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Date: Aug 08, 2019To: "Jing Hao" From: "The Green Journal" em@greenjournal.orgSubject: Your Submission ONG-19-1326

RE: Manuscript Number ONG-19-1326

Preeclampsia Cost of Illness Analysis: Maternal and Infant Healthcare Costs

Dear Dr. Hao:

Your manuscript has been reviewed by the Editorial Board and by special expert referees. Although it is judged not acceptable for publication in Obstetrics & Gynecology in its present form, we would be willing to give further consideration to a revised version.

If you wish to consider revising your manuscript, you will first need to study carefully the enclosed reports submitted by the referees and editors. Each point raised requires a response, by either revising your manuscript or making a clear and convincing argument as to why no revision is needed. To facilitate our review, we prefer that the cover letter include the comments made by the reviewers and the editor followed by your response. The revised manuscript should indicate the position of all changes made. We suggest that you use the "track changes" feature in your word processing software to do so (rather than strikethrough or underline formatting).

Your paper will be maintained in active status for 21 days from the date of this letter. If we have not heard from you by Aug 29, 2019, we will assume you wish to withdraw the manuscript from further consideration.

REVIEWER COMMENTS:

Reviewer #1: This is a retrospective cost-analysis of 5 years of paired maternal/neonatal outcomes from a large EHR in a single integrated healthcare system. Strengths include the inclusion of both normal and hypertensive pregnancies as a comparison to those with preeclampsia.

Introduction

1) The role of the funding source is clear in terms of data integrity. However, it is unclear what the funding source actually paid for (salary support? statistical software? conference costs? this should be clarified).

2) The order of preeclampsia, hypertension, and normal is sometimes presented differently both in description and in data throughout. It would be helpful to be consistent throughout.

Methods

1) How many (%) exclusions were there? Specifically for BMI given data quality issues. As well as cost (and why was the distribution so large?)

2) What preeclampsia risk factors were adjusted for?

3) The populations are matched on maternal characteristics but not neonatal (namely gestational age at delivery). It would be helpful to know how much of the increased cost on the neonatal end were related to simply prematurity vs other health outcomes associated with preeclampsia.

4) The Charlson Comorbidity Index is not specifically for the obstetric population (i.e. T2DM vs GDM). It would be useful to explain what this index entails for the reader's benefit as well as why the decision was made to use this index vs an obstetric index. Finally, this should be discussed in the limitations section of the discussion.

Results(none)

Discussion

1) Why is the mean infant cost at several gestational ages less for preeclampsia vs HTN (Table 2). This would be useful to discuss (and would be a good reason for why the neonatal costs should be matched or adjusted for by prematurity)

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2) Same comment as above (HTN vs preeclampsia) for length of stay (Table 5)

3) The date of the Joint Commission early indicators list used would be helpful as this list is updated every 6-12 months.

Reviewer #2: Dear Author(s)

I find this piece of research very interesting in order to display the economic impact of prclampsia in the US.

My main concern is related to the methods used.On the one hand the matching design in order to reduce confounding , does not allow to analyze the matching variables. ( which may not be of importance in this research);however the fact of conveniently matching the interest cohort to the normal and hypertension ones ( on the matching variables ), may introduce selecting bias.It could even underestimate the real cost of preclampsia, would the selected normal pregnancies overepresent chronic conditions to better match with the preeclampsia and hypertension cohorts.

Another concern arises following the exclusion of preterm deliveries in the normal cohort. Conversely, this underestimates cost of preterm deliveries in the nonhypertensive cohort by excluding them, overestimating the cost of preclampsia.

I would suggest using multivariable regression models to tackle these inconveniences.

On the one hand all pairs could be analyzed and no selection bias would be introduced and representativeness of the results would be warranted.

To my mind, matching in this study selects the normal cohort in a way where differential error could take place.

I hope to have contributed to better conduct the communication of this research.

Reviewer #3: This is a analysis of the economic costs for women and infants with either preeclampsia or hypertension within the Geisinger Health system sponsored by Industry specifically Progenity

Innovative model

Objective is well defined

1. It does seem as if you have some secondary outcomes: In Materials and Methods you state "Frequencies of caesarean delivery (CD) and adverse events were summarized and compared using Chi-squared tests and the mean gestational age at delivery and LOS were compared using ANOVA. Should these be stated as secondary outcomes as they are related to cost?

2. Can you please describe in a couple of sentences how Charlson Comorbidity Index was used in this trial for matching in Materials and Methods

3. Results: Maternal adverse events seems poorly defined throughout the text as most readers will not go to Appendix 3. Lines 209-211 and Table 4 "Women in the preeclampsia cohort had higher rates of CD at 50.0% versus 38.3% and 29.6% in hypertension and normal cohorts, respectively, and greater rates of maternal adverse events." In summary what are the adverse events? for both mother and baby. I understand that Appendix 3 has a list of ICD9 and 10 codes but a list of the most common that contributed would be important. Was it hemorrhage? renal failure? fetal distress? Some summary in the Materials and Methods and then the Results would be importantDiscussion

4. "This study is the first cost-of-illness analysis of preeclampsia using primary data to provide directly observable U.S. case-based healthcare cost estimates for both mothers and infants from a payer perspective, with comparisons to both normal and hypertensive pregnancies." Note that claims of priority (eg, first reports) are discouraged because they are often difficult to prove. If your claim of first report is based on a systematic search of the literature, that search should be described(search engine, search terms, time, and languages encompassed by the search). For example:This is the first case (MEDLINE; 1966-May 2004; English language; search terms: "hirsutism," "adrenal," and "menopause") A search of MEDLINE (English language; 1966-2003;search terms: "hypertension" and "pregnancy") revealed no other cases. Please see Guide for Writing for Obstetrics and Gynecology 4th Edition found on the home page of Obstetrics and Gynecology (page 13-14)

5. Lines 232-272 are devoted to a detailed comparison of the Steven's article. This can be condensed with the only the highlights as they are very different studies

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6. Again you mention adverse events, Table 4 is about adverse events but again the clinician is left wondering which adverse events are most prevalent. It's also a time to highlight some of the findings like

7. Women with preeclampsia who required delivery <28 weeks (typically the earlier the gestational age the more severe the disease) had a 100% cesarean rate and those with hypertension had an 83% rate

8. Was renal failure or hemorrhage or fetal distress affecting management of mother?

9. One limitation is that adverse events are limited by the ICD 9-10 codes and are not SMM codes by CDC, just discuss. Example I didn't see ICU admission. To my eye maternal adverse events were more common in women giving birth less than 33 weeks. Is this true?

