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Date: Jul 08, 2022 To: "Martha Ruzic"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1143
RE: Manuscript Number ONG-22-1143
Adoption of Adjunctive Azithromycin Prophylaxis for Pre-labor Cesarean Births Dear Dr. Ruzic:
Thank you for sending us your work for consideration for publication in Obstetrics & Gynecology. Your manuscript has been reviewed by the Editorial Board and by special expert referees. The Editors would like to invite you to submit a revised version for further consideration.
If you wish to revise your manuscript, please read the following comments submitted by the reviewers and Editors. Each point raised requires a response, by either revising your manuscript or making a clear argument as to why no revision is needed in the cover letter.
To facilitate our review, we prefer that the cover letter you submit with your revised manuscript include each reviewer and Editor comment below, followed by your response. That is, a point-by-point response is required to each of the EDITOR COMMENTS (if applicable), REVIEWER COMMENTS, STATISTICAL EDITOR COMMENTS (if applicable), and EDITORIAL OFFICE COMMENTS below. Your manuscript will be returned to you if a point-by-point response to each of these sections is not included.
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EDITOR COMMENTS: Please put actual rates in Abstract.
REVIEWER COMMENTS:
Reviewer #1: ONG 22-1143
In the manuscript under review, we evaluate the results of a retrospective analysis evaluating postoperative infections before and after implementation of adjunctive azithromycin. Using data from over 2800 patients, the authors conclude that adjunctive azithromycin for pre-labor cesareans was associated with lower odds of postpartum infections.
A few comments on the manuscript are as follows:
ABSTRACT
1. No major issues identified.
INTRODUCTION
2. A strong argument is made for this analysis.
METHODS
3. Line 112 - How was the study timeline chosen?
4. Line 185-186 what was the expected rate of change the authors were expecting to find? In other words, was a sample size calculated?
RESULTS
5. There is a concern that the logistic regression has over adjusted for potential confounders given the overall rate of
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the outcomes of interest.
6. How were all other changes made to SSI prevention (change to skin prep, time spent on skin prep, etc) incorporated into this analysis? Could the difference in rates represent the effect of these changes rather than then antibiotics used?
DISCUSSION
7. Line 310 - why is supplementary table 2 included in this manuscript? This entire paragraph is focusing on results from the C/SOAP trial and do not appear to be as relevant to the discussion of the results of this analysis.
8. Without a sample size calculation, I would add the possibility of type I error as a limitation.
Reviewer #2: This is a retrospective cohort study of patients admitted to a tertiary center for pre-labor cesarean birth with analysis of pre- and post-implementation of adjunctive azithromycin surgical prophylaxis. Thank you for undertaking this important topic.
Introduction
1. Line 96, you reference an economic analysis of the impact of azithromycin in scheduled cesarean deliveries, and you note that use of adjunctive azithromycin in pre-labor cesarean births is understudied. Can you provide additional
information on what prior studies have shown? What are their limitations? Why is your study necessary, and how do you address prior study limitations?
Methods
1. Line 131 - your institutional management of PPROM includes ampicillin and amoxicillin with azithromycin orally on days 1 and 5. I am familiar with a PPROM antibiotic regimen that includes a single dose of azithromycin orally on day 1.
Please provide a reference for the protocol used at your institution.
2. Sample size - I do not see a discussion on how you determined your study period or your sample size. With the number of patients you included, what difference in infection rates would you be able to detect?
3. Line 139-143 - do you have information on compliance with the new protocol? Did it change over time?
4. Perhaps consider plotting your data on a run chart (p-chart) showing changes in your outcome (infection rates over time. You should see a decrease in infection rates with the implementation of your new protocol. You can also document when other interventions or changes occurred such as the change in surgical preparation during your study period.
5. Line 147 - You note that antibiotics are given before skin incision or as soon as possible after. Do you have information on how often they are administered prior to cesarean (this is important and could affect your primary study outcome).
6. Do you have a reference for the surgical preparation used prior to January 2016 (Line 155)?
7. Do you have a reference for the surgical/vaginal preparation used after January 2016?
8. How compliant are providers and staff with the recommended surgical preparations?
9. Skin closure was based on surgeon preference (line 179) - do you have information on how frequently staples vs.
suture is used?
Discussion
1. Line 298 - You discuss the C/SOAP trial. Compared to the data presented in table 4, the C/SOAP trial appears to have had a higher wound infection (6.6%) and higher endometritis rate (6.1%) than you had at baseline (3.4% wound infection and 0.2% endometritis). Perhaps this higher apriori risk in labored patient is affecting their results. Also the lower infection rate in your population means a larger sample size is necessary to detect a difference.
2. Line 320 you discuss why your study may have had less of an effect than C/SOAP and I would add the lower apriori risk of infection to this as well.
