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Date: 11/18/2022
To: "Elizabeth A Suarez"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1836
RE: Manuscript Number ONG-22-1836
Postpartum Opioid-Related Mortality in Publicly Insured Patients Dear Dr. Suarez:
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.
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EDITOR COMMENTS:
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REVIEWER COMMENTS:
Reviewer #1:
This is a cohort study evaluating the incidence and risk factors for postpartum opioid overdose deaths among individuals with opioid use disorder using healthcare utilization data from the Medicaid Analytic eXtract (MAX) linked to the National Death Index in the US from 2006-2013. Pregnant individuals with opioid use disorder have a higher incidence of
postpartum death due to opioid overdose and other preventable premature deaths compared to postpartum individuals without opioid use disorder. Use of medication assisted therapy for opioid use disorder is associated with lower opioid- related mortality.
Abstract:
1. Line 10 - Saying "diagnosed" implies these patients were just diagnosed with opioid use disorder. It seems to be more that they were documented to have opioid use disorder.
2. Methods - I'd recommend briefly describing statistical methods used.
Introduction
The introduction is of appropriate length. The authors made a convincing case for the need to complete this study.
View Letter
4 12/12/2022, 3:04 PM
1. Line 34-35 - Citation for this would be helpful.
Methods
1. Line 53 - May be helpful to explain why 3 months of continuous coverage was chosen.
2. Line 61 - Unclear why table denotations are "e"Table. This occurs throughout the paper.
3. Line 90 - Would be helpful to define severe maternal morbidity 4. Line 96 - Was re-enrollment documented/accounted for?
Results
1. Line 144 - Do you have any data on type of medication assisted therapy?
Discussion
A thorough, clear discussion of the strengths and weaknesses of the study. I would recommend including support for why data from prior to 2013 is relevant to 2022, more so than just stating OUD remains prevalent.
Reviewer #2:
General:
This submission describes the incidence and associated characteristics for maternal mortality in the initial 12 months following delivery in patients with opioid use disorder (OUD) in comparison to the general population.
1. The manuscript is impressively articulate.
2. Why was a 12-month postpartum interval selected? Most physicians would consider the postpartum interval (at least that which falls under the purveyance of obstetrics) to comprise the initial 6-weeks following delivery.
3. (Lines 15-23): Consider including data from the comparative group (general population) in the Results section of the abstract (Figure 2).
4. (Lines 27-28): The authors describe "increased support during the first year is critical" for OUD patients; as the current manuscript is exclusively descriptive and does not address efficacy of potential interventions consider omitting this sentence.
5. (Line 95): Per my review of the study methodology, the authors compared the mortality rates in the OUD patient subgroup to the entire Medicaid population; if this is correct, would it potentially be more valid to compare the mortality rates in the OUD patients to the Medicaid population absent the OUD subgroup (essentially comparing OUD to non-OUD mortality rates)?
6. The included patient population spans the years of 2006-2016; were ICD-10 codes (Line 64) in effect during this interval? My understanding is that these were phased in during the mid-2010s, with ICD-9 codes utilized prior to this time.
7. (Line 54): I am presuming "3 months prior to delivery" included deliveries occurring at viable gestational ages (i.e. not including miscarriages or previable deliveries); however this should be clarified.
8. (Line 70): Why do the authors speculate the rate of maternal death due to opioid overdose is under-reported, particularly as the incidence in the current study is approximately 20-fold higher than the general population?
9. (Line 72): The rationale of including all maternal deaths coded as either opioid overdose or to which OUD is a "primary or contributing cause" as opioid overdose is unclear; this would seem to artificially inflate the frequency of opioid
overdose?
10. Was the source data sufficiently detailed to allow the authors to determine any correlation between preterm delivery (more common in the OUD population) and maternal mortality?
11. Similarly, did any correlation exist for method of delivery?
12. Recognizing the absolute values will be small, consider adding percentages to the incidences described in the paragraph from Lines 123-130.
13. (Lines 129-130) If the timing of maternal mortalities was similar to the general population, would this not suggest that perhaps the antecedent pregnancy represented an incidental event? (i.e. is this a limitation of the analysis?)