10. Reference 5 Fingar KR, Mabry-Hernandez I, Ngo-Metzger Q, Wolff T, Steiner CA, Elixhauser A.350 Delivery Hospitalizations Involving Preeclampsia and Eclampsia, 2005-2014 2017 Where did this come from?

STATISTICAL EDITOR'S COMMENTS:

1. Table 1: Need to add units for age, BMI

2. Table 5: There are no units stated for length of stay (I presume days), but need to clarify. LOS is likely skewed, so should also include medians and could consolidate mean(SD) into one column.

EDITORIAL OFFICE COMMENTS:

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funder(s).

(4) In the manuscript, a new heading—"Role of the Funding Source"—should be inserted before the Methods and contain a detailed description of the sponsor's role as well as the following language:

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*From Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good publication practice for communicating company-sponsored medical research: GPP3. Ann Intern Med 2015;163:461-4.

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Obstetrics & Gynecology

Nancy C. Chescheir, MD, Editor-in-Chief

September 11th, 2019

RE: Manuscript Number ONG-19-1326

Dear Dr. Chescheir,

Thank you very much for reviewing our submission and the opportunity to revise our manuscript titled “Preeclampsia Cost of Illness Analysis: Maternal and Infant Healthcare Costs”. In this letter, we have provided a detailed point-by-point response to each of the received comments from the reviewers and editors. We also have attached our revised manuscript using track changes feature. I confirm I have read the Instructions for Authors.

Updated Reporting Guideline Check: Our study is a cost-of-illness study, for which there are no applicable reporting guidelines (e.g., Consolidated Health Economic Evaluation Reporting Standards (CHEERS)). Since our study is a retrospective observational study, the closest guideline would be STROBE which is for observational studies in epidemiology including cohort, case-control and cross-sectional studies, however, our study is not a specific epidemiology study that fits any of the three study types. The method and study design of this study is based on published literature, especially a systematic review of current methods of cost-of-illness studies.1 However, we feel the STROBE guideline can be seen as a general guideline for observational studies, thus we select to include the STROBE guideline along with our manuscript. And the checklist with the page numbers where each item appears in our manuscript is attached. Updated Ethical and transparent publication practices of industry-sponsored study: The study was funded by Progenity, Inc. A contract was executed between Progenity, Inc. and Geisinger in the form of milestone payments for agreed upon study activities. Payments made to Geisinger covered the salary of Geisinger research investigators and staff who are part of the research team of this study as well as indirect costs. Funding was also used to reimburse the 2018 ISPOR conference expenses where the lead author presented preliminary findings of this study. Lastly, funding will be used to cover potential manuscript publication fees. The report/manuscript of this study and the study design have been reviewed and approved by Progenity, Inc., the sponsor of this study, and they approved the decision to submit the article for publication, however they were not involved in the study design development and implementation, or the collection, analysis and interpretation of the data.

1 Onukwugha E, McRae J, Kravetz A, Varga S, Khairnar R, Mullins CD. Cost-of-Illness Studies: An Updated Review of Current Methods. Pharmacoeconomics. 2016 Jan;34(1):43-58. doi: 10.1007/s40273-015-0325-4. Review. PubMed PMID: 26385101.

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The authors had access to relevant aggregated study data and other information (such as study protocol, analytic plan and report, validated data table, and clinical study report) required to understand and report research findings. The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation development, and are willing to take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the research, data analysis, and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors’ personal interests, financial or non-financial, relating to this research and its publication have been disclosed. Thank you for considering our work. We look forward to hearing from you. Sincerely, Jing Hao, PhD, MD, MS, MPH Department of Population Health Sciences Geisinger

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Following are point-to-point responses to reviewer comments. Blue font represents the revised text in manuscript (also in track-changes in manuscript). REVIEWER COMMENTS: Reviewer #1: This is a retrospective cost-analysis of 5 years of paired maternal/neonatal outcomes from a large EHR in a single integrated healthcare system. Strengths include the inclusion of both normal and hypertensive pregnancies as a comparison to those with preeclampsia. Introduction

1) The role of the funding source is clear in terms of data integrity. However, it is unclear what the funding source actually paid for (salary support? statistical software? conference costs? this should be clarified).

Response: We thank the reviewer for requesting details about the role of the funding source for improved clarification. We have now added the following statement in both the cover letter and the “Role of funding source” section in manuscript.

“The study was funded by Progenity, Inc. A contract was executed between Progenity, Inc. and Geisinger in the form of milestone payments for agreed upon study activities. Payments made to Geisinger covered the salary of Geisinger research investigators and staff who are part of the research team of this study as well as indirect costs. Funding was also used to reimburse the 2018 ISPOR conference expenses where the lead author presented preliminary findings of this study. Lastly, funding will be used to cover potential manuscript publication fees.”

2) The order of preeclampsia, hypertension, and normal is sometimes presented differently

both in description and in data throughout. It would be helpful to be consistent throughout.

Response: We appreciate this important reminder. We have now applied a uniform order to the three cohorts throughout the manuscript with track-changes. Methods

1) How many (%) exclusions were there? Specifically for BMI given data quality issues. As well as cost (and why was the distribution so large?)