3. Line 334 - you mention that your study was better powered than Pierce et. al. What was your power?
4. Line 337, you call for a prospective study. Would this be for all cesarean deliveries or a trial for non-labored cesareans only? Would such a trial be feasible with the known apriori cesarean infection rates for wither all cesarean deliveries or for non-labored cesareans?
5. Line 343-344, you state that there was no variation in surgical technique or intraoperative management, but you don't have information on types of skin closures used over this 5-year period. Also your abdominal/vaginal prep changed at the same time as you implemented the azithromycin (you say this in line 365), so I don't think you can say this.
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6. Line 354 - I agree, this is an issue. Is there any way to get additional information about compliance?
7. Overall this seems more like a quality improvement protocol, where you are doing a bundle of evidence-based interventions to improve patient care at your institution, and I think including information about the changes in outcomes over time in a p-chart and compliance with the bundle would be helpful in presenting the data
8. Line 385 - I think you have to note that you had lower odds of post-cesarean delivery infections with the addition of adjunctive azithromycin to standard antibiotics and changes in surgical preparation to chlorhexidine-alcohol and addition of a vaginal preparation for high-risk patients.
Table 2: For several of the components of the composite primary outcome (endometritis, deep wound infection, intra abd abscess, UTI), the counts are few, there is low power to discern a difference and the aORs are likely over fitted, due to the small counts. Suggest highlighting or emboldening the aORs that were statistically significant to distinguish them from the others for the reader. Again, several of the secondary outcomes have over fitted aORs and several had low power to discern any difference in outcome rates.
Table 3: BE < 12, pH < 7.0 and neonatal death each were underpowered and lacked sufficient counts to allow for multivariable adjustment with 8 variables. Those aORs are likely over fitted.
Table 4, Supplemental Tables 1, 2: Same issues as with Table 2 re: power and over fitting the aOR model.
General: Given the multiple factors that differed at baseline, should corroborate the multivariable analysis with matching algorithm for the primary maternal and neonatal outcomes.
Editor: Please put actual rates in Abstract.
STATISTICAL EDITOR COMMENTS:
Table 2: For several of the components of the composite primary outcome (endometritis, deep wound infection, intra abd abscess, UTI), the counts are few, there is low power to discern a difference and the aORs are likely over fitted, due to the small counts. Suggest highlighting or emboldening the aORs that were statistically significant to distinguish them from the others for the reader. Again, several of the secondary outcomes have over fitted aORs and several had low power to discern any difference in outcome rates.
Table 3: BE < 12, pH < 7.0 and neonatal death each were underpowered and lacked sufficient counts to allow for multivariable adjustment with 8 variables. Those aORs are likely over fitted.
Table 4, Supplemental Tables 1, 2: Same issues as with Table 2 re: power and over fitting the aOR model.
General: Given the multiple factors that differed at baseline, should corroborate the multivariable analysis with matching algorithm for the primary maternal and neonatal outcomes.
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author has given approval to the final form of the revision.
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UABMEDICINE
OBSTETRICS & GYNECOLOGY
August 22, 2022
Jason D. Wright, MD, Editor-in-Chief Obstetrics and Gynecology
Dear Dr. Wright,
Attached along with this cover letter is the electronic version of our revised original research paper titled, “Adoption of Adjunctive Azithromycin Prophylaxis for Pre-labor Cesarean Births”
for your consideration for publication in Obstetrics and Gynecology.
In June 2022, we submitted the above manuscript and were invited to submit a revised version for further consideration. We have spent the last several weeks diligently reviewing and
addressing the issues brought to light in the reviewers comments. You will see our point-by-point responses below. We would like to thank you for the opportunity to improve our research paper and we appreciate your consideration of our revised manuscript.
This study was approved by the IRB in December 2018, and the IRB approval (# 300002492 ) was
maintained and valid throughout the course of this study. In addition, this paper was presented
virtually as a poster presentation at the 41
thAnnual Meeting of the Society for Maternal-Fetal
Medicine.
All co-authors contributed to the design and implementation of this study and assisted in revision of drafts of the manuscript. I, Martha Ruzic, have reviewed and edited the submission to omit any identifying information. I hereby submit this self-blinded manuscript for consideration in Obstetrics and Gynecology. I state full primary authorship of the attached document and ethical adherence in my work. This manuscript is an honest, accurate, and transparent account of the study being reported without important aspects omitted. The authors of this manuscript have no conflicts of interest to relate. This manuscript is solely submitted to this journal.
Thank you in advance for your consideration of this revised manuscript for publication.
Sincerely,
Martha F. Ruzic, MD
Maternal-Fetal Medicine Women & Infants Center 1700 6th Avenue South
The University of Alabama at Birmingham Mailing Address:
176F Suite 1 0270 619 19TH ST S
BIRMINGHAM, AL 35294
EDITOR COMMENTS:
Please put actual rates in Abstract.
