adenomyosis incidence, prevalence and treatment: … · 2 24 condensation: a recent 10-year...
Post on 26-Aug-2020
1 Views
Preview:
TRANSCRIPT
Journal Pre-proof
ADENOMYOSIS INCIDENCE, PREVALENCE AND TREATMENT: UNITED STATESPOPULATION-BASED STUDY 2006-2015
Onchee YU, MS, Renate SCHULZE-RATH, MD, Ms. Jane GRAFTON, BS, Ms. KellyHANSEN, BS, Delia SCHOLES, PhD, Susan D. REED, MD, MPH
PII: S0002-9378(20)30023-5
DOI: https://doi.org/10.1016/j.ajog.2020.01.016
Reference: YMOB 13054
To appear in: American Journal of Obstetrics and Gynecology
Received Date: 23 August 2019
Revised Date: 9 January 2020
Accepted Date: 9 January 2020
Please cite this article as: YU O, SCHULZE-RATH R, Jane GRAFTON M, Kelly HANSEN M, SCHOLESD, REED SD, ADENOMYOSIS INCIDENCE, PREVALENCE AND TREATMENT: UNITED STATESPOPULATION-BASED STUDY 2006-2015 American Journal of Obstetrics and Gynecology (2020), doi:https://doi.org/10.1016/j.ajog.2020.01.016.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Inc.
1
ADENOMYOSIS INCIDENCE, PREVALENCE AND TREATMENT: UNITED STATES 1
POPULATION-BASED STUDY 2006-2015 2
Authors: Onchee YU, MS1, Renate SCHULZE-RATH, MD2, Ms. Jane GRAFTON, BS1, 3
Ms. Kelly HANSEN, BS1, Delia SCHOLES, PhD1, Susan D. REED, MD, MPH3 4
Author affiliations: 5
1 Kaiser Permanente Washington Health Research Institute, Kaiser Permanente 6
Washington, Seattle, Washington, USA 7
2 Global Epidemiology, Bayer AG, Berlin, Germany 8
3 Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, 9
Washington, USA 10
Disclosures: Dr. Schulze-Rath is employed by Bayer and all other authors receive 11
research funding from Bayer AG. 12
Presentation: Oral presentation at the Society of Endometriosis and Uterine Disorders 13
Annual Meeting, May 15-18, 2019, Montreal, Quebec Canada 14
Funding Source: Bayer AG provided financial support for the conduct of the research. 15
Bayer did not have a role in the study design; data collection, analysis and interpretation 16
of data or in the writing of the report; and in the decision to submit the article for 17
publication. Bayer did review the manuscript prior to publication. 18
Corresponding author: 19
Susan D. Reed, MD, MPH 20
Professor and Vice Chair, Department of Obstetrics and Gynecology 21
University of Washington School of Medicine 22
Telephone: (206) 667-6509, Fax:206 744-5249, reeds@uw.edu 23
2
Condensation: A recent 10-year population-based cohort shows a 1% incidence of 24
adenomyosis among women ages 16-60 years; incidence was higher among black vs 25
white women. 26
Short Title: Adenomyosis Incidence, Prevalence, Trends and Treatment 27
AJOG at a Glance 28
A. Why was the study conducted? 29
• Adenomyosis symptoms are disabling. 30
• Population-based cohort studies of incidence, prevalence, trends and 31
treatment of adenomyosis are lacking. 32
B. What are the key findings? 33
• Overall incidence among 333,693 women ages 16-60 (2006-2015) was 1%; 34
higher for black vs white women and highest for ages 41-45. 35
• 91% of incident cases had ICD-9 symptom-related codes. 36
• Adenomyosis co-occurrence was: 18% endometriosis and 47% uterine 37
fibroids. 38
• 82% of women had hysterectomies, almost 70% had imaging studies 39
suggestive of adenomyosis, and 38% used chronic pain medications. 40
C. What does this study add to what is already known? 41
• Women in their early 40s are at highest risk for symptomatic adenomyosis. 42
• Incidence rates are disproportionately high among black women. 43
• Co-occurrence with uterine fibroids and endometriosis is high. 44
• Health care burden is substantial. 45
3
Key words: abnormal uterine bleeding, chart review, diagnosis codes, diagnostic 46
accuracy, dysmenorrhea, electronic health record, endometriosis, health care utilization, 47
hysterectomy, menorrhagia, positive predictive value, secular trends, treatment 48
patterns, uterine fibroids 49
4
Structured Abstract 50
Background: Adenomyosis symptoms are disabling. Population-based data on 51
incidence and prevalence of adenomyosis are lacking that could guide future evidence-52
based treatments and clinical management. 53
Objective: To evaluate the incidence, 10-year secular trends, and prevalence of 54
adenomyosis diagnoses and to describe symptoms and treatment patterns in a large 55
U.S. cohort. 56
Study Design: We performed a retrospective population-based cohort study of women 57
aged 16-60 years of age in 2006-2015, enrolled in Kaiser Permanente Washington, a 58
mixed-model health insurance and care delivery system. Adenomyosis diagnoses 59