Response: We demonstrated details about step by step exclusion results in Figure 1, for an initial population of 16,545 women. Figure 1 shows 43 patients were excluded for BMI data quality criteria and a total of 169 patients were excluded due to cost data criteria (22 patients in preeclampsia cohort, 30 in hypertension cohort and 117 in normal cohort). Note that these

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exclusions were not always conducted from the initial population. For example, the exclusion due to cost data criteria was conducted after other exclusion criteria were applied, therefore making it inconsistent to measure the % of exclusion based on the initial population. Thus, we did not describe this information in the manuscript, and instead offer a detailed step by step figure accounting for the number of all exclusions along the way may to provide the greatest amount of information and complete transparency. The distributions of maternal and infant costs are expected to be large due to different levels of complexity of pregnancy (normal full term versus with complications including hypertension and preeclampsia) and delivery (the infants may have extended and costly stays in NICU).

2) What preeclampsia risk factors were adjusted for? Response: The objective of our study was to analyze the incremental costs of preeclampsia compared to normal and hypertensive pregnancies. We used matched control cost-of-illness methodology to match other major factors that might influence the cost differences among the three cohorts so that the incremental costs observed only reflect the increased costs due to preeclampsia. Thus, we match on risk factors of preeclampsia (age, parity and BMI), that are also associated with healthcare costs independent of developing preeclampsia, as well as Charlson Comorbidity Index to match on patients’ general comorbidities that would influence the costs. After reading this comment, we realized the language used relevant to this part is not clear enough, thus we revised the original sentence of

“Three study cohorts were matched using a 1:1:1 ratio based on maternal age (< 20 years, 20-34 years, ≥ 35 years), nulliparity, obesity status (BMI < or ≥ 30), and Charlson Comorbidity Index scores based on peer-reviewed literature 14,15 and in consultation with a clinician expert to adjust for preeclampsia risk factors.”,

to “Three study cohorts were matched using a 1:1:1 ratio based on maternal age (< 20 years, 20-34 years, ≥ 35 years), nulliparity, obesity status (BMI < or ≥ 30), and the mean of Charlson Comorbidity Index scores. Age, parity and obesity are risk factors for preeclampsia and are associated with healthcare costs in pregnancy independent of developing preeclampsia.14,15 The Charlson Index Scores account for the patients’ general comorbid conditions that are associated with costs not relevant to preeclampsia.” (under “Study Design”)

3) The populations are matched on maternal characteristics but not neonatal (namely

gestational age at delivery). It would be helpful to know how much of the increased cost on the neonatal end were related to simply prematurity vs other health outcomes associated with preeclampsia.

Response: That is correct. As stated in response to #2) above, the objective of our study was to analyze the incremental costs of preeclampsia compared to normal and hypertensive pregnancies. We used matched control cost-of-illness methodology. To do so, we first matched other major factors that would influence the cost differences among the three cohorts. The factors such as older age, first pregnancy and obesity that are risk factors of preeclampsia and are associated

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with higher healthcare costs independent of developing preeclampsia, and the factor of higher Charlson Comorbidity Index score is also associated with higher costs non-relevant to preeclampsia. Thus, after matching, the incremental costs that we observed are expected to only reflect the increased costs due to consequences/outcomes of preeclampsia. We did not match neonatal characteristics such as gestational age at delivery because prematurity is the key outcome and the main driver of the increased costs due to preeclampsia among other adverse outcomes (as we observed in our study) that account for the economic burden of preeclampsia in pregnancy. In our study, especially demonstrated in Figure 3 (see below), the results indicated that prematurity is a main drive of the increased costs of preeclampsia. However, our study methods do not quantify how much of the increased infant costs were related to simply prematurity vs other health outcomes associated with preeclampsia. One approach could involve matching other health outcomes, however it is beyond the research objective of our current study.

Figure 3. Costs by Cohort by Gestational Week (2015 USD)

3.A. Maternal costs; 3.B. Infant costs; 3.C. Maternal and infant combined costs

4) The Charlson Comorbidity Index is not specifically for the obstetric population (i.e.

T2DM vs GDM). It would be useful to explain what this index entails for the reader's benefit as well as why the decision was made to use this index vs an obstetric index. Finally, this should be discussed in the limitations section of the discussion.

Response: Thanks for the discussion on selections and decisions for risk factors to match among cohorts, including comments #2) and #3) above. As stated in responses to the above two comments, Charlson Comorbidity Index score which represents patients’ general comorbid conditions was matched so that a patient’s non-pregnancy conditions, for example severe chronic diseases that can drive total healthcare costs, among the three cohorts are matched or equaled out

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at baseline, similar to the practice used to match treatment and control group subjects in a controlled clinical trial. We are not aware of any widely used comorbid index that is specific to obstetrics. Our review of literature indicated an index was being developed but was not used in common practice or cited frequently.2 In our matching, we matched age, parity and obesity that are considered obstetric factors that would indicate increased risk for complicated pregnancy. However, besides factors that are specific to obstetric, we still have to match on general comorbid conditions to eliminate non-pregnancy drivers of healthcare costs that are not relevant to preeclampsia to estimate the incremental costs of preeclampsia. We selected the Charlson index score as it is a commonly used index in research to represent general comorbid conditions. As the reviewer suggested, we provided additional explanation for the Charlson index and why it was used for matching (detailed in responses to comments #2 and #3). Results (none) Discussion

1) Why is the mean infant cost at several gestational ages less for preeclampsia vs HTN (Table 2). This would be useful to discuss (and would be a good reason for why the neonatal costs should be matched or adjusted for by prematurity)

Response: We appreciate the reviewer’s attention to these details and we have identified the primary reason to explain these findings which appear counterintuitive. This outcome is mainly because of the small sample size for the most premature birth sub-groups when stratified by gestational week. Specifically, there are only 6 hypertension cases in the <28 weeks group. This is why only descriptive statistics were provided for sub-cohort level, and the inferential statistics to compare statistically significant differences among cohorts were only conducted on the overall 3 cohorts level, not on the sub-cohort level. We have now added the following statement for clarification under “Study Design”:

“Due to small sample size, only descriptive statistics in sub-groups stratified by gestational week were presented; inferential statistics to compare statistically significant differences among cohorts were only conducted on the 3 cohorts at the overall level.”