RESPONSE: Thank you. We have added the outcome rates to the Abstract (edited lines 38-53).
REVIEWER COMMENTS:
Reviewer #1: In the manuscript under review, we evaluate the results of a retrospective analysis evaluating postoperative infections before and after implementation of adjunctive azithromycin.
Using data from over 2800 patients, the authors conclude that adjunctive azithromycin for pre- labor cesareans was associated with lower odds of postpartum infections.
A few comments on the manuscript are as follows:
ABSTRACT
1. No major issues identified.
INTRODUCTION
2. A strong argument is made for this analysis.
METHODS
3. Line 112 - How was the study timeline chosen?
RESPONSE: Thank you for pointing out the need to include this relevant information. A large obstetrical database of all deliveries occurring at our institution from 2013 to 2018 was created for multiple obstetric studies by those listed under authors and a previous study from the database was published by Lu et al.
This was added to the Methods section (edited lines 134-135 and citation added). Additionally, the timeline of 2013 to 2018 ensures approximately equal time frames before and after our institutional protocol change regarding prophylactic antibiotics (edited lines 175-176).
4. Line 185-186 what was the expected rate of change the authors were expecting to find? In other words, was a sample size calculated?
RESPONSE: Thank you for this question. We did not calculate an a priori sample size for this retrospective analysis, as our sample size was fixed given our 6 year, previously described, database.
However, post hoc analysis using the baseline event rate in the C/SOAP trial found that a sample size of over 1300 per group provided an 80% power to detect a reduction of 12% to 8.7% (OR=0.69) from the pre-AZI to post-AZI period. We do note that our observed event rates were much lower than in the C/SOAP trial; however, our sample size still provided >80% power to detect rate reductions from 4.8% to as low as 2.7% (OR = 0.55) in the post-AZI period. Thus, we had sufficient power to detect large
differences between time periods. This was added to the Discussion (edited lines 423-434).
RESULTS
5. There is a concern that the logistic regression has over adjusted for potential confounders given the overall rate of the outcomes of interest.
RESPONSE: Thank you for this concern. Prior to data gathering for our study, the model variables were chosen. Given this, we understand that over-fitting may have occurred, and this does represent a
limitation of our study. We present unadjusted and adjusted odds ratios for the reader, in order that they
see both. However, the primary outcome of composite infection was significant in adjusted and
unadjusted analysis, suggesting the importance of this outcome regardless of overfitting or not. Further, we do not present results where the multivariate model did not converge, meaning where there was the potential for obvious over-fitting, we did not present them given that risk. Additionally, when the models were generated, we removed the covariates that had CI of 0-9999 in order that the final models are appropriate. Therefore, we have added this to the Limitations section (edited lines 457-461), and is also noted in the footnotes for Tables 2, 3, and 4 the models with fewer covariates included in order to get useful results.
6. How were all other changes made to SSI prevention (change to skin prep, time spent on skin prep, etc) incorporated into this analysis? Could the difference in rates represent the effect of these changes rather than then antibiotics used?
RESPONSE: Thank you for this comment. The changes that were made in surgical site infection prevention were not incorporated into our analysis, as they have not necessarily been shown to decrease infectious rates in our population. It is possible that these changes contributed to our primary outcome, and we recognize this as a limitation of our study in edited lines 448-450. Furthermore, we now include an evaluation of the interaction of the effect of year and the primary outcome. The interactive effect was non-significant (p=0.239), which indicates a similar effect of groups on outcomes regardless of year. This lack of effect modification by year may support the suggestion that other small changes which were unaccounted for likely do not explain our findings (Lines 439-440).
DISCUSSION
7. Line 310 - why is supplementary table 2 included in this manuscript? This entire paragraph is focusing on results from the C/SOAP trial and do not appear to be as relevant to the discussion of the results of this analysis.
RESPONSE: This comment is helpful, thank you. We included this table to show that there was a significant reduction in infectious morbidity in laboring cesareans with the addition of azithromycin which supports the Level 1 evidence from the C/SOAP randomized controlled trial when used in routine practice. If it is preferable to remove this, we certainly can but felt it was important to address as our institution put into place the antibiotic protocol changes across all cesareans.
8. Without a sample size calculation, I would add the possibility of type I error as a limitation.
RESPONSE: Yes, thank you for this suggestion. Post hoc analyses using our event rate in our cohort noted that our sample size still provided an 80% power to detect a rate reduction from 4.8% in the pre- AZI period to a rate as low as 2.7% in the post-AZI period (OR=0.55). Per discussion with our
statisticians, while our observed effect size was smaller than this, it was statistically significant, and the observed difference is clinically reasonable. We added this to our limitations section on edited lines 430- 434.
Reviewer #2: This is a retrospective cohort study of patients admitted to a tertiary center for pre- labor cesarean birth with analysis of pre- and post-implementation of adjunctive azithromycin surgical prophylaxis. Thank you for undertaking this important topic.