identified by International Classification of Diseases (ICD) 9th and 10th edition codes and 60
potential covariates were extracted from computerized databases. Women with prior 61
hysterectomy, and for incidence estimates women with prior adenomyosis diagnoses, 62
were excluded. Linear trends in incidence rates over the 10-year study period were 63
evaluated using Poisson regression. Rates and trend tests were examined for all 64
women adjusting for age using direct standardization to the 2015 study population, by 65
age groups, and by race/ethnicity. Chart reviews were performed to validate diagnostic 66
accuracy of ICD codes in identifying adenomyosis incidence. Symptoms and treatment 67
patterns at diagnosis and in the following 5 years were assessed. 68
Results: 333,693 women contributed 1,185,855 woman-years (2006-2015) for 69
incidence calculations. Associated symptom-related codes (menorrhagia or abnormal 70
uterine bleeding, dysmenorrhea or pelvic pain, dyspareunia, and infertility) were 71
observed in 90.8%; 18.0% had co-occurrent endometriosis codes and 47.6% had co-72
5
occurrent uterine fibroid codes. The overall adenomyosis incidence was 1.03% or 28.9 73
per 10,000 woman-years with a high of 30.6 in 2007 and a low of 24.4 in 2014. Overall 74
age-adjusted estimated incidence rates declined during the 10-year study interval 75
(linear trend p<0.05). Incidence was highest for women 41-45 years (69.1 per 10,000 76
woman-years in 2008) and was higher for black (highest 44.6 per 10,000 woman-years 77
in 2011) vs white women (highest 27.9 per 10,000 woman-years in 2010). Overall 78
prevalence in 2015 was 0.8% and was highest among women aged 41-45 (1.5%). 79
Among the 624 potential adenomyosis cases identified by diagnostic codes in 2012-80
2015 and with sufficient information in the medical record to determine true case status, 81
490 were confirmed as incident cases, yielding a 78.5% (95% confidence interval: 82
75.1%, 81.7%) positive predictive value of adenomyosis ICD-9/ICD-10 codes for 83
identifying an incident adenomyosis case. Health care burden was substantial: 82.0% of 84
women had hysterectomies, nearly 70% had imaging studies suggestive of 85
adenomyosis, and 37.6% used chronic pain medications. 86
Conclusions: Adenomyosis burden to the individual and the health care system is 87
high. Incidence rates are disproportionately high among black women. These findings 88
are of concern, as currently available long-term medical therapies remain limited 89
beyond hysterectomy. Our data and methodologies are novel and could serve as a 90
foundation to guide clinicians and health care systems to develop clinical management 91
plans and track outcomes for women with adenomyosis. 92
6
INTRODUCTION 93
Adenomyosis is the aberrant location of endometrial glandular tissue within the 94
uterine myometrium[1] often associated with cyclical uterine pain, dyspareunia, 95
abnormal uterine bleeding (AUB) such as menorrhagia, spotting or bleeding before and 96
after menses and infertility.[2] Adenomyosis may be associated with endometriosis and 97
uterine fibroids.[3, 4] Until the last decade adenomyosis was considered a surgical 98
diagnosis made at the time of hysterectomy. But increasingly, imaging studies, 99
particularly pelvic ultrasound, has defined features indicative of adenomyosis, including 100
a globular enlarged uterus, indistinct or irregular endometrial myometrial junction, 101
heterogeneous myometrium and myometrial cysts.[5, 6] Diagnostic accuracy of 102
ultrasound for adenomyosis is unknown as prior studies evaluating this outcome were 103
performed in select populations.[5] 104
Adenomyosis symptoms can be disabling and have been treated medically, 105
despite no FDA approved therapies[1], and surgically.[7] Better data on efficacy of 106
medical treatment would assist women who prefer not to have hysterectomy. Tools that 107
can track adenomyosis incidence, prevalence and treatment response will be important 108
as new therapies targeted at the pathogenesis of the disease - sex steroid regulation, 109
inflammation, apoptosis and neuroangiogenesis manipulation[7, 8] - are developed. 110
Despite considerable public health burden, associated costs of care, and impacts on the 111
lives of many women, reliable population-based incidence estimates of adenomyosis do 112
not exist[3] and studies on prevalence vary widely.[9] To address this gap, we 113
conducted a retrospective cohort study using electronic health records (EHR) to 114
estimate the incidence of symptomatic adenomyosis over a 10-year period (2006-2015) 115
