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Date: Oct 03, 2022 To: "Jason D. Wright"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1496
RE: Manuscript Number ONG-22-1496
Utilization of Conservative Therapies Prior to Hysterectomy for Uterine Leiomyoma Dear Dr. Wright:
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, and STATISTICAL EDITOR COMMENTS (if applicable) below.
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Your submission will be maintained in active status for 21 days from the date of this letter. If we have not heard from you by Oct 24, 2022, we will assume you wish to withdraw the manuscript from further consideration.
EDITOR COMMENTS:
Please note the following:
* Since only 2 years were assessed before hyst and a significant number of interventions could have taken place prior to that, would be preferable to de-emphasize some of the data interpretation. For example, "Conservative medical and surgical therapies MAY BE underutilized in women with uterine leiomyoma who undergo hysterectomy". Please define MSA in the text/Table 1. Also, please clarify what is meant by the term 'Pregnancy' in the accompanying Table 1. It is unclear how broadly applicable the findings are, in terms of limitations/Discussion when acknowledging that >half of pts in this database were from a single geographic location - is this a database issue, or did you stratify by race/ethnicity?
* Help us reduce the number of queries we add to your manuscript after it is revised by reading the Revision Checklist at https://journals.lww.com/greenjournal/Documents/RevisionChecklist_Authors.pdf and making the applicable edits to your manuscript.
REVIEWER COMMENTS:
Reviewer #1:
Main points
1. It would help set the state in the intro about how novel this study is and how it related to the work on this topic that preceded it. Lines 26-32 can be removed to make this for this (most of the readership is already familiar with those general statements).
2. aRRs
a. Most aRRs in table 2 are close to 1. How should readers interpret that in a clinical setting?
b.
View Letter
1 of 3 10/11/2022, 1:55 PM
Other points 1. Line 32-35.
A. My interpretation of what the authors wrote here is that they think medical therapy should be offered before
hysterectomy. However, while it is certainly true in some cases, it does not apply to many. If you look at the ACOG practice bulletin on this closely (Management of fibroids), they are careful about wording this. Of course, some women don't get medical therapy when they should, and others don't get surgery when they should in the imperfect world of modern medicine. My suggestion is to consider some sort of "threshold" , or % of women that should get medical therapy if you think you need to objectify this, but I personally would not do that because it will vary widely depending on patient population and practice setting. I do think it is useful to describe the use of conservative treatments, I just don't think we can call it "underuse" out of context.
B. References 3 and 4 used to back up statements in those lines are studies. Opinions coming out of those studies are what the authors wrote. I am not sure that will quality as "many recommend" since ACOG chose not to take this stand. I am not aware of any other professional society that does.
C. In line 93 authors state that references 3 and 4 ("prior studies") found that surgeons do not adhere to management guidelines, but what guidelines are you referring to? Those are not mentioned in this sentence.
D. I would also argue that 40% of women with fibroids receiving non-surgical intervention is actually quite good. Why do you think it should be less?
E. aRR for AUB favors non-surgery, which backs up this argument. This tells me that patients without pain (which I assume translate into bulk) component from fibroids are not going right into surgery, which seems c/w current practice patterns.
2. Line 42. I was not clear if all patients in the cohort had a claim within 14 days and 24 months of continuous coverage prior to surgery by accident, or if that was an inclusion/exclusion criteria. I assume it was an inclusion criteria.
3. Lines 65-66. Since to be included in the cohort patients had to have a diagnosis of fibroids, then AUB, endometriosis, and pelvic pain were other diagnoses listed? I suggest stating that for clarify
4. Line 68. I think you meant to write "in the 24 months prior", not "in the 24-prior"
5. It appears that reference 3 is incorrectly listed. Is it this one?
Corona LE, Swenson CW, Sheetz KH, Shelby G, Berger MB, Pearlman MD, Campbell DA Jr, DeLancey JO, Morgan DM. Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative. Am J Obstet Gynecol.