Introduction
1. Line 96, you reference an economic analysis of the impact of azithromycin in scheduled
cesarean deliveries, and you note that use of adjunctive azithromycin in pre-labor cesarean births is
understudied. Can you provide additional information on what prior studies have shown? What
are their limitations? Why is your study necessary, and how do you address prior study limitations?
RESPONSE: Thank you for this comment. There is only one other study to our knowledge (Pierce et al) which showed no benefit of universal adoption of adjunctive azithromycin. However this study
contradicts the level 1 evidence provided by the C/SOAP trial. We have added a sentence in the introduction (edited lines 124-125 and citation added) addressing this information, and we also discuss that analysis this in more detail later in our Discussion.
Methods
1. Line 131 - your institutional management of PPROM includes ampicillin and amoxicillin with azithromycin orally on days 1 and 5. I am familiar with a PPROM antibiotic regimen that includes a single dose of azithromycin orally on day 1. Please provide a reference for the protocol used at your institution.
RESPONSE: Thank you for this comment. The ACOG practice bulletin “Prelabor Rupture of
Membranes” recommends use of latency antibiotics for patients with PPROM including ampicillin IV 2g every 6 hours and erythromycin IV 250mg every 6 hours for 48 hours, followed by oral amoxicillin 250mg every 8 hours and oral erythromycin 333mg every 8 hours for a total of 7 days. They also suggest that some centers have replaced the use of erythromycin with azithromycin when erythromycin is not available or tolerated. Many institutions use varying protocols for their latency antibiotic management of PPROM. It has been our institutional protocol for > 10 years however to provide a second dose of azithromycin on day 5. We have added to the Methods section a description of our institutional protocol, the choice for azithromycin over erythromycin, and added the citation of the above ACOG practice bulletin (edited lines 166-167). Furthermore, the number of patients with PPROM was balanced between the pre-AZI and post-AZI groups, so we do not anticipate that that would materially alter our results. We also performed a sensitivity analysis excluding patients with PPROM and noted no significant change in our primary outcome (described in edited lines 330-332).
2. Sample size - I do not see a discussion on how you determined your study period or your sample size. With the number of patients you included, what difference in infection rates would you be able to detect?
RESPONSE: Please see responses above regarding ascertainment of study period and sample size calculations as discussed in the responses to Reviewer 1.
3. Line 139-143 - do you have information on compliance with the new protocol? Did it change over time?
RESPONSE: Thank you for this comment. Unfortunately, we do not have information regarding the compliance of this protocol per se. It is important to note that this new protocol was instituted as an
“order-set” in our electronic medical record as a pre-checked order to be given to all patients undergoing cesarean. However, we do know that >95% of patients in the post-AZI group received azithromycin which suggests excellent compliance with this protocol, and this was added to the Discussion (edited line 439). Additionally, we also included a washout period 10-12/2015 in order to account for this between the pre-AZI and post-AZI time periods.
4. Perhaps consider plotting your data on a run chart (p-chart) showing changes in your outcome (infection rates over time). You should see a decrease in infection rates with the
implementation of your new protocol. You can also document when other interventions or changes
occurred such as the change in surgical preparation during your study period.
RESPONSE: Thank you for this suggestion. Run charts are typical of quality improvement (QI) studies.
QI protocols evaluate the implementation of a practice or protocol which has been shown to be effective or beneficial. In our analysis, we are testing the efficacy of an intervention that has not yet been shown to be effective in our population of pre-labor cesarean, and therefore our analysis is not that of QI, and a run- chart would be inappropriate. Further, our orderset as described above was changed with resultant >95%
compliance. To affirm our findings, we performed an interaction analysis by year on the primary outcome, and found a p-value of 0.239, meaning that year was not a significant impact term. This was added to the discussion (edited lines 439-440).
5. Line 147 - You note that antibiotics are given before skin incision or as soon as possible after. Do you have information on how often they are administered prior to cesarean (this is important and could affect your primary study outcome).
RESPONSE: Thank you for this question. Given that we were studying pre-labor (nonemergent) cesareans, it is exceedingly unlikely that patients received antibiotics following skin incision. We added information about how the antibiotics are administered – the cefazolin is given in the preoperative holding area however the azithromycin is given in the OR as it requires a pump (edited lines 187-190). However, we unfortunately do not have exact detail regarding timing of antibiotic administration and incision in our cases. However, these antibiotics are nearly always confirmed by anesthesia during the time out that they are infusing.
6. Do you have a reference for the surgical preparation used prior to January 2016 (Line 155)?
RESPONSE: Yes, and thank you for pointing out that we were lacking a reference here. The reference has been added (edited lines 197 and 214, reference source #24).