14. (Line 206): Only 28% of opioid overdose deaths occurred in the OUD population; could this provide a potential explanation for the higher rate of postpartum opioid prescriptions to this group? (i.e. providers may be less reluctant to prescribe opioids to a non-OUD population)
View Letter
2 of 4 12/12/2022, 3:04 PM
15. (Lines 206-209) As the authors note, only 40% (composite of antepartum and postpartum) of patients who died from opioid overdose carried an antecedent diagnosis f OUD; this would seem to inherently limit potential opportunities for intervention (Line 202, Lines 253-258). Is the source data set sufficient to discriminate between prescription and illicit substance overdose?
16. (Line 225): Given that OAT in the OUD population was associated with reduced risk of opioid overdose-related mortality, why do the authors feel that "all-cause" mortality reduction could be secondary to misclassification? Although this may be correct, I would suggest providing a rationale.
Reviewer #3:
This manuscript is an analysis of data from 2006-2013 examining postpartum deaths related to OUD. Maternal death remains inconsistently assessed and this manuscript details the methods of death clearly and explicitly, including all manners of death (often omitted from other maternal death publications). The approach is one that has been reported before to address large database linkages-a methodology required to study a rare event.
Postpartum data in general are difficult to analyze due to the number of places postpartum patients may receive care, with claims data being the best approach to identification of care over a long period of time-a year. The combination of large database and use of claims data are significant strengths of the study of an important topic. This is a very well done and written manuscript of a critical topic; the methods were complicated and very well described.
Of the comments below, each issue was addressed in the manuscript, just might be emphasized sooner to help the reader.
There are a few clarifications that will help:
(1) The methods clearly describe the process if case identification linked to delivery and death data and the inclusion of deaths that occurred specifically the year after delivery. The use of the term pregnancy deaths throughout the manuscript was of course necessary in the context of definition, but in other areas of the manuscript emphasis that these represent postpartum deaths would be helpful to the reader. The sentence on line 45 is an example: examined the cause of death in postpartum individuals and that vulnerability of people with OUD are especially vulnerable in the postpartum period, for example.
(2) Specifically stating when the OUD dx was made (pre-pregnancy, in pregnancy, postpartum, at the time of death) would assist interpretation and emphasize where gaps in identification exist. Appreciate that some the info in the discussion, a sentence in results as the population is described would help
(3) In Table 1 specify if opioid dispensing includes MOUD (best to define who has MOUD and then exclude for clarity) (4) ED utilization is high but is the place of routine OB triage in some places, especially rural areas-I understand not a focus of this paper but understanding these visits in this cohort would be valuable
(5) The number of outpt visits in each group suggests mostly adequate prenatal care-this is just an observation not noted (6) There appears to be an increase in opioid overdose after day 150. It would be quite valuable to know whether the status of MOUD prescribed in pregnancy stopped around that time-I realize different scope of paper but very important to know in this dataset (looks like in fig 3 n=190+38 in preg and postpartum 65+<11 postpartum-so there is a drop off I presume)
(7) Fig 2 invaluable-again understanding impact of leaving MOUD treatment PP contributed to deaths
(8) The identification in Fig 3 that SMM is more common in people with OUD that experience OD death than OUD control is worth more discussion with some discussion of SMM-this could be a clue to a higher risk group
STATISTICAL EDITOR COMMENTS:
lines 115-122: These counts and incidences are important enough to be included in a Table in main text. Should include all point estimates and their CIs.
lines 123-130: These should also in a Table format. However, since the denominator is ~ 49,000, should round all incidence rates to nearest integer per 100,000, not to 0.1 per 100,000. The same applies to Fig 2, column of pregnant individuals with OUD.
View Letter
4 12/12/2022, 3:04 PM
-- Sincerely,
Torri D. Metz, MD, MS Deputy Editor, Obstetrics
The Editors of Obstetrics & Gynecology
__________________________________________________
In compliance with data protection regulations, you may request that we remove your personal registration details at any time. (Use the following URL: https://www.editorialmanager.com/ong/login.asp?a=r). Please contact the publication office if you have any questions.