If we take a closer look at these descriptive results, these findings do make sense. First of all, after 1:1:1 matching, both hypertension and preeclampsia cohorts have 712 patients, and fewer patients in the hypertension cohort experienced premature delivery compared to the preeclampsia cohort: 6 vs. 19 cases for <28 weeks, 24 vs. 116 cases for 28-33 weeks, and 46 vs. 172 for 34-36 weeks. These counts indicate that preeclampsia is associated with a higher rate of premature delivery, and is reflected in our findings that “Women with preeclampsia delivered at 36.5 gestational weeks on average, 3 weeks earlier than mothers with normal pregnancies averaging 2 Bateman BT, Gagne JJ. The Obstetric Comorbidity Index predicts severe maternal morbidity. BJOG. 2015 Dec;122(13):1756. doi: 10.1111/1471-0528.13297. Epub 2015 Feb 2. PubMed PMID: 25639706.

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39.5 weeks (p<0.0001) and slightly over 2 weeks earlier than mothers with hypertension averaging 38.7 weeks (p<0.0001).” Second, due to the small sample size in the premature hypertension sub-cohort by gestational age, the observed higher mean infant costs can be skewed by few extreme cases. Third, these higher infant costs in some preterm delivery sub-cohorts are consistent with our findings on infant length of stay in the same sub-cohorts; that premature infants in the hypertension cohort had longer average days of stay than premature infants in the preeclampsia cohort which contributed to higher infant costs. Finally, these observations altogether indicate and confirm that prematurity is the main driver of higher infant costs. Based on above discussion, we have now added the following on these observations under “Discussion”:

“The observations of lower mean infant costs and average infant LOS in some of the premature gestational weeks in the preeclampsia cohort compared to the hypertension cohort were partially due to small sample sizes in these gestational week sub-groups. Mean costs and LOS can be skewed by a few extreme cases. And in combination with the findings that preeclampsia is associated with higher rates of preterm delivery also indicate and confirm that preterm delivery is the main drive of higher infant costs.”

The responses on why we did not match on neonatal characteristics including prematurity is included in Methods comment #3) above.

2) Same comment as above (HTN vs preeclampsia) for length of stay (Table 5) Response: See responses above to Results comment #1).

3) The date of the Joint Commission early indicators list used would be helpful as this list is updated every 6-12 months.

Response: Thank you for this reminder. The date is now added (under Supplementary Appendix 1).

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Reviewer #2: Dear Author(s) I find this piece of research very interesting in order to display the economic impact of preeclampsia in the US.

1. My main concern is related to the methods used. On the one hand the matching design in order to reduce confounding , does not allow to analyze the matching variables. ( which may not be of importance in this research);however the fact of conveniently matching the interest cohort to the normal and hypertension ones ( on the matching variables ), may introduce selecting bias.It could even underestimate the real cost of preclampsia, would the selected normal pregnancies overepresent chronic conditions to better match with the preeclampsia and hypertension cohorts. Another concern arises following the exclusion of preterm deliveries in the normal cohort. Conversely, this underestimates cost of preterm deliveries in the nonhypertensive cohort by excluding them, overestimating the cost of preclampsia. I would suggest using multivariable regression models to tackle these inconveniences. On the one hand all pairs could be analyzed and no selection bias would be introduced and representativeness of the results would be warranted. To my mind, matching in this study selects the normal cohort in a way where differential error could take place. I hope to have contributed to better conduct the communication of this research.

Response: We thank the reviewer for this comment and thoughtful analysis. Most importantly, we agree with the observation that matching (as a general technique to reduce confounding) is likely to create some cohorts that are similar to each other but not representative of the larger populations from which they were drawn; we would argue, however, that the trade-off is consistent with the goals of our particular study. We were not interested in reporting on characteristics of the ‘normal’ population or mothers with hypertension; our stated goal was to study mothers with preeclampsia and to estimate the incremental cost difference between mothers with preeclampsia and mothers who were similar but had no preeclampsia. In this particular case, our 1:1:1 matching method was able to utilize almost all of the mothers with preeclampsia in our population (712 out of 736, or 97%) so we think the risk of selection bias in that cohort was very small. In the other two populations (which were larger to begin with), it is true that we used smaller percentages of the available patients (712 out of 4210 normal pregnancies, or 17%, and 712 out of 1005 hypertensive mothers, or 70%), but our goal was to reduce confounding between preeclampsia and cost and not to present unbiased estimates of the larger populations in those latter two cases. We maintain our belief that matching was, and is still, the best-suited strategy for that purpose. To the reviewer’s second point, we shared his/her concern (when designing the study) that preterm deliveries were not considered for inclusion in the ‘normal’ cohort. However, we could find no satisfactory alternative definition in the literature and found it challenging to clearly define and quantify “normal” pregnancy. We finally decided to adopt this restrictive definition of