7. Do you have a reference for the surgical/vaginal preparation used after January 2016?
RESPONSE: Yes, thank you for this question. That information is provided in edited citation number 24, which has been recited again as above (edited line 223, reference source #24)
8. How compliant are providers and staff with the recommended surgical preparations?
RESPONSE: This is an important question, however this was beyond the scope of our study. This being said, our surgical preparation for cesarean deliveries is standardized for all patients, regardless of provider. Therefore, we would expect very high compliance. Given this, no changes have been made.
9. Skin closure was based on surgeon preference (line 179) - do you have information on how frequently staples vs. suture is used?
RESPONSE: Thank you for pointing out this information for us to add. Using historical data from our institution from 2013-2018, >95% of incisions were Pfannenstiel and <5% were midline vertical. This was added to the Methods section (edited line 225). All Pfannenstiel incisions are closed with suture unless there is an operative emergency or hemodynamically instable patient, which is rare. With regards to midline vertical incisions, these are most often closed with staples but is ultimately up to surgeon preference.
Discussion
1. Line 298 - You discuss the C/SOAP trial. Compared to the data presented in table 4, the
C/SOAP trial appears to have had a higher wound infection (6.6%) and higher endometritis rate
(6.1%) than you had at baseline (3.4% wound infection and 0.2% endometritis). Perhaps this higher a priori risk in labored patient is affecting their results. Also the lower infection rate in your population means a larger sample size is necessary to detect a difference.
RESPONSE: Yes, we agree that our lower baseline rate of composite infectious outcome, wound infection and endometritis are likely related to the difference in laboring versus pre-labor cesarean, that being that laboring cesarean is associated with higher infectious morbidity than pre-labor cesarean. Thank you for this statement. While the C/SOAP trial had a relative risk of 0.51, our analysis demonstrated an adjusted OR of 0.60 with use of adjunctive azithromycin. We have reiterated this in our Discussion as well (edited lines 375-381). The power calculations are discussed as above.
2. Line 320 you discuss why your study may have had less of an effect than C/SOAP and I would add the lower apriori risk of infection to this as well.
RESPONSE: Please see responses above regarding a priori risk of infection in laboring vs pre-labor patients. This has been expanded upon in the Discussion.
3. Line 334 - you mention that your study was better powered than Pierce et. al. What was your power?
RESPONSE: Thank you for your comment. We had a larger sample size in our cohort, and we have revised the wording of that section accordingly. We have described the power calculations in the above responses.
4. Line 337, you call for a prospective study. Would this be for all cesarean deliveries or a trial for non-labored cesareans only? Would such a trial be feasible with the known apriori cesarean infection rates for wither all cesarean deliveries or for non-labored cesareans?
RESPONSE: Yes, we feel as if a trial for non-labored or pre-labor cesareans is warranted given there is already level I evidence (C/SOAP) for labored cesareans. This has been clarified in the manuscript (edited line 409).
5. Line 343-344, you state that there was no variation in surgical technique or intraoperative management, but you don’t have information on types of skin closures used over this 5-year period. Also your abdominal/vaginal prep changed at the same time as you implemented the azithromycin (you say this in line 365), so I don’t think you can say this.
RESPONSE: Yes, thank you and we do understand this concern. We have added in data regarding skin closure (>95% Pfannenstiel and <5% midline vertical, edited line 225) at our institution from 2013-2018, and this did not measurably change over the study timeframe. While there were changes in skin
preparation, we do not feel as if there were changes in surgical technique or intraoperative management (i.e., skin closure).
6. Line 354 - I agree, this is an issue. Is there any way to get additional information about compliance?
RESPONSE: 4.59% (149 out of 3247) patients in the post-AZI group did not receive azithromycin. This is described in the Discussion line 439. This small fraction of the patients is unlikely to have any
demonstratable effect on our sample size and results. Please see above response regarding protocol
compliance with respect to Reviewer #1.
7. Overall this seems more like a quality improvement protocol, where you are doing a bundle of evidence-based interventions to improve patient care at your institution, and I think including information about the changes in outcomes over time in a p-chart and compliance with the bundle would be helpful in presenting the data
RESPONSE: Thank you for this concern. We do however feel as if this is not a quality improvement (QI) protocol and instead a true research analysis. QI protocols typically evaluate the implementation of a practice or protocol which has already been shown to be effective or beneficial. We are testing the
efficacy of an intervention that has not yet been clearly shown to be effective (adjunctive azithromycin) in our population of pre-labor cesarean. An interaction analysis by year was performed and a p-value of 0.239 was found, meaning there was not a significant impact of year on the primary outcome.
8. Line 385 - I think you have to note that you had lower odds of post-cesarean delivery infections with the addition of adjunctive azithromycin to standard antibiotics and changes in surgical preparation to chlorhexidine-alcohol and addition of a vaginal preparation for high-risk patients.