7
and symptomatic adenomyosis prevalence (2015) in a U.S. population. Secondary 116
aims were to estimate incidence rates by age, and by race/ethnicity, to evaluate trends, 117
and to describe symptoms and treatment practice patterns. Furthermore, we performed 118
chart reviews to assess the accuracy of diagnosis codes in identifying incident 119
adenomyosis. We also estimated the proportion of cases who had imaging changes 120
prior to their diagnosis that could be indicative of adenomyosis, thus estimating the 121
proportion of women that might benefit from medical therapies. 122
Methods 123
Study setting and cohort 124
This retrospective cohort study was conducted at Kaiser Permanente 125
Washington (KPWA), a mixed-model health insurance and care delivery system based 126
in Seattle, Washington. KPWA provides comprehensive care on a prepaid basis to 127
approximately 650,000 individuals in 22 Washington counties. It contracts with the KP 128
Physicians group to provide care within an integrated group practice division (GPD) for 129
approximately 70% of enrollees. The remaining 30% are insured by this health plan 130
and receive care from non-KP provider networks located in geographic areas not served 131
by KPWA medical centers. The KPWA population generally reflects the underlying 132
community it serves with respect to age, race, and gender.[10] The cohort consisted of 133
all women ages 16-60 years in 2006-2015 enrolled at KPWA for a minimum of 2 years 134
with at least one health care utilization at KPWA in the 2 years before cohort entry on 135
January 1, 2006 through December 31, 2015. We further restricted to women who did 136
not have a record of hysterectomy at least 61 days (or 2 months) prior to cohort entry. 137
8
All study methods received approval from KPWA’s Human Subjects Institutional Review 138
Board. 139
Data collection 140
We utilized KPWA electronic health care data sources. A notable feature of 141
KPWA is the depth and longevity of its multiple computerized databases, extensively 142
used for patient care and research for nearly 50 years. Information on enrollment, 143
demographics, healthcare utilization, height and weight, diagnoses, procedures, 144
pharmacy dispensings, radiology and laboratory results have been maintained in 145
automated databases since 1977. A fully integrated EHR that documents all patient 146
care and contacts, including clinic notes, phone and email communications in KPWA-147
owned clinics began in 2005. All automated data sources are linked using the 148
member’s unique health record number. 149
Race/ethnicity data were not complete in all years and for women who were not 150
enrolled in the GPD. As a result, the analyses by race/ethnicity were restricted to GPD 151
enrollees. To obtain more complete race/ethnicity data on women enrolled in the GPD, 152
we augmented race/ethnicity data from the EHR with data extracted via Natural 153
Language Processing. Our prior research showed a reduction from 19% to 13% in 154
women with unknown race/ethnicity using these methods.[11] 155
Identification of adenomyosis cases and potentially associated symptoms 156
We identified incident adenomyosis cases by selecting all women with 157
International Classification of Diseases, 9th revision (ICD-9) diagnosis code 617.0 or 10th 158
revision (ICD-10) N80.0. We restricted the analyses of potential incident cases to 159
women without an adenomyosis diagnosis in the 2 years prior to study entry. To assess 160
9
the current burden of disease, we estimated adenomyosis prevalence among women 161
enrollees in 2015 regardless of their history of adenomyosis diagnosis. 162
Symptoms and two conditions potentially associated with adenomyosis were 163
identified from ICD-9 diagnosis codes (Table 1). 164
Description of treatment and utilization patterns 165
We assessed treatment and utilization patterns on the incident diagnosis date 166
and in the following 5 years among women who had an ICD-9 adenomyosis code in 167
2006-2010. Four treatments were of interest: 1) hysterectomy (61 days prior to 168
diagnosis through 5 years post-diagnosis) as identified by procedure codes, 2) 169
laparoscopy and/or laparotomy from procedure codes, 3) dispensing of pain 170
medications including opioid and nonsteroidal anti-inflammatory drugs (NSAID) in the 171
pharmacy data, and 4) dispensing of hormone medications including progesterone, oral 172
contraceptives, danazol, progesterone intrauterine devices, and gonadotropin releasing 173