View Letter
4 12/12/2022, 3:04 PM
Torri D. Metz, MD, MS Deputy Editor, Obstetrics Obstetrics & Gynecology
December 9, 2022
Dear Dr. Metz,
Thank you for your comprehensive review of our study. Informed by the reviewers’ and editors’ comments, we have made revisions to the manuscript that we believe have improved the presentation and discussion of our study. We have responded to specific reviewer
comments below.
Thank you for considering our revised manuscript. We look forward to your decision.
Sincerely, Elizabeth Suarez
REVIEWER COMMENTS:
Reviewer #1:
This is a cohort study evaluating the incidence and risk factors for postpartum opioid overdose deaths among individuals with opioid use disorder using healthcare utilization data from the Medicaid Analytic eXtract (MAX) linked to the National Death Index in the US from 2006-2013.
Pregnant individuals with opioid use disorder have a higher incidence of postpartum death due to opioid overdose and other preventable premature deaths compared to postpartum individuals without opioid use disorder. Use of medication assisted therapy for opioid use disorder is
associated with lower opioid-related mortality.
Abstract:
1. Line 10 - Saying "diagnosed" implies these patients were just diagnosed with opioid use disorder. It seems to be more that they were documented to have opioid use disorder.
Response: Thank you for noting this. We have updated references of “diagnosis” of opioid use disorder to “record of” throughout the paper.
2. Methods - I'd recommend briefly describing statistical methods used.
Response: We have added the following to the abstract (addition underlined): “Risk factors for opioid overdose death were assessed using odds ratios and descriptive statistics and included demographics, health care utilization, obstetric conditions, comorbidities, and medications used.”
Introduction
The introduction is of appropriate length. The authors made a convincing case for the need to complete this study.
3. Line 34-35 - Citation for this would be helpful.
Response: Citations for the statement that “individuals with OUD may be at increased risk for other causes of maternal mortality” appear in the lines following this statement. We note a potential increased risk of suicide, homicide, drug-related accidents, medical complications, and obstetric complications, with citations.
Methods
4. Line 53 - May be helpful to explain why 3 months of continuous coverage was chosen.
Response: We required 3 months of continuous coverage to allow for measurement of risk factors prior to delivery. We chose 3 months instead of a longer period prior to delivery to avoid limiting the size our of cohort. Pregnancy is a criterion for Medicaid eligibility, therefore requiring continuous enrollment for a long duration prior to delivery (e.g., for the entire duration of
pregnancy) would exclude many pregnant individuals who became eligible while already pregnant. Requiring enrollment for 3 months prior to delivery balances our concerns about cohort size while still allowing measurement of risk factors through recorded diagnoses in visits prior to delivery.
We have added the following to the paper (lines 56-57): “We required 3 months of continuous enrollment prior to delivery to allow for assessment of OUD and risk factors in pregnancy.”
5. Line 61 - Unclear why table denotations are "e"Table. This occurs throughout the paper.
Response: The references to “eTable” throughout are for tables in the supplementary materials.
It is unclear if the supplementary materials were properly uploaded in the original submission.
We have ensured they are included in this resubmission, and have updated to style to meet journal requirements (reference to eTables and eFigures now identified with “Appendix #”).
6. Line 90 - Would be helpful to define severe maternal morbidity
Response: We have added the following definition for severe maternal morbidity (lines 96-97, addition underlined): “Delivery characteristics included stillbirth, preterm birth, cesarean delivery, and severe maternal morbidity, which was defined as a composite of potentially life-threatening conditions caused or aggravated by pregnancy (Appendix 3).”
The full list of conditions included in the composite variable are included in Appendix 3.
7. Line 96 - Was re-enrollment documented/accounted for?
Response: We followed individuals until disenrollment and did not assess whether they re- enrolled within the year postpartum. We expect that re-enrollment would be relatively rare.
Results
8. Line 144 - Do you have any data on type of medication assisted therapy?
Response: Yes, we have data on the specific medication used, which included buprenorphine (either monotherapy or naloxone combination therapy) and methadone. Most individuals on OAT in our cohort are treated with buprenorphine, consistent with expected trends of OAT use in pregnancy. However, given the small number of treated OUD patients that have an opioid overdose death in our cohort (<11, with the actual count obscured to follow Centers for
Medicare and Medicaid Services cell size suppression policies), we cannot report on individual medication types in the manuscript.