RESPONSE: Yes, thank you for this comment. We address in our limitations that there were also changes to the skin and vaginal preparation that may have contributed to this outcome, however per the above, year was not a significant term in effect modification on the primary outcome.
STATISTICAL EDITOR COMMENTS:
Table 2: For several of the components of the composite primary outcome (endometritis, deep wound infection, intra abd abscess, UTI), the counts are few, there is low power to discern a difference and the aORs are likely over fitted, due to the small counts. Suggest highlighting or emboldening the aORs that were statistically significant to distinguish them from the others for the reader. Again, several of the secondary outcomes have over fitted aORs and several had low power to discern any difference in outcome rates.
RESPONSE: Thank you. We have bolded the significant aOR which are significant in Table 2. With respect to the possibility of over-fitting, we have also presented unadjusted odds ratios, and the primary outcome of composite infection was significant in adjusted and unadjusted analysis. We do not present results where the multivariate model did not converge, meaning where there was the potential for obvious over-fitting, we did not present them given that risk. Additionally, when the models are generated, we removed the covariates that had CI of 0-9999 to that the final models are appropriately (described in Discussion edited lines 457-461). Therefore, we have noted in the footnotes for Table 2 the models with fewer covariates included in order to get useful results.
Table 3: BE < 12, pH < 7.0 and neonatal death each were underpowered and lacked sufficient counts to allow for multivariable adjustment with 8 variables. Those aORs are likely over fitted.
RESPONSE: Thank you for this comment. Similar to the above, we added footnotes to Table 3 regarding the covariates used in each model.
Table 4, Supplemental Tables 1, 2: Same issues as with Table 2 re: power and over fitting the aOR model.
RESPONSE: Thank you for this comment. Please see above.
General: Given the multiple factors that differed at baseline, should corroborate the multivariable analysis with matching algorithm for the primary maternal and neonatal outcomes.
RESPONSE: Thank you for this concern. We did perform multivariable analysis adjusting for covariates that differed significantly between groups in this retrospective analysis, but did not perform a matching algorithm or propensity score type analysis that may address some imbalances between study periods. All of these designs, including the one we present, aim to reduce the potential of confounding. However, no method is perfect – as each has its limitations. While propensity scores may account for some of the potential differences between our groups a priori, they do have their limitations and cannot take into account unmeasured confounding, similar case with matching. The aims of these alternate analyses is to mimic a randomized control trial, but all have their limitations. Based on the strength of our data, we believe that the next step is an RCT as described in our conclusions. As all of these retrospective methods, regardless of what we choose, will fall short, we did not adjust our analytic methods to account for
matching or propensity scores.
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1. If your article is accepted, the journal will publish a copy of this revision letter and your point- by-point responses as supplemental digital content to the published article online. You may opt out by writing separately to the Editorial Office at [email protected], and only the revision letter will be posted.
RESPONSE: Thank you.
2. When you submit your revised manuscript, please make the following edits to ensure your submission contains the required information that was previously omitted for the initial double- blind peer review:
* Funding information (ie, grant numbers or industry support statements) should be disclosed on the title page and at the end of the abstract. For industry-sponsored studies, describe on the title page how the funder was or was not involved in the study.
* Include clinical trial registration numbers, PROSPERO registration numbers, or URLs at the end of the abstract (if applicable).
* Name the IRB or Ethics Committee institution in the Methods section (if applicable).
* Add any information about the specific location of the study (ie, city, state, or country), if necessary for context.
RESPONSE: Thank you. This study was not funded by a grant, nor was it a clinical trial. IRB cited on line 139.
3. Obstetrics & Gynecology's Copyright Transfer Agreement (CTA) must be completed by all authors. When you uploaded your manuscript, each coauthor received an email with the subject,
"Please verify your authorship for a submission to Obstetrics & Gynecology." Please ask your coauthor(s) to complete this form, and confirm the disclosures listed in their CTA are included on the manuscript's title page. If they did not receive the email, they should check their spam/junk folder. Requests to resend the CTA may be sent to [email protected].
RESPONSE: Yes, the above was completed.
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explanation in the manuscript of who classified individuals' race, ethnicity, or both, the
classifications used, and whether the options were defined by the investigator or the participant. In addition, describe the reasons that race and ethnicity were assessed in the Methods section and/or in table footnotes. Race and ethnicity must have been collected in a formal or validated way. If it was not, it should be omitted. Authors must enumerate all missing data regarding race and
ethnicity as in some cases missing data may comprise a high enough proportion that it compromises statistical precision and bias of analyses by race.
Use "Black" and "White" (capitalized) when used to refer to racial categories.
List racial and ethnic categories in tables in alphabetic order. Do not use "Other" as a category;
use "None of the above" instead.
Please refer to "Reporting Race and Ethnicity in Obstetrics & Gynecology"
at https://edmgr.ovid.com/ong/accounts/Race and Ethnicity.pdf.