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normal pregnancy of being full term with no complications and included a second ‘control’ cohort, the mothers with hypertension (in which preterm births were included). Based on our research question, i.e. to estimate the incremental costs of preeclampsia, we consider this approach offering a lower and upper bound in terms of comparison cohorts as an advantage of our study, especially when compared to the literature where preeclampsia was compared to all non-preeclampsia pregnancies.3,4 In addition, as discussed in response to some of the other comments here, we think it is clear from our findings and evidence that mothers with preeclampsia are at a much higher risk of needing to deliver prematurely, and that the premature deliveries lead to significantly increased costs. It is our intent to estimate the incremental effect of preeclampsia on preterm deliveries and its corresponding cost rather than imply that the gestational age is somehow independent or not related at all to the presence of preeclampsia. Finally, we do not agree with the reviewer’s suggestion that multivariable regression would be a better way to conduct this analysis. Whenever possible, even in a retrospective or observational study, we try to re-create the design-based approach of a gold-standard prospective randomized trial as much as feasibly possible. In both matching and regression approaches, you have the limitation that you can only address confounding due to observed confounders (vs. a randomized trial where theoretically unobserved confounders are balanced as well), but matching has the distinct advantage over regression in that you can transparently report how well those observed confounders are successfully balanced among the cohorts. In our case, because we explicitly matched on the main confounders suggested by our clinical expert (e.g., age, nulliparity, BMI) we know and can demonstrate (in tables) that the cohorts were balanced with respect to those factors and they cannot be confounding the results of the study. Regression, in contrast, has several disadvantages including the need to make assumptions about the relationships (linear or other) among confounders and between confounder and outcome, an inability to overcome lack of overlap among the cohorts, and a lack of a statistic that can quantify the degree to which confounding has been removed. As discussed in our first paragraph above, the only advantage we see to regression is that all patients (in all 3 populations) could have been included, but again, we see this as more of a drawback than a benefit since our primary aim is to measure an incremental effect between just one cohort (the mothers with preeclampsia, most of whom were utilized) and mothers who were otherwise similar to them. We believe that our current analysis as it stands, and not a new regression analysis, is still the most appropriate way to answer our research question.

3 Fingar KR, Mabry-Hernandez I, Ngo-Metzger Q, Wolff T, Steiner CA, Elixhauser A. Delivery Hospitalizations Involving Preeclampsia and Eclampsia, 2005–2014. 2017. https://hcup-us.ahrq.gov/reports/statbriefs/sb222-Preeclampsia-Eclampsia-Delivery-Trends.jsp Accessed September 6, 2019. 4 Stevens W, Shih T, Incerti D, et al. Short-term costs of preeclampsia to the United States health care system. American journal of obstetrics and gynecology. Sep 2017;217(3):237-248 e216.

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Reviewer #3: This is an analysis of the economic costs for women and infants with either preeclampsia or hypertension within the Geisinger Health system sponsored by Industry specifically Progenity Innovative model Objective is well defined

1. It does seem as if you have some secondary outcomes: In Materials and Methods you state "Frequencies of caesarean delivery (CD) and adverse events were summarized and compared using Chi-squared tests and the mean gestational age at delivery and LOS were compared using ANOVA. Should these be stated as secondary outcomes as they are related to cost?

Response: To address this comment, we added the following sentence under “Study Design” to add clarification and be consistent with how results were presented under the “Results” section:

“Besides costs, birth-related outcomes including gestational age at delivery, the frequency of adverse maternal outcomes during pregnancy and adverse infant outcomes of higher prevalence were reported using corresponding ICD-9 codes identified in a recently published preeclampsia cost study (Supplementary Appendix 3)”

2. Can you please describe in a couple of sentences how Charlson Comorbidity Index was

used in this trial for matching in Materials and Methods Response: Yes, thank you for this comment. We have now revised the statement under “Study Design” to the following to provide some details about why we used the Charlson Index and how it is matched:

“Three study cohorts were matched using a 1:1:1 ratio based on maternal age (< 20 years, 20-34 years, ≥ 35 years), nulliparity, obesity status (BMI < or ≥ 30), and the mean of the Charlson Comorbidity Index scores. Age, parity and obesity are risk factors for preeclampsia and are associated with healthcare costs in pregnancy independent of developing preeclampsia.14,15 The Charlson Index Scores account for the patients’ general comorbid conditions that are associated with costs not relevant to preeclampsia.” (under “Study Design”)

3. Results: Maternal adverse events seems poorly defined throughout the text as most

readers will not go to Appendix 3. Lines 209-211 and Table 4 "Women in the preeclampsia cohort had higher rates of CD at 50.0% versus 38.3% and 29.6% in hypertension and normal cohorts, respectively, and greater rates of maternal adverse events." In summary what are the adverse events? for both mother and baby. I understand that Appendix 3 has a list of ICD9 and 10 codes but a list of the most common that contributed would be important. Was it hemorrhage? renal failure? fetal distress? Some summary in the Materials and Methods and then the Results would be important

Response: Thank you for pointing this out. We have now listed the maternal and infant adverse events that we analyzed under “Study Design” and the footnote of Table 4.

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“Maternal adverse events in our analysis were limited to renal failure, eclamptic seizure, thrombocytopenia, and severe intra- and post-partum hemorrhage. The infant adverse events included fetal distress, respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of prematurity (stage >3), necrotizing enterocolitis, Bell’s (grade >2), intraventricular hemorrhage (stage>3), and sepsis.”

Discussion

4. "This study is the first cost-of-illness analysis of preeclampsia using primary data to provide directly observable U.S. case-based healthcare cost estimates for both mothers and infants from a payer perspective, with comparisons to both normal and hypertensive pregnancies." Note that claims of priority (eg, first reports) are discouraged because they are often difficult to prove. If your claim of first report is based on a systematic search of the literature, that search should be described(search engine, search terms, time, and languages encompassed by the search). For example:This is the first case (MEDLINE; 1966-May 2004; English language; search terms: "hirsutism," "adrenal," and "menopause") A search of MEDLINE (English language; 1966-2003;search terms: "hypertension" and "pregnancy") revealed no other cases. Please see Guide for Writing for Obstetrics and Gynecology 4th Edition found on the home page of Obstetrics and Gynecology (page 13-14)

Response: We conducted a literature search which supports our claim that “this study is the first cost of illness analysis of preeclampsia using primary data to provide directly observable U.S. case-based healthcare cost estimates for both mothers and infants from a payer perspective, with comparisons to both normal and hypertensive pregnancies.” Supporting search description:

“Search date: 9/3/2019; PubMed; 1/1/1990-8/31/2019; English language; humans; Title/Abstract search terms: “preeclampsia” or “pre-eclampsia” AND “cost”; search results: 213 records revealed no other cases.” (under Discussion. Strengths and Limitations)

5. Lines 232-272 are devoted to a detailed comparison of the Steven's article. This can be

condensed with the only the highlights as they are very different studies Response: The submitted version contained a comparison to the Stevens et al study that was 726 words and 5 paragraphs in length. This has been revised to 484 words in 4 paragraphs, a 33% reduction in word length. (Due to the length, please refer to this section in manuscript with track-changes.)