Discussion
9. A thorough, clear discussion of the strengths and weaknesses of the study. I would recommend including support for why data from prior to 2013 is relevant to 2022, more so than just stating OUD remains prevalent.
Response: Thank you for this comment about the discussion section. Our estimate of the incidence of postpartum opioid overdose death from 2006-2013 is consistent with estimates from more recent data. We found that 10% of postpartum deaths were due to opioid overdose, which is also consistent with more contemporary estimates. In recent years, OUD may be more likely to be diagnosed and recorded; while this likely increases the size of the pregnant
population with OUD, we do not expect this to impact mortality incidence rates.
We have added the following to the paper (lines 248-250, additions underlined): “The data used in this analysis include the most recently available data from the NDI for Medicaid beneficiaries
nationwide, which includes years 2006-2013. Nevertheless, our estimates of the incidence of opioid overdose death and the proportion of postpartum deaths attributable to opioid were consistent with estimates using more recent data.1,13”
Reviewer #2:
General:
This submission describes the incidence and associated characteristics for maternal mortality in the initial 12 months following delivery in patients with opioid use disorder (OUD) in comparison to the general population.
1. The manuscript is impressively articulate.
Response: Thank you for this kind comment about our work.
2. Why was a 12-month postpartum interval selected? Most physicians would consider the postpartum interval (at least that which falls under the purveyance of obstetrics) to comprise the initial 6-weeks following delivery.
Response: The CDC Pregnancy Mortality Surveillance System defines pregnancy-associated mortality as deaths occurring during pregnancy and within one year after delivery. We are unable to assess deaths during pregnancy in our data but assessed death in the year after delivery to enable some comparison between our results and other reports of pregnancy- associated mortality. Additionally, previous evidence showed that approximately half of all drug- related deaths and suicides occurring during pregnancy or within one year after delivery
occurred after 42 days postpartum (Margerison, Obstet Gynecol 2022;139:172–80), suggesting individuals are still at high risk of mortality in this later postpartum period.
3. (Lines 15-23): Consider including data from the comparative group (general population) in the Results section of the abstract (Figure 2).
Response: We include the incidence of postpartum opioid overdose death in the full population of pregnant individuals in the abstract. Due to word count restrictions, it is not feasible to report incidence estimates for other causes of death in the full population in the abstract.
4. (Lines 27-28): The authors describe "increased support during the first year is critical" for OUD patients; as the current manuscript is exclusively descriptive and does not address efficacy of potential interventions consider omitting this sentence.
Response: We have deleted this sentence from the abstract.
5. (Line 95): Per my review of the study methodology, the authors compared the mortality rates in the OUD patient subgroup to the entire Medicaid population; if this is correct, would it potentially be more valid to compare the mortality rates in the OUD patients to the Medicaid population absent the OUD subgroup (essentially comparing OUD to non-OUD mortality rates)?
Response: A comparison of OUD to non-OUD mortality rates would be a valid comparison, however we chose not to define a non-OUD population for multiple reasons. First, we were interested in estimating the incidence of postpartum opioid overdose death in the full Medicaid
population (as well as the incidence of other causes of postpartum death). Second, our project was intended to be descriptive and it was not our objective to make formal inferences
comparing pregnant individuals with and without OUD. Third, since OUD may be
underdiagnosed and under-recorded in claims data, a population without an OUD diagnosis or treatment may not be a completely OUD-free population. Finally, since OUD is rare (occurring in approximately 1% of the cohort), incidence of death is likely to be very similar between the non- OUD cohort and the full cohort.
6. The included patient population spans the years of 2006-2016; were ICD-10 codes (Line 64) in effect during this interval? My understanding is that these were phased in during the mid- 2010s, with ICD-9 codes utilized prior to this time.
Response: ICD-10 codes have been used for cause of death classification on death certificates in the US since 1999. This differs from the ICD-10 Clinical Modification (ICD-10-CM), which is used for clinical documentation and billing and has been used in the US since October 2015.
Our study period includes 2006-2013, therefore only ICD-9-CM codes were used when defining OUD and risk factors.
7. (Line 54): I am presuming "3 months prior to delivery" included deliveries occurring at viable gestational ages (i.e. not including miscarriages or previable deliveries); however this should be clarified.