RESPONSE: Thank you and changes have been made. Racial categories are listed to describe maternal demographics. White and Black are capitalized. “Other” has been removed and replaced with “None of the above.”
5. ACOG uses person-first language. Please review your submission to make sure to center the person before anything else. Examples include: "People with disabilities" or "women with disabilities" instead of "disabled people" or "disabled women"; "patients with HIV" or "women with HIV" instead of "HIV-positive patients" or "HIV-positive women"; and "people who are blind" or "women who are blind" instead of "blind people" or "blind women."
RESPONSE: Thank you. This verbiage is used throughout.
6. The journal follows ACOG's Statement of Policy on Inclusive Language
(https://www.acog.org/clinical-information/policy-and-position-statements/statements-of-
policy/2022/inclusive-language). When possible, please avoid using gendered descriptors in your manuscript. Instead of "women" and "females," consider using the following: "individuals;"
"patients;" "participants;" "people" (not "persons"); "women and transgender men;" "women and gender-expansive patients;" or "women and all those seeking gynecologic care."
RESPONSE: Yes, thank you. This has been adjusted and “patients” is used throughout.
7. Standard obstetric and gynecology data definitions have been developed through the reVITALize initiative, which was convened by the American College of Obstetricians and Gynecologists and the members of the Women's Health Registry Alliance. Obstetrics & Gynecology has adopted the use of the reVITALize definitions. Please access the obstetric data definitions
at https://www.acog.org/practice-management/health-it-and-clinical-informatics/revitalize- obstetrics-data-definitions and the gynecology data definitions at https://www.acog.org/practice- management/health-it-and-clinical-informatics/revitalize-gynecology-data-definitions. If use of the reVITALize definitions is problematic, please discuss this in your point-by-point response to this letter.
RESPONSE: Yes, thank you. The reVITALize definition of cesarean birth in congruent with ours.
8. Make sure your manuscript meets the following word limit. The word limit includes the
manuscript body text only (for example, the Introduction through the Discussion in Original
Research manuscripts), and excludes the title page, précis, abstract, tables, boxes, and figure
legends, reference list, and supplemental digital content. Figures are not included in the word count.
Original Research: 3,000 words
RESPONSE: We do understand this word limit, however, extensive revisions and additional information has been provided in the manuscript in response to the Reviewer Comments. Due to this, our manuscript is over the word limit. If there are sections which the Reviewers feel should be shorter, we can certainly make these adjustments.
9. Specific rules govern the use of acknowledgments in the journal. Please review the following guidelines and edit your title page as needed:
* All financial support of the study must be acknowledged.
* Any and all manuscript preparation assistance, including but not limited to topic development, data collection, analysis, writing, or editorial assistance, must be disclosed in the acknowledgments.
Such acknowledgments must identify the entities that provided and paid for this assistance, whether directly or indirectly.
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* If all or part of the paper was presented at the Annual Clinical and Scientific Meeting of the American College of Obstetricians and Gynecologists or at any other organizational meeting, that presentation should be noted (include the exact dates and location of the meeting or indicate whether the meeting was held virtually).
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* Do not use only authors' initials in the acknowledgement or Financial Disclosure; spell out their names the way they appear in the byline.
RESPONSE: Thank you. We have abided by the above guidelines.
10. Be sure that each statement and any data in the abstract are also stated in the body of your manuscript, tables, or figures. Statements and data that appear in the abstract must also appear in the body text for consistency. Make sure there are no inconsistencies between the abstract and the manuscript, and that the abstract has a clear conclusion statement based on the results found in the manuscript.
In addition, the abstract length should follow journal guidelines. Please provide a word count.
Original Research: 300 words
RESPONSE: Abstract word count is 332. As mentioned previously, statistics were added to the abstract per Reviewer request, which did somewhat lengthen the abstract.
11. Only standard abbreviations and acronyms are allowed. A selected list is available online
at http://edmgr.ovid.com/ong/accounts/abbreviations.pdf. Abbreviations and acronyms cannot be
used in the title or précis. Abbreviations and acronyms must be spelled out the first time they are used in the abstract and again in the body of the manuscript.
RESPONSE: Thank you. Abbreviations are first spelt out prior to being used.
12. The journal does not use the virgule symbol (/) in sentences with words, except with ratios.
Please rephrase your text to avoid using "and/or," or similar constructions throughout the text.
You may retain this symbol if you are using it to express data or a measurement.
RESPONSE: The symbol “/” is only used when discussing the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial as this is how the trial is referred to in the original research study.
13. ACOG avoids using "provider." Please replace "provider" throughout your paper with either a specific term that defines the group to which are referring (for example, "physicians," "nurses,"
etc.), or use "health care professional" if a specific term is not applicable.
RESPONSE: The term “Health care provider” was used once, however we have now replaced this with
“health care professional”. Thank you.
