Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis

Yiqun Miao; Yun Zhou; Shuliang Zhao; Wenwen Liu; Aihua Wang; Yuanyuan Zhang; Yanan Li; Huimin Jiang

doi:10.1371/journal.pone.0274882

Peer Review History

Original SubmissionJune 28, 2022
9 Aug 2022 Decision Letter - Hasan Tolga Celik, Editor PONE-D-22-17592Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A meta-analysisPLOS ONE Dear Dr. Wang, 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 Sep 23 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. 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. 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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: 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: Methylxanthines, including caffeine citrate and aminophylline, is the most common pharmacologic treatment for apnea of prematurity. However, due to the lack of high-quality evidence, there are no clear suggestions or guidelines on how to choose between caffeine and aminophylline. This meta-analysis aimed to assess the comparative efficacy and safety of caffeine and aminophylline for AOP, and provide reliable evidence for clinical medication in the treatment for apnea of prematurity. This meta-analysis reveals that caffeine citrate and aminophylline have similar therapeutic effectiveness on respiratory function, but caffeine has fewer side effects and should be considered first for treatment. So this research is a nice work. Yours sincerely, Reviewer #2: Dear Authors, The study is well designed, writing and grammar are clear. There were limited RCTs in the study and it’s difficult to recommend the optimal treatment. Early caffeine initiation is recommended in the literature. In a study, early caffeine initiation (initial dose on the 1st day of life) was associated with a decreased need for invasive ventilatory support and lower incidence of IVH and PDA (PLoS ONE 12(12): e0189152. https://doi.org/10.1371/journal.pone.0189152X) that they recommend the initiation of caffeine treatment in the first 24 hours of life. The initiation time of caffeine treatment and its relationship with adverse effects can be mentioned in the discussion section. The dose of caffeine treatment can be challenging because of the limited hepatic, renal, and respiratory function of the preterm infants. A metaanalysis found that higher doses of caffeine (10-20 mg/kg daily) were associated with greater efficacy than lower doses (5-10 mg/kg daily) and that higher doses were more closely associated with withdrawal from the ventilator, but higher doses were also more associated with tachycardia than lower doses (Chen J, Jin L, Chen X. Efficacy and Safety of Different Maintenance Doses of Caffeine Citrate for Treatment of Apnea in Premature Infants: A Systematic Review and Meta-Analysis. Biomed Res Int. 2018 Dec 24;2018:9061234. doi: 10.1155/2018/9061234.). In this study, the optimal caffeine dose cann’t be given. This can be discussed more detailed in the discussion section. The total adverse effects were not clear and described in general. There are also studies that show long-term safety of caffeine therapy for apnea of prematurity, Mürner-Lavanchy et al reported that neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine (Mürner-Lavanchy IM, Doyle LW, Schmidt B, Roberts RS, Asztalos EV, Costantini L, Davis PG, Dewey D, D'Ilario J, Grunau RE, Moddemann D, Nelson H, Ohlsson A, Solimano A, Tin W, Anderson PJ; Caffeine for Apnea of Prematurity (CAP) Trial Group. Neurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea of Prematurity. Pediatrics. 2018 May;141(5):e20174047. doi: 10.1542/peds.2017-4047.) Long-term effects of caffeine therapy can be specified in the total adverse effects discussion section. Further controlled studies are needed to confirm the comparative usefulness of caffeine. ****** 6. 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Revision 1
16 Aug 2022 Author Response Dear Editors: Thank you for providing us with such a great opportunity to submit a revised version of our manuscript. We appreciate your warm help with our manuscript. Meanwhile, we would like to express our sincere gratitude to all reviewers for their detailed and constructive comments on our manuscript. According to those helpful suggestions, we have revised the manuscript to make our results convincing. Revised portions are marked in red on the paper. The main corrections in the paper and the responses to the reviewers' comments are as follows. At the same time, we ensure that the manuscript meets PLOS ONE's style requirements. The corresponding author's ORCID ID is 0000-0001-9144-2805, we've validated and updated it in ‘Update my Information’. We mentioned the retrieval date in the abstract and method section: Methods: PubMed, Scopus, Embase, EBSCO, Web of Science, and Cochrane databases were systematically searched from May 1975 to June 2022 (Page2 line34);We searched Embase, PubMed, Web of Science, EBSCO, Cochrane, and Scopus databases from May 1975 to June 2022 for all relevant articles(Page4 line87). At your suggestion we have changed the title to “Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis”. In addition, we have checked all the references to ensure that they are complete and correct. Thank you again for your time and help with our manuscript. We hope you will be satisfied with the revised version and look forward to hearing from you. Sincerely, The authors Encl. Responses to the comments from Reviewer 1 and 2. Reply to Reviewer #1 Dear Reviewer, Thank you very much for your time spent in reviewing our manuscript and for your encouraging comments on its merits. After careful consideration, we have further revised the article. We hope that you will be more satisfied with the revised version. Comments: “Methylxanthines, including caffeine citrate and aminophylline, is the most common pharmacologic treatment for apnea of prematurity. However, due to the lack of high-quality evidence, there are no clear suggestions or guidelines on how to choose between caffeine and aminophylline. This meta-analysis aimed to assess the comparative efficacy and safety of caffeine and aminophylline for AOP, and provide reliable evidence for clinical medication in the treatment for