Response: The cohort included deliveries ending in live birth or stillbirth, as noted on line 53.
The minimum gestational age included is 20 weeks (for stillbirths). Therefore, the period of 3 months prior to delivery encompassed only the pregnancy period for all deliveries included in the cohort.
8. (Line 70): Why do the authors speculate the rate of maternal death due to opioid overdose is under-reported, particularly as the incidence in the current study is approximately 20-fold higher than the general population?
Response: Previous studies have noted that drug-specific overdose deaths are under-reported due to use of non-specific codes for overdoses that do not report a specific drug (Slavova, Public Health Rep 2015;130(4):339–42; and Buchanich, Public Health Rep 2018;133(4):423–
31). We additionally found that some death cases had opioid-specific codes (overdose and opioid use disorder codes) but did not have overdose as the primary cause of death. Both of these scenarios may contribute to an under-reporting of opioid-specific overdose deaths. A discussion of the potential for underestimating the incidence of opioid overdose death can be found on lines 253-258.
9. (Line 72): The rationale of including all maternal deaths coded as either opioid overdose or to which OUD is a "primary or contributing cause" as opioid overdose is unclear; this would seem to artificially inflate the frequency of opioid overdose?
Response: Our definition for opioid overdose death requires that the primary cause of death is drug-related overdose and the contributing cause is due to opioids. This definition is likely very specific but may miss some cases that are not explicitly coded as overdose as the primary cause of death. Therefore, we also included cases where opioid overdose or opioid use disorder are primary or contributing causes. We have revised our description of this sensitivity analysis to better describe what our extended definition captures. Also, we identified a minor mistake in our coding of this extended definition and have corrected the reported estimate of the incidence of
opioid overdose using this definition on lines 140-141 (6 per 100,000 deliveries corrected to 5.8 per 100,000 deliveries).
Changes made to the text (lines 73-78): “In a sensitivity analysis, the definition of opioid
overdose death was broadened to include any death with a code that indicates opioid overdose or OUD as a primary or contributing cause (Appendix 2) in order to capture potential opioid- related cases that did not meet our primary definition of opioid overdose death.”
10. Was the source data sufficiently detailed to allow the authors to determine any correlation between preterm delivery (more common in the OUD population) and maternal mortality?
Response: In Table 3, we report odds ratios for the relationship between preterm birth and opioid overdose death in the OUD population and in the full population. Across both
populations, we observed that preterm birth was associated with an increased incidence of opioid overdose death.
We have added the following to the paper to emphasize this result (line 143-145, addition underlined): “Opioid overdose death was more likely among individuals with pregnancy complications (e.g., stillbirth, severe maternal morbidity), preterm birth, cesarean delivery, comorbidities, tobacco use, prescription opioid analgesic indications, OUD, and other substance use disorders (Figure 3).”
11. Similarly, did any correlation exist for method of delivery?
Response: In Table 3, we report odds ratios for cesarean delivery and opioid overdose death and observed that having a cesarean delivery was associated with opioid overdose death in both the OUD population and the full population.
We have added the following to the paper to emphasize this result (line 143-145, addition underlined): “Opioid overdose death was more likely among individuals with pregnancy complications (e.g., stillbirth, severe maternal morbidity), preterm birth, cesarean delivery, comorbidities, tobacco use, prescription opioid analgesic indications, OUD, and other substance use disorders (Figure 3).”
12. Recognizing the absolute values will be small, consider adding percentages to the incidences described in the paragraph from Lines 123-130.
Response: To avoid complicating the presentation of results, we present mortality incidence estimates per 100,000 population throughout the paper. This is a common presentation of mortality statistics.
13. (Lines 129-130) If the timing of maternal mortalities was similar to the general population, would this not suggest that perhaps the antecedent pregnancy represented an incidental event? (i.e. is this a limitation of the analysis?)
Response: Our cohort only includes pregnant/postpartum individuals. We did not compare to mortality rates in a non-pregnant/postpartum population. We have clarified this line in the paper to avoid confusion (now lines 137-138): “The timing of maternal deaths was similar to that observed in the full population of postpartum individuals (eFigure 1).”
