentence on “the large number of infants… “ recommend separating this point from the sentence and highlight the incidence of NAS is a sequela/consequence from the opioid epidemic AUTHORS’ RESPONSE: We have made both of the suggested revisions noted above. 172 Indent, again consider neonate rather than “newborn infant” and rephrase this sentence for clarity. AUTHORS’ RESPONSE: We have made this change throughout. 181 Indent. Curious are these rates including infants treated in the intensive care, meaning are these NAS neonates of all gestational ages compared to all conditions/neonates. Would be a great point to highlight if so.. AUTHORS’ RESPONSE: Yes, these rates include infants treated in intensive care. We have added text to better point that out (methods section, paragraph 2). 191 Indent. 205 Rephrase “past studies,” consider “Previous studies reported…” AUTHORS’ RESPONSE: We have made the suggested change. Page 12 207 delete duplicate that 232 consider rephrasing “we are planning..” consider “future studies may investigate..” AUTHORS’ RESPONSE: We have made the changes suggested above. Page 13 264 Discussion/Conclusions – Consider deleting discussion AUTHORS’ RESPONSE: We have separated out the discussion and conclusion sections as recommended by both reviewers. Attachments Attachment Submitted filename: NAS PloS One_response to reviewers ERE-1_CMH.docx https://doi.org/10.1371/journal.pone.0248476.r002
1 Mar 2021 Decision Letter - Barbara Wilson Engelhardt, Editor Characterization of Neonatal Abstinence Syndrome in Arizona from 2010-2017 PONE-D-20-17306R1 Dear Dr. Hepp, 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, Barbara Wilson Engelhardt, MD Academic Editor PLOS ONE Additional Editor Comments (optional): Dear Dr. Hepp, In their 2nd review of your article, following your revision, both reviewers found adequate response to their comments/concerns. They accepted the revised paper. I concur and support accepting your paper. Your epidemiologic work and results are interesting and contributing significantly to the understanding of the current Opioid epidemic. I have 2 minor concerns: First, you make mention of the work by Dr. Stephen Patrick's group several times throughout your paper. It is not necessary to use his name in the abstract. Secondly you use the term NAS and may want to consider the now often used NOWS in your title and as the predominant term throughout the paper. All the best, B Engelhardt, Academic Editor 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: Yes 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: I appreciate the authors' attention to their revisions. I have no further comments or concerns about the publication of this submission. Excellent work! 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: Yes:** Laurie L. Meschke Reviewer #2: No https://doi.org/10.1371/journal.pone.0248476.r003
Formally Accepted
28 Apr 2021 Acceptance Letter - Barbara Wilson Engelhardt, Editor PONE-D-20-17306R1 Characterization of Neonatal Opioid Withdrawal Syndrome in Arizona from 2010-2017 Dear Dr. Hepp: 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. Barbara Wilson Engelhardt Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0248476.r004

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