6. Again you mention adverse events, Table 4 is about adverse events but again the

clinician is left wondering which adverse events are most prevalent. It's also a time to highlight some of the findings like

Response: A footnote is now included in Table 4. Detailed responses are provided under comment #3.

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7. Women with preeclampsia who required delivery <28 weeks (typically the earlier the

gestational age the more severe the disease) had a 100% cesarean rate and those with hypertension had an 83% rate

Response: We are not quite sure of the reviewer’s question in this comment, but guessing the reviewer may be thinking why patients in hypertension cohort had less than 100% cesarean rate when delivery occurred <28 weeks. As noted in responses to reviewer 1’s Discussion comment #1), please note of the small sample size for the most premature sub-groups when stratified by gestational week. There were only 6 patients in the hypertension <28 weeks group and 1 patient did not have cesarean delivery which is clinically realistic. But the comparison at this small sample size has no clinical or statistical significance. That’s why we only presented descriptive statistics for sub-cohort level, and the inferential statistics to compare statistically significant differences among cohorts were only conducted on the 3 cohorts at the overall level. As noted in the responses to reviewer 1’s comment, we have now added such statement for clarification under “Study Design”:

“Due to small sample size, only descriptive statistics in sub-groups stratified by gestational week were presented; inferential statistics to compare statistically significant differences among cohorts were only conducted on the 3 cohorts at the overall level.”

8. Was renal failure or hemorrhage or fetal distress affecting management of mother? Response: Renal failure and hemorrhage are maternal adverse events of higher prevalence associated with preeclampsia, and fetal distress is one of the infant adverse events associated with preeclampsia. We included analyses on these adverse events mainly to demonstrate the consequences of preeclampsia compared to the other two cohorts, and assume the treatments of these adverse events contributed to increased costs of preeclampsia.

9. One limitation is that adverse events are limited by the ICD 9-10 codes and are not SMM codes by CDC, just discuss. Example I didn't see ICU admission. To my eye maternal adverse events were more common in women giving birth less than 33 weeks. Is this true?

Response: Although the SMM indicators were not specifically used, the ICD9-10 codes on which the SMM indicators are based were used. I am copying Table 4 here to better address the second part of the comment. Based on the descriptive statistics at sub-cohort level stratified by gestational week, the maternal adverse events in the preeclampsia cohort appear to be slightly more common in women giving birth at less than 33 weeks compared to delivery at a longer gestational age. This trend is not quite observed in hypertension cohort. But due to the small sample size, we don’t know whether the differences have statistical significance. This trend is much more obvious in terms of infant adverse events.

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Table 4. Maternal and Infant Adverse Events

Cohort Gestational Week N

Maternal Adverse Events

Infant Adverse Events

Infant Death

Caesarean Section

Delivery

N (%) N (%) N (%) N (%) Normal < 28 0 0 (.0%) 0 (.0%) 0 (.0%) 28-33 0 0 (.0%) 0 (.0%) 0 (.0%) 34-36 0 0 (.0%) 0 (.0%) 0 (.0%) ≥ 37 712 29 (4.1%) 5 (.7%) 2 (.3%) 211 (29.6%) Total 712 29 (4.1%) 5 (.7%) 2 (.3%) 211 (29.6%) Hypertension < 28 6 1 (16.7%) 6 (100.0%) 1 (16.7%) 5 (83.3%) 28-33 24 2 (8.3%) 15 (62.5%) 1 (4.2%) 14 (58.3%) 34-36 46 6 (13.0%) 5 (10.9%) 0 (.0%) 23 (50.0%) ≥ 37 636 58 (9.1%) 8 (1.3%) 4 (.6%) 231 (36.3%) Total 712 67 (9.4%) 34 (4.8%) 6 (.8%) 273 (38.3%) Preeclampsia < 28 19 3 (15.8%) 19 (100.0%) 2 (10.5%) 19 (100.0%) 28-33 116 22 (19.0%) 61 (52.6%) 0 (.0%) 78 (67.2%) 34-36 172 25 (14.5%) 14 (8.1%) 2 (1.2%) 82 (47.7%) ≥ 37 405 49 (12.1%) 10 (2.5%) 1 (.3%) 177 (43.7%) Total 712 99 (13.9%)a 104 (14.6%)b 5 (.7%)c 356 (50.0%)d

a: There is a statistically significant difference in the frequency of maternal adverse events between the preeclampsia, normal, and hypertension cohorts (p<0.0001), comparing preeclampsia and normal (p<0.0001) and preeclampsia and hypertension (p=0.016). b: There is a statistically significant difference in the frequency of infant adverse events between the preeclampsia, normal, and hypertension cohorts (p<0.0001), comparing preeclampsia and normal (p<0.0001) and preeclampsia and hypertension (p<0.0001). c: There is no statistically significant difference in the frequency of infant death between the preeclampsia, normal, and hypertension cohorts (p=0.3656), comparing preeclampsia with normal (p=0.4460) and preeclampsia and hypertension (p=0.9434). d: There is a statistically significant difference in the frequency of caesarean section delivery between the preeclampsia, normal, and hypertension cohorts (p<0.0001), comparing preeclampsia and normal (p<0.0001) and preeclampsia and hypertension (p<0.0001). Maternal adverse events in our analysis were limited to renal failure, eclamptic seizure, thrombocytopenia, and severe intra- and post-partum haemorrhage. The infant adverse events included fetal distress, respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of prematurity (stage >3), necrotizing enterocolitis, Bell’s (grade >2), intraventricular haemorrhage (stage>3), and sepsis.

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10. Reference 5 Fingar KR, Mabry-Hernandez I, Ngo-Metzger Q, Wolff T, Steiner CA, Elixhauser A.350 Delivery Hospitalizations Involving Preeclampsia and Eclampsia, 2005-2014 2017 Where did this come from?