14. In your abstract, manuscript Results sections, and tables, the preferred citation should be in terms of an effect size, such as odds ratio or relative risk or the mean difference of a variable between two groups, expressed with appropriate confidence intervals. When such syntax is used, the P value has only secondary importance and often can be omitted or noted as footnotes in a Table format. Putting the results in the form of an effect size makes the result of the statistical test more clinically relevant and gives better context than citing P values alone.
Please standardize the presentation of your data throughout the manuscript submission. For P values, do not exceed three decimal places (for example, "P = .001").
Express all percentages to one decimal place (for example, 11.1%"). Do not use whole numbers for percentages.
RESPONSE: Adjusted odds ratios are used in the abstract with confidence intervals. When presenting percentages or confidence intervals, we have used the above guidelines.
15. Please review the journal's Table Checklist to make sure that your tables conform to journal style. The Table Checklist is available at http://edmgr.ovid.com/ong/accounts/table checklist.pdf.
RESPONSE: Thank you. We feel as if our tables conform to journal style.
16. Please review examples of our current reference style
at https://edmgr.ovid.com/ong/accounts/ifa suppl refstyle.pdf. Include the digital object identifier (DOI) with any journal article references and an accessed date with website references.
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"Clinical Guidance" at the top). If the reference is still available on the site and isn't listed as
"Withdrawn," it's still a current document. In most cases, if an ACOG document has been withdrawn, it should not be referenced in your manuscript.
Please make sure your references are numbered in order of appearance in the text.
RESPONSE: Thank you. We feel as if our reference style is in concordance with the journal style.
17. Figure 1: Please check or explain n values (cesarean births less exclusions does not equal live births, live births less exclusions does not equal delivery in study period). Please upload as a figure file on Editorial Manager.
RESPONSE: We apologize for this error. This has been corrected.
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RESPONSE: Yes, thank you.
Date: Aug 31, 2022
To: "Martha Ruzic" [email protected] From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1143R1
RE: Manuscript Number ONG-22-1143R1
Adoption of Adjunctive Azithromycin Prophylaxis for Pre-labor Cesarean Births Dear Dr. Ruzic:
As requested initially by our Statistical Editor, we would like you to include propensity score matching (or some other matching algorithm of your choice).
That is not to say that it would be superior to multivariable regression or that it is flawless method. But it is an alternative method which, if the findings are similar, would strengthen your paper by addressing the multiple baseline differences.
If the findings were essentially the same, then you could put most of the new material in supplemental and concisely summarize it in main text.
Please return the version of the manuscript that you received by email and include your edits using track changes. Also, please respond to the queries in the manuscript.
Sincerely,
The Editors of Obstetrics & Gynecology
***
If you choose to revise your manuscript, please submit your revision through Editorial Manager at
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Again, your manuscript will be maintained in active status for 21 days from the date of this letter. If we have not heard from you by Oct 05, 2022, we will assume you wish to withdraw the manuscript from further consideration.
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The Editors of Obstetrics & Gynecology
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View Letter https://www.editorialmanager.com/ong/ViewLetter.aspx?id=1051458&l...
1 of 1 10/11/2022, 12:21 PM
UABMEDICINE
OBSTETRICS & GYNECOLOGY
October 5, 2022
Jason D. Wright, MD, Editor-in-Chief Obstetrics and Gynecology
Dear Dr. Wright,
Attached along with this cover letter is the electronic version of our revised original research paper titled, “Adoption of Adjunctive Azithromycin Prophylaxis for Pre-labor Cesarean Births”
for your consideration for publication in Obstetrics and Gynecology.
In August 2022, we submitted the above manuscript and were asked to perform additional analyses including propensity score matching. Along with our manuscript, you will find an supplemental table with this new data.
This study was approved by the IRB in December 2018, and the IRB approval (# 300002492 ) was maintained and valid throughout the course of this study. In addition, this paper was presented virtually as a poster presentation at the 41
thAnnual Meeting of the Society for Maternal-Fetal Medicine.
All co-authors contributed to the design and implementation of this study and assisted in revision
of drafts of the manuscript. I, Martha Ruzic, have reviewed and edited the submission to omit
any identifying information. I hereby submit this self-blinded manuscript for consideration in Obstetrics and Gynecology. I state full primary authorship of the attached document and ethical adherence in my work. This manuscript is an honest, accurate, and transparent account of the study being reported without important aspects omitted. The authors of this manuscript have no conflicts of interest to relate. This manuscript is solely submitted to this journal.
Thank you in advance for your consideration of this revised manuscript for publication.
Sincerely,
Martha F. Ruzic, MD
Maternal-Fetal Medicine Women & Infants Center 1700 6th Avenue South
The University of Alabama at Birmingham Mailing Address:
176F Suite 1 0270 619 19TH ST S BIRMINGHAM, AL 352