2015 Mar;212(3):304.e1-7. doi: 10.1016/j.ajog.2014.11.031. Epub 2014 Dec 23. PMID: 25542564.
6. Table 1-abbreviations need to be spelled out in the footnote
Reviewer #2: This manuscript is a retrospective cohort review of 138,263 patients who underwent hysterectomy for fibroids with the primary outcome measure of characterizing and identifying factors associated with underuse of
conservative treatments prior to hysterectomy among commercially insured patients in the U.S. The majority of patients were ages 41-50 (60.8%), lived in the South (52.0%), and lived in metropolitan statistical areas (81.3%). 69.6% of patients had a modified Elixhauser comorbidity score of at least 1. Abnormal uterine bleeding was reported in 79.6% of the cohort while 12.5% had endometriosis and 45.4% pelvic pain. Overall, 59.7% of patients did not receive conservative interventions in the 24 - prior to undergoing hysterectomy. A total of 36.7% of patients received medical therapy while 7.1% had other surgical interventions. The most common medical interventions were oral contraceptives 4 (19.0%) and progesterone (14.8%), while GnRH agonists were used in 3.6%, GnRH antagonists in 0.1%, tranexamic acid in 4.4%, and levonorgestrel IUDs in 2.4%. The most common surgical interventions were endometrial ablation (5.5%) and hysteroscopy (1.3%), uterine artery embolization (0.4%) and myomectomy (0.4%). In a multivariable model (Table 2), older patients (56-60 yo vs. 18-35 years, aRR=0.63; 95% CI, 0.60-0.66) and women living in non-MSA regions were less likely to receive conservative interventions. In contrast, patients who underwent hysterectomy more recently (2019 vs. 2011, aRR=1.07; 95% CI, 1.04-1.10), residents in the western U.S. (west vs. northeast, aRR 1.07; 95% CI 1.04-1.09), those with medical comorbidities, patients with abnormal uterine bleeding (aRR=1.82; 95% CI, 1.78-1.86) and endometriosis (aRR=1.18; 95% CI, 1.16-1.20) or those with a prior venous thromboembolism (aRR=1.08; 95% CI 1.04-1.14) were more likely to receive a preoperative intervention. Similar trends were noted in a model examining only medical interventions. The authors concluded that their findings are in line with prior studies that have found that many hysterectomies that are performed for benign indications do not adhere to management guidelines.
Introduction - The introduction is very brief and makes generalized statements with regard to pre-hysterectomy therapies and without consideration of the patient's personal desire and choice of treatment. Primary AIM of the manuscript is stated.
Methods - Inclusion and exclusion criteria are clearly stated. Method of data extraction is identified as well as the statistical analysis.
3 10/11/2022, 1:55 PM
Results - The data is presently simply, and results are framed within statistical significance. The demographic table is clear and labeled appropriately, Table 2 should be presented as an odds ratio - and re labeled as such.
Discussion - The discussion is thin and does not delve very deeply into reasoning or theorizing as to the reasoning behind the manuscript's findings.
In its current format the manuscript is very superficial in regards to the need for this type of analysis and the insight and/or theorizing behind the stated results. A more robust introduction and discussion is warranted.
STATISTICAL EDITOR COMMENTS:
General: Over an nine-year period, there were ~ 137k cases identified thru the database. This seems like a serious undercount of ~ 500,000 cases per year in the US. Need to justify how this sample is representative and can be extrapolated to US population.
Table 2: Need units for age strata. Should use a stricter inference threshold than p < 0.05 (and 95% CIs), based on the large number of stats comparisons. This would only change a few of the results, ie, those with CIs that have boundaries close to 1.00. Also, under Any Medical Intervention, Ischemic stroke, with a point estimate = 0.85 (0.77-0.93), why is that entry not designated as p < 0.05? Unless a typo, it should be.
--
John O. Schorge, MD Deputy Editor, Gynecology
The Editors of Obstetrics & Gynecology
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View Letter
3 10/11/2022, 1:55 PM
Dear Dr. Schorge,
Thank you for the opportunity to submit our work to Obstetrics & Gynecology. Below, please find point-by-point responses to each of the comments raised in the peer review.
EDITOR COMMENTS:
Please note the following:
1. Since only 2 years were assessed before hyst and a significant number of interventions could have taken place prior to that, would be preferable to de-emphasize some of the data
interpretation. For example, "Conservative medical and surgical therapies MAY BE underutilized in women with uterine leiomyoma who undergo hysterectomy".
We thank the Editor for the comment and have changed the Precis as suggested.
2. Please define MSA in the text/Table 1.
MSA is defined as metropolitan statistical area. This has been added as a footnote as suggested.
3. Also, please clarify what is meant by the term 'Pregnancy' in the accompanying Table 1.
Pregnancy with abortive outcome, normal pregnancy, complications of pregnancy, childbirth and puerperium within 2 years before hysterectomy. This has been added to the manuscript.