hormone (GnRH) antagonists. For pain medication use, we further identified chronic 174
users as women who had at least 7 fills of opioid and/or NSAIDs which equated to 175
approximately 7 months of use. For hormone medication use, we defined chronic users 176
as those women who had at least 3 fills of oral progesterone and/or oral contraception, 177
at least 3 fills of danazol, at least 3 injectable progesterone fills, any implant 178
progesterone, any progesterone intrauterine devices, or GnRH injections which equated 179
to over 6 months of use. 180
Case validation 181
Two trained abstractors and a study clinician (SDR) reviewed medical records of 182
enrollees with adenomyosis diagnosis codes in years 2012-2015. True incident cases 183
10
identified at chart review were women who had surgical or imaging diagnosis of 184
adenomyosis in the index period (defined as 60 days before and 60 days after the 185
automated index diagnosis date) without a prior adenomyosis code and without prior 186
imaging studies with possible or probable adenomyosis. By definition, incident cases 187
diagnosed by imaging had the word “adenomyosis” in the body or in the impression of 188
the imaging report. Cases defined by imaging could include words like “possible, 189
probable, or unable to rule out” adenomyosis. Incident cases may have had prior 190
imaging with characteristics suggestive of adenomyosis but without the word 191
“adenomyosis” in the imaging report. 192
Statistical analyses 193
Women contributed person-time from the date when they became eligible for the 194
study through the earliest date of disenrollment from KPWA, their 61st birthday, date of 195
hysterectomy (if it occurred after study entry), or study end date of December 31, 2015. 196
Annual incidence rates of adenomyosis were calculated for all women (16-60 years), 197
age-adjusted using direct standardization to the 2015 study population. Linear trends in 198
annual adenomyosis incidence rates over the 10-year study period (2006-2015) were 199
evaluated using Poisson regression. Rates and linear trends were also examined for 200
each 5-year age group (16-20 years through 56-60 years). 201
We examined annual adenomyosis incidence rates by race/ethnicity among 202
women enrollees in GPD only (due to more complete race/ethnicity capture). Groups 203
included Hispanic, and non-Hispanic groups: black, white, Asian, Hawaiian/Pacific 204
Islander, Native American, and other or unknown race/ethnicity. Annual incidence rates 205
11
were calculated for all women in each race/ethnicity group, age-adjusted using direct 206
standardization to the 2015 race/ethnicity-specific study cohort. 207
We estimated the overall and age-specific prevalence of adenomyosis for the 208
most recent study year (2015). The denominator consisted of all women who 209
contributed any person-time in 2015; women who also received an adenomyosis 210
diagnosis during or before 2015 comprised the numerator. 211
Among women with an incident adenomyosis diagnosis in 2006-2010, the 212
proportions with symptoms potentially associated with adenomyosis in the 2 years prior 213
to and 5 years following the diagnosis were calculated. We also estimated the 214
proportion of incident cases who had an ICD-9 code for uterine fibroids or 215
endometriosis. Treatment and utilization patterns were assessed by determining the 216
proportions of women who experienced a surgical procedure or had a medication fill on 217
the day of diagnosis or in the following 5 years. 218
To determine the accuracy of ICD codes in identifying incident cases of 219
adenomyosis, positive predictive values (PPV) were calculated from chart review 220
(proportion of true cases among all potential cases identified by ICD codes). We 221
estimated the proportion of incident cases who had prior ultrasounds with characteristic 222
features of adenomyosis, but without the word “adenomyosis” in the imaging report. 223
The proportion of cases identified by imaging with surgical confirmation was estimated. 224
RESULTS 225
Adenomyosis incidence and prevalence 226
A total of 333,693 women without an adenomyosis diagnosis in the past 2 years 227
contributed 1,185,855 woman-years during the 10-year study period. Of these, 3,425 228
12
women received a first diagnosis of adenomyosis and were considered potential 229
incident cases. Mean age at study cohort entry was 41.5 years for case women and 230
37.5 years for non-case women (Table 2). Women with adenomyosis diagnoses were 231