14. (Line 206): Only 28% of opioid overdose deaths occurred in the OUD population; could this provide a potential explanation for the higher rate of postpartum opioid prescriptions to this group? (i.e. providers may be less reluctant to prescribe opioids to a non-OUD population) Response: We agree that providers may be less likely to prescribe opioids to patients with known opioid use disorder. In our data, postpartum opioid dispensings were more common among individuals with opioid overdose death than the matched controls. This difference was large in the full population (79.3% of opioid overdose deaths vs 56.7% of matched controls had a postpartum opioid dispensing) and smaller in the OUD population (55.3% vs 46.8%,
respectively). In our data, we are unable to directly measure physician willingness to prescribe opioids to postpartum patients, but this is an interesting consideration for future studies.
15. (Lines 206-209) As the authors note, only 40% (composite of antepartum and postpartum) of patients who died from opioid overdose carried an antecedent diagnosis of OUD; this would seem to inherently limit potential opportunities for intervention (Line 202, Lines 253- 258). Is the source data set sufficient to discriminate between prescription and illicit substance overdose?
Response: Thank you for this observation. It is true that many of the potential interventions we noted would require recognition of OUD in the patient. However, it is clear from our data that those patients identified with OUD are a particularly high-risk group that would benefit substantially from increased intervention.
The ICD-10 codes used to identify the overdose as opioid-related offer some specificity about the type of opioid (opium, heroin, methadone, other opioids, other synthetic narcotics, other and unspecified narcotics). However, this is not enough information to classify the source as
prescription or illicit in most cases (except for the opium and heroin codes).
16. (Line 225): Given that OAT in the OUD population was associated with reduced risk of opioid overdose-related mortality, why do the authors feel that "all-cause" mortality reduction could be secondary to misclassification? Although this may be correct, I would suggest providing a rationale.
Response: Our statement on line 225 (now line 233) is specific to non-opioid related deaths, not all-cause deaths (which would include opioid overdose deaths). We did not intend to imply that misclassification of cause of death was the primary reason why we observed an association between OAT and lower risk of non-opioid overdose death. This line in the discussion lists potential reasons for this decrease in non-opioid related mortality with OAT in the OUD population, which includes misclassification (some non-opioid deaths are actually opioid overdoses) and indirect benefits through overall better health and care.
Reviewer #3:
This manuscript is an analysis of data from 2006-2013 examining postpartum deaths related to OUD. Maternal death remains inconsistently assessed and this manuscript details the methods of death clearly and explicitly, including all manners of death (often omitted from other maternal death publications). The approach is one that has been reported before to address large database linkages-a methodology required to study a rare event.
Postpartum data in general are difficult to analyze due to the number of places postpartum patients may receive care, with claims data being the best approach to identification of care
over a long period of time-a year. The combination of large database and use of claims data are significant strengths of the study of an important topic. This is a very well done and written manuscript of a critical topic; the methods were complicated and very well described.
Of the comments below, each issue was addressed in the manuscript, just might be emphasized sooner to help the reader. There are a few clarifications that will help:
1. The methods clearly describe the process if case identification linked to delivery and death data and the inclusion of deaths that occurred specifically the year after delivery. The use of the term pregnancy deaths throughout the manuscript was of course necessary in the context of definition, but in other areas of the manuscript emphasis that these represent postpartum deaths would be helpful to the reader. The sentence on line 45 is an example:
examined the cause of death in postpartum individuals and that vulnerability of people with OUD are especially vulnerable in the postpartum period, for example.
Response: Thank you for noting this useful clarification. We have made edits throughout the manuscript to clearly identify the deaths as occurring in the postpartum period.
2. Specifically stating when the OUD dx was made (pre-pregnancy, in pregnancy, postpartum, at the time of death) would assist interpretation and emphasize where gaps in identification exist. Appreciate that some the info in the discussion, a sentence in results as the
population is described would help.
Response: We assessed OUD in the 3 months prior to delivery, including the delivery encounter. We cannot differentiate between new diagnoses and documentation of prevalent conditions in this 3-month period. In response to comment 1 by reviewer 1, we have changed
“diagnosed OUD” to “record of OUD” throughout the manuscript to avoid implying that we are capturing new diagnoses. This assessment window is reported in the methods under
“Pregnancy cohort and linkage to NDI” (lines 62-63).