Response: Thanks for pointing this out. We have carefully checked all references and made format corrections. For this reference, the link to the AHRQ HCUP statistical brief #222 has been added: https://hcup-us.ahrq.gov/reports/statbriefs/sb222-Preeclampsia-Eclampsia-Delivery-Trends.jsp

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STATISTICAL EDITOR'S COMMENTS:

1. Table 1: Need to add units for age, BMI Response: Thanks for this reminder. Units are now added for age and BMI in Table 1.

2. Table 5: There are no units stated for length of stay (I presume days), but need to clarify. LOS is likely skewed, so should also include medians and could consolidate mean(SD) into one column.

Response: Thanks for this comment. Unit for LOS is added in Table 5. And medians are also added.

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EDITORIAL OFFICE COMMENTS:

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Response: Based on follow up communications with co-authors and the editorial office, this should be completed now. But let us know if you are still missing one or more forms. Thanks!

3. Obstetrics & Gynecology follows the Good Publication Practice (GPP3)* guideline for manuscripts that report results that are supported or sponsored by pharmaceutical, medical device, diagnostics and biotechnology companies. The GPP3 is designed to help individuals and organization maintain ethical and transparent publication practices. (1) Adherence to the GPP3 guideline should be noted in the cover letter. (2) For publication purposes, the portions of particular importance to industry-sponsored research are below. In your cover letter, please indicate whether the following statements are true or false, and provide an explanation if necessary: (2a) All authors had access to relevant aggregated study data and other information (for example, the study protocol) required to understand and report research findings. (2b) All authors take responsibility for the way in which research findings are presented and published, were fully involved at all stages of publication and presentation development and are willing to take public responsibility for all aspects of the work.

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(2c) The author list accurately reflects all substantial intellectual contributions to the research, data analyses, and publication or presentation development. Relevant contributions from persons who did not qualify as authors are disclosed in the acknowledgments. (2d) The role of the sponsor in the design, execution, analysis, reporting, and funding (if applicable) of the research has been fully disclosed in all publications and presentations of the findings. Any involvement by persons or organizations with an interest (financial or nonfinancial) in the findings has also been disclosed. (2e) All authors have disclosed any relationships or potential competing interests relating to the research and its publication or presentation.

Response: This part is already included in cover letter as well as manuscript main text. Based on reviewer comments on more clarification on the role of the funder (Reviewer #1, Comment #1), in the updated cover letter and manuscript, we added the following statement:

“The study was funded by Progenity, Inc. A contract was executed between Progenity, Inc. and Geisinger in the form of milestone payments for agreed upon study activities. Payments made to Geisinger covered the salary of Geisinger research investigators and staff who are part of the research team of this study as well as indirect costs. Funding was also used to reimburse the 2018 ISPOR conference expenses where the lead author presented preliminary findings of this study. Lastly, funding will be used to cover potential manuscript publication fees.”

(3) The abstract should contain an additional heading, "Funding Source," and should provide an abbreviated listing of the funder(s).

Response: Thanks for reminding us. This section is now added to the Abstract.

(4) In the manuscript, a new heading—"Role of the Funding Source"—should be inserted before the Methods and contain a detailed description of the sponsor's role as well as the following language: "The authors had access to relevant aggregated study data and other information (such as study protocol, analytic plan and report, validated data table, and clinical study report) required to understand and report research findings. The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation development, and are willing to take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the research, data analysis, and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors' personal interests, financial or non-financial, relating to this research and its publication have been disclosed." Authors should only include the above statement if all of it is true, and they should attest to this in the cover letter (see #2, above).

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*From Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good publication practice for communicating company-sponsored medical research: GPP3. Ann Intern Med 2015;163:461-4.

Response: The section of “Role of the Funding Source” is already included in the manuscript. Based on reviewer comments on more clarification on the role of the funder (Reviewer #1, Comment #1), in the updated cover letter and manuscript, we added the following statement:

“The study was funded by Progenity, Inc. A contract was executed between Progenity, Inc. and Geisinger in the form of milestone payments for agreed upon study activities. Payments made to Geisinger covered the salary of Geisinger research investigators and staff who are part of the research team of this study as well as indirect costs. Funding was also used to reimburse the 2018 ISPOR conference expenses where the lead author presented preliminary findings of this study. Lastly, funding will be used to cover potential manuscript publication fees.”

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Response: This is a cost-of-illness study. The closest guideline is STROBE for observational studies in epidemiology. This section is now updated in the revised cover letter.

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Response: This comment is not applicable to our study/paper.

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Response: Thanks for the reminder. The current manuscript is within 5,500 word limit.

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Response: All included in manuscript already.

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Response: We have reviewed the abstract and compared results with the manuscript and confirm consistency in reporting results. The current word count of abstract is included.

10. Only standard abbreviations and acronyms are allowed. A selected list is available online at https://nam05.safelinks.protection.outlook.com/?url=http%3A%2F%2Fedmgr.ovid.com%2Fong%2Faccounts%2Fabbreviations.pdf&amp;data=02%7C01%7Cjhao%40geisinger.edu%7C9bc411cffd3f4d27e1da08d71c3dbf41%7C37d46c567c664402a16055c2313b910d%7C0%7C1%7C637008923856562889&amp;sdata=NgqNaKmYmq%2Fg%2BaLTLr9cvvJT2Cur4nQU5Szi4A8GidQ%3D&amp;reserved=0. 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: Thanks for the reminder.

11. The commercial name (with the generic name in parentheses) may be used once in the body of the manuscript. Use the generic name at each mention thereafter. Commercial names should not be used in the title, précis, or abstract.

Response: No commercial product was involved in this study.

12. The journal does not use the virgule symbol (/) in sentences with words. 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: Thanks! This symbol is now edited throughout the manuscript.

13. 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.