4. It is unclear how broadly applicable the findings are, in terms of limitations/Discussion when acknowledging that >half of pts in this database were from a single geographic location - is this a database issue, or did you stratify by race/ethnicity?
The Southern U.S. is always over represented in administrative databases due to the geographic characterization of patients in these data sets. The MarketScan database is a compilation of patients with employer sponsored group health insurance or Medicaid through 12 states and is broadly representative of the U.S. population.
Reviewer #1 Main points
1. It would help set the state in the intro about how novel this study is and how it related to the work on this topic that preceded it. Lines 26-32 can be removed to make this for this (most of the readership is already familiar with those general statements).
We appreciate the Reviewer’s comment. However, given the space constraints of the research
letter we have not further expanded the Introduction.
2. aRRs
a. Most aRRs in table 2 are close to 1. How should readers interpret that in a clinical setting?
We agree with the comment, many of the risk ratios are near one. As such, the magnitude of the association is relatively small. As with any analysis of observational data, statistical significance does not necessarily imply clinical significance.
Other points 1. Line 32-35.
A. My interpretation of what the authors wrote here is that they think medical therapy should be offered before hysterectomy. However, while it is certainly true in some cases, it does not apply to many. If you look at the ACOG practice bulletin on this closely (Management of fibroids), they are careful about wording this. Of course, some women don't get medical therapy when they should, and others don't get surgery when they should in the imperfect world of modern medicine. My suggestion is to consider some sort of "threshold" , or % of women that should get medical therapy if you think you need to objectify this, but I personally would not do that because it will vary widely depending on patient population and practice setting. I do think it is useful to describe the use of conservative treatments, I just don't think we can call it
"underuse" out of context.
We appreciate the reviewer’s concern and certainly agree, treatment should be individualized, and we do not intend to imply that all women should be treated medically. To our knowledge there is no data on a threshold for medical management but this could certainly be worth exploring in future study. However, it would seem that whenever appropriate medical therapy should be considered as first line treatment prior to surgery.
B. References 3 and 4 used to back up statements in those lines are studies. Opinions coming out of those studies are what the authors wrote. I am not sure that will quality as "many
recommend" since ACOG chose not to take this stand. I am not aware of any other professional society that does.
Studies 3 and 4 provide data on use of alternative treatment prior to hysterectomy. We have attempted to soften our conclusions and do not imply that all women should undergo medical therapy. However, most would agree that when feasible less invasive, less costly therapy should be employed prior to surgical interventions.
C. In line 93 authors state that references 3 and 4 ("prior studies") found that surgeons do not adhere to management guidelines, but what guidelines are you referring to? Those are not mentioned in this sentence.
References 3 and 4 specifically reference ACOG documents for specific gynecologic diseases
and symptoms. For example Morgan et al. (reference 3) describes ACOG guidelines that
recommend alternative therapies for ovulatory dysfunction, AUB, endometriosis, and
leiomyomas. Our analysis specifically focused on fibroids.
actually quite good. Why do you think it should be less?
We respectfully disagree. There are numerous medical and less invasive surgical measures available for the treatment of fibroids. While not absolute, guidelines generally encourage an attempt at a less invasive therapy. As described above, while not everyone perhaps should attempt conservative therapy, it would seem there may be room for improvement based on our data.
E. aRR for AUB favors non-surgery, which backs up this argument. This tells me that patients without pain (which I assume translate into bulk) component from fibroids are not going right into surgery, which seems c/w current practice patterns.
We agree that AUB was associated with an attempt at other therapies. This is in line with the availability of highly efficacious medical treatments for AUB and in line with ACOG guidelines.
2. Line 42. I was not clear if all patients in the cohort had a claim within 14 days and 24 months of continuous coverage prior to surgery by accident, or if that was an inclusion/exclusion criteria. I assume it was an inclusion criteria.
These were inclusion criteria. We wanted to develop a framework to ensure adequate coverage prior to hysterectomy to identify medical claims and to ensure that hysterectomy was indeed performed for fibroids.
3. Lines 65-66. Since to be included in the cohort patients had to have a diagnosis of fibroids, then AUB, endometriosis, and pelvic pain were other diagnoses listed? I suggest stating that for clarify
This has been added to the Methods as suggested.
4. Line 68. I think you meant to write "in the 24 months prior", not "in the 24-prior"
This was a typographical error and has been corrected.
5. It appears that reference 3 is incorrectly listed. Is it this one?
1