3. In Table 1 specify if opioid dispensing includes MOUD (best to define who has MOUD and then exclude for clarity)
Response: Opioid dispensings reported in Table 1 do not include MOUD. We have added the following to the methods section to clarify this definition (line 97-101, additions underlined):
“Healthcare utilization metrics were assessed both during the 3 months prior to delivery and during the postpartum period and included receipt of OAT as well as the number of opioid dispensings (excluding medications for OAT), outpatient visits, emergency department visits, inpatient visits, and distinct generic prescription drugs dispensed.”
4. ED utilization is high but is the place of routine OB triage in some places, especially rural areas-I understand not a focus of this paper but understanding these visits in this cohort would be valuable
Response: Thank you for noting this. We agree that an analysis of the diagnoses related to emergency room visits (and other healthcare visits) leading up to the overdose event would be useful information for future studies.
5. The number of outpt visits in each group suggests mostly adequate prenatal care-this is just an observation not noted
Response: The assessment of healthcare utilization during pregnancy includes visits occurring in the 3 months prior to delivery, therefore we cannot comment on the adequacy of prenatal care throughout pregnancy. However, we do agree that there appears to be high utilization of outpatient services in this cohort.
6. There appears to be an increase in opioid overdose after day 150. It would be quite
valuable to know whether the status of MOUD prescribed in pregnancy stopped around that time-I realize different scope of paper but very important to know in this dataset (looks like in fig 3 n=190+38 in preg and postpartum 65+<11 postpartum-so there is a drop off I presume) Response: Of the individuals that had an opioid overdose death, a very small number were on OAT in pregnancy (<11, as reported in Figure 3). Among those, less than 50% had evidence of continued OAT postpartum. However, due to this small number of individuals on OAT who have an opioid overdose postpartum, it is difficult to draw conclusions about timing of OAT
discontinuation and overdose. We are currently working on a related paper in Medicaid data assessing retention in treatment during pregnancy and the postpartum period and the risk of overdose (both fatal and non-fatal events) using a larger cohort of pregnant individuals from 2000-2018.
7. Fig 2 invaluable-again understanding impact of leaving MOUD treatment PP contributed to deaths
Response: Of the individuals with a non-opioid overdose death, 22 were on OAT in pregnancy and 16 were on OAT postpartum (as reported in Appendix 5). We did not assess how many patients who were on OAT in pregnancy continued treatment postpartum, but these numbers suggest there is a drop in utilization of OAT in the postpartum period.
8. The identification in Fig 3 that SMM is more common in people with OUD that experience OD death than OUD control is worth more discussion with some discussion of SMM-this could be a clue to a higher risk group
Response: Thank you for this observation. We have added a short discussion of this to the paper (lines 183-185): “Pregnant individuals with OUD are at greater risk of severe maternal morbidity. We found that OUD patients with severe maternal morbidity had a much greater risk of opioid overdose death, signaling that severe maternal morbidity is a marker of a particularly high-risk group.”
STATISTICAL EDITOR COMMENTS:
1. lines 115-122: These counts and incidences are important enough to be included in a Table in main text. Should include all point estimates and their CIs.
Response: We have updated Figure 2 to include the cumulative incidence of mortality by any cause and to include the counts for each population size. The cumulative incidence estimates with confidence intervals for specific causes of death are included in Figure 2. We do not present counts of deaths by each cause because counts for many categories, especially for the OUD population, are <11. We are required to obscure counts of <11 to follow Centers for Medicare and Medicaid Services cell size suppression policies. If the editor prefers we present all cumulative incidence estimates in table format instead of inclusion of Figure 2, we can make
that change.
2. lines 123-130: These should also in a Table format. However, since the denominator is ~ 49,000, should round all incidence rates to nearest integer per 100,000, not to 0.1 per 100,000. The same applies to Fig 2, column of pregnant individuals with OUD.
Response: Thank you for this suggestion. We have updated the text and Figure 2 to round to the nearest integer per 100,000 for the OUD population. As noted above, the cumulative incidence estimates by cause of death are presented in Figure 2. If preferred these can be reported in a table in place of Figure 2.