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If appropriate, please include number needed to treat for benefits (NNTb) or harm (NNTh). When comparing two procedures, please express the outcome of the comparison in U.S. dollar amounts. Please standardize the presentation of your data throughout the manuscript submission. For P values, do not exceed three decimal places (for example, "P = .001"). For percentages, do not exceed one decimal place (for example, 11.1%").

Response: We have now reported effect size where applicable in abstract, manuscript and tables (table 2 and 5). The NNTb and NNTh are not applicable to our study. Thanks, the presentation of data is now standardized based on instruction.

14. We discourage claims of first reports since they are often difficult to prove. How do you know this is the first report? If this is based on a systematic search of the literature, that search should be described in the text (search engine, search terms, date range of search, and languages encompassed by the search). If on the other hand, it is not based on a systematic search but only on your level of awareness, it is not a claim we permit.

Response: This study is the first cost of illness analysis of preeclampsia using primary data to provide directly observable U.S. case-based healthcare cost estimates for both mothers and infants from a payer perspective, with comparisons to both normal and hypertensive pregnancies. Supporting search that is now included in manuscript: [PubMed; 1/1/1990-8/31/2019; English language; humans; Title/Abstract search terms: “preeclampsia” or “pre-eclampsia” and “cost”; search results: 213 records revealed no other cases.]

15. Please review the journal's Table Checklist to make sure that your tables conform to journal style. The Table Checklist is available online here: https://nam05.safelinks.protection.outlook.com/?url=http%3A%2F%2Fedmgr.ovid.com%2Fong%2Faccounts%2Ftable_checklist.pdf&amp;data=02%7C01%7Cjhao%40geisinger.edu%7C9bc411cffd3f4d27e1da08d71c3dbf41%7C37d46c567c664402a16055c2313b910d%7C0%7C1%7C637008923856562889&amp;sdata=UkV31WcpfdUg0vqJUexEPs24P%2BGXqBqJ1n%2FMVQA0d%2Fc%3D&amp;reserved=0.

Response: I confirm the Table checklist was referred to update the tables.

16. The American College of Obstetricians and Gynecologists' (ACOG) documents are frequently updated. These documents may be withdrawn and replaced with newer, revised versions. If you cite ACOG documents in your manuscript, be sure the reference you are citing is still current and available. If the reference you are citing has been updated (ie, replaced by a newer version), please ensure that the new version supports whatever statement you are making in your manuscript and then update your reference

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list accordingly (exceptions could include manuscripts that address items of historical interest). If the reference you are citing has been withdrawn with no clear replacement, please contact the editorial office for assistance (obgyn@greenjournal.org). In most cases, if an ACOG document has been withdrawn, it should not be referenced in your manuscript (exceptions could include manuscripts that address items of historical interest). All ACOG documents (eg, Committee Opinions and Practice Bulletins) may be found via the Clinical Guidance & Publications page at https://nam05.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.acog.org%2FClinical-Guidance-and-Publications%2FSearch-Clinical-Guidance&amp;data=02%7C01%7Cjhao%40geisinger.edu%7C9bc411cffd3f4d27e1da08d71c3dbf41%7C37d46c567c664402a16055c2313b910d%7C0%7C1%7C637008923856562889&amp;sdata=%2F0vgKmWHTiRh8uvHl%2FPrNIGe5mzzBJiJ4VsrFW9Xcg4%3D&amp;reserved=0.

Response: The reference of cited ACOG document is now updated to the current version and confirmed it still supports the statement in manuscript.

17. The Journal's Production Editor had the following to say about the figures in your manuscript: "Figure 1: Please upload a high resolution version of this figure. Figure 2: Please add a y-axis to this figure." When you submit your revision, art saved in a digital format should accompany it. If your figure was created in Microsoft Word, Microsoft Excel, or Microsoft PowerPoint formats, please submit your original source file. Image files should not be copied and pasted into Microsoft Word or Microsoft PowerPoint. When you submit your revision, art saved in a digital format should accompany it. Please upload each figure as a separate file to Editorial Manager (do not embed the figure in your manuscript file). If the figures were created using a statistical program (eg, STATA, SPSS, SAS), please submit PDF or EPS files generated directly from the statistical program. Figures should be saved as high-resolution TIFF files. The minimum requirements for resolution are 300 dpi for color or black and white photographs, and 600 dpi for images containing a photograph with text labeling or thin lines. Art that is low resolution, digitized, adapted from slides, or downloaded from the Internet may not reproduce.

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Response: Figure 1 is now saved as high resolution. Figure 2, y-axis is added. Please let us know if further adjustments are needed.

18. Authors whose manuscripts have been accepted for publication have the option to pay an article processing charge and publish open access. With this choice, articles are made freely available online immediately upon publication. An information sheet is available at https://nam05.safelinks.protection.outlook.com/?url=http%3A%2F%2Flinks.lww.com%2FLWW-ES%2FA48&amp;data=02%7C01%7Cjhao%40geisinger.edu%7C9bc411cffd3f4d27e1da08d71c3dbf41%7C37d46c567c664402a16055c2313b910d%7C0%7C1%7C637008923856562889&amp;sdata=H2J7sisZTXctS9fMtgk%2FeiLDFah0o5UJiVWLD979t4o%3D&amp;reserved=0. The cost for publishing an article as open access can be found at https://nam05.safelinks.protection.outlook.com/?url=http%3A%2F%2Fedmgr.ovid.com%2Facd%2Faccounts%2Fifauth.htm&amp;data=02%7C01%7Cjhao%40geisinger.edu%7C9bc411cffd3f4d27e1da08d71c3dbf41%7C37d46c567c664402a16055c2313b910d%7C0%7C1%7C637008923856562889&amp;sdata=DaCfGhIHFIL7gBi3L2AepR7JMpuLHYHi0Q3VuRJqR2w%3D&amp;reserved=0. Please note that if your article is accepted, you will receive an email from the editorial office asking you to choose a publication route (traditional or open access). Please keep an eye out for that future email and be sure to respond to it promptly.

Response: Ok. Thanks for letting us know. Will keep an eye on this email.