apnea of prematurity. This meta-analysis reveals that caffeine citrate and aminophylline have similar therapeutic effectiveness on respiratory function, but caffeine has fewer side effects and should be considered first for treatment. So this research is a nice work.” Thank you very much for your affirmation of this article. We hope you will find this revised version more satisfactory. We are more than happy to make any further changes that will improve the article and facilitate successful publication. Sincerely, The Authors Reply to Reviewer #2 Dear Reviewer, We are really grateful to you for your time and efforts put into the comments. Those comments are all valuable and helpful for revising and improving our paper. We have studied all comments carefully and have made conscientious corrections. We appreciate your clear and detailed feedback and hope that the explanation has fully addressed all your concerns. Comments1: The study is well designed, writing and grammar are clear. There were limited RCTs in the study and it’s difficult to recommend the optimal treatment. Early caffeine initiation is recommended in the literature. In a study, early caffeine initiation (initial dose on the 1st day of life) was associated with a decreased need for invasive ventilatory support and lower incidence of IVH and PDA (PLoS ONE 12(12): e0189152. https://doi.org/10.1371/journal.pone.0189152X) that they recommend the initiation of caffeine treatment in the first 24 hours of life. The initiation time of caffeine treatment and its relationship with adverse effects can be mentioned in the discussion section. Response 1: Thank you for your good advice. Your suggestions really mean a lot to us. After careful consideration, we have added relevant content in the discussion section: Some studies have further shown that prophylactic use of caffeine for preterm infants at risk of apnea reduced the duration of mechanical ventilation[31]. Borszewska-Kornacka[32] found that preventive use of caffeine within 24 hours after birth can reduce the use of invasive ventilator and the incidence of IVH and PDA compared with therapeutic use of caffeine. However, whether caffeine should be used prophylactically in all preterm infants remains controversial. (Page8 line221) Comments 2: The dose of caffeine treatment can be challenging because of the limited hepatic, renal, and respiratory function of the preterm infants. A meta analysis found that higher doses of caffeine (10-20 mg/kg daily) were associated with greater efficacy than lower doses (5-10 mg/kg daily) and that higher doses were more closely associated with withdrawal from the ventilator, but higher doses were also more associated with tachycardia than lower doses (Chen J, Jin L, Chen X. Efficacy and Safety of Different Maintenance Doses of Caffeine Citrate for Treatment of Apnea in Premature Infants: A Systematic Review and Meta-Analysis. Biomed Res Int. 2018 Dec 24;2018:9061234. doi: 10.1155/2018/9061234.). In this study, the optimal caffeine dose cann’t be given. This can be discussed more detailed in the discussion section. Response 2: Thanks for your valuable comments. Your suggestions are really important to us. Through thinking and consulting literature, we have added relevant content in the discussion section: In addition, the dosage of caffeine therapy can be challenging because of the limited hepatic, renal, and respiratory function of preterm infants. A previous study has shown that high doses of caffeine lead to the decrease of mesenteric blood flow and serious feeding intolerance of caffeine generally appears at concentrations >60 mg/L[30]. But chen[38] found that higher doses of caffeine (10-20 mg/kg daily) were more effective than lower doses (5-10 mg/kg daily) and that higher doses were more closely associated with withdrawal from the ventilator. (Page9 line248) Comments3: The total adverse effects were not clear and described in general. There are also studies that show long-term safety of caffeine therapy for apnea of prematurity, Mürner-Lavanchy et al reported that neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine (Mürner-Lavanchy IM, Doyle LW, Schmidt B, Roberts RS, Asztalos EV, Costantini L, Davis PG, Dewey D, D'Ilario J, Grunau RE, Moddemann D, Nelson H, Ohlsson A, Solimano A, Tin W, Anderson PJ; Caffeine for Apnea of Prematurity (CAP) Trial Group. Neurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea of Prematurity. Pediatrics. 2018 May;141(5):e20174047. doi: 10.1542/peds.2017-4047.) Long-term effects of caffeine therapy can be specified in the total adverse effects discussion section. Further controlled studies are needed to confirm the comparative usefulness of caffeine. Response 3: Thanks for your valuable comments. It's a great help for us to have your suggestions. Through consideration and literature review, we modified the problem in the revised manuscript: Liu[42] has shown that caffeine may have a direct long-term neuroprotective effect on the developing brain. Mürner-Lavanchy et al[43] also reported that caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine. In order to truly prove the safety of caffeine citrate, more long-term follow-up studies are necessary.(Page10 line274) Thank you very much for your affirmation and suggestions on this article. We hope the revised version will make you even more satisfied. If there is anything that needs to be modified, please do not hesitate to point it out. We are more than happy to make any further changes that improve the article. Sincerely, The Authors Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0274882.r002
7 Sep 2022 Decision Letter - Hasan Tolga Celik, Editor Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis PONE-D-22-17592R1 Dear Dr. Aihua Wang 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, Hasan Tolga Celik, M.D. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0274882.r003
Formally Accepted
9 Sep 2022 Acceptance Letter - Hasan Tolga Celik, Editor PONE-D-22-17592R1 Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis Dear Dr. Wang: 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. Hasan Tolga Celik Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0274882.r004

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