more likely to be non-Hispanic black. Among 3,425 women with an incident diagnosis 232
of adenomyosis, 47.7% received the diagnosis during an inpatient stay and 40.3% 233
during an outpatient visit. On the date of adenomyosis diagnosis, 18.0% were also 234
diagnosed with endometriosis and 47.6% were also diagnosed with uterine fibroid(s). 235
The overall incidence of adenomyosis was 1.03% or 28.9 per 10,000 women-236
years with a high of 30.6 per 10,000 women-years in 2007 and a low of 24.4 in 2014 237
(Figure 1). Incidence was highest for women ages 41-45 years and peaked at 69.1 per 238
10,000 women-years in 2008. Adenomyosis incidence was significantly lower among 239
Asian women in 2010, 2012 and 2015, and higher among non-Hispanic black women in 240
2008, 2009, 2011 and 2013 (highest 44.6 per 10,000 woman-years in 2011) compared 241
with Non-Hispanic white women (highest 27.9 per 10,000 woman-years in 2010) (Figure 242
2). Incidence rates declined significantly over the 10-year study interval overall, and 243
among women ages 36-40 years (p-values for linear trend<0.05). Adenomyosis 244
diagnosed during an inpatient visit decreased over time (from 70% in the first 3 years of 245
the study to 25% in the last 3 years of the study), while diagnosis during an outpatient 246
visit increased. 247
A total of 135,162 women ages 16-60 years contributed person-time in 2015 with 248
1,068 having a previous adenomyosis diagnosis. Thus, the prevalence of adenomyosis 249
in 2015 was 0.8%; it was highest among women ages 41-45 years at 1.5% (Figure 3). 250
Symptoms and treatments 251
13
Among 1,768 incident adenomyosis cases diagnosed 2006-2010, ICD-9 codes 252
consistent with 4 potential adenomyosis symptom groups (menorrhagia or abnormal 253
uterine bleeding, dysmenorrhea or pelvic pain, dyspareunia, and infertility) were noted 254
in 90.8% of cases. Over half of women experienced at least 2 symptoms, with 255
abnormal bleeding or menorrhagia being the most common (78.9%) followed by 256
dysmenorrhea or pelvic pain (63.0%). 257
Almost all women (96.3%) received at least 1 of the 4 treatments of interest. 258
Overall, 82.0% of incident cases underwent hysterectomy, and 21.7% had a 259
laparoscopy or laparotomy (Table 3). Over 72% of adenomyosis cases used pain 260
medications; 37.6% were chronic users. Less than 20% used hormone medications; 261
10.4% were chronic users. Hysterectomy occurred more often among older women 262
(46-60 years), while laparoscopy/laparotomy was more common in younger women (16-263
45 years). Hormone therapy was more common among younger women and use was 264
often long-term. There was no difference in pain medication use between younger and 265
older women. However, there were slightly more chronic pain medication users among 266
younger women. 267
Accuracy of adenomyosis diagnosis codes 268
Chart review was completed on 642 potential incident adenomyosis cases 269
identified by ICD-9/ICD-10 codes in 2012-2015. There were 152 (23.7%) women, who 270
did not have a current diagnosis of adenomyosis confirmed at surgery or with 271
“adenomyosis” diagnosed on imaging report. Of these 152 women, 18 (2.8%) had 272
insufficient information in the chart and 7 (1.1%) had sufficient information but no 273
rationale for an assigned adenomyosis ICD code. Adenomyosis was diagnosed outside 274
14
of the index period in 47 (7.3%), endometriosis and not adenomyosis was diagnosed in 275
55 (8.6%) and 25 (3.9%) women had “other”, likely miscoded diagnoses. 276
Among the 624 potential adenomyosis cases identified by diagnostic codes with 277
sufficient information in the EHR to determine true case status, 490 were confirmed as 278
incident cases, yielding a 78.5% (95% confidence interval: 75.1%, 81.7%) PPV of 279
adenomyosis ICD-9/ICD-10 codes for identifying an incident adenomyosis case. 280
Adenomyosis and imaging 281
Of the 490 women with incident adenomyosis confirmed on chart review, 482 282
(98.4%) had surgical confirmation during or after the index period; the remaining 8 283
(1.6%) were diagnosed by imaging only. Nearly one-third of the 482 women with a 284
surgical diagnosis of incident adenomyosis also had pre-operative imaging findings 285
compatible with adenomyosis (149 or 30.9%). Out of the 490 women with incident 286
adenomyosis, 180 (36.7%) had prior imaging during the study period with 287
characteristics of adenomyosis [5,6], but the word adenomyosis was not found in the 288
report. Thus, nearly 70% of confirmed incident adenomyosis cases had imaging 289
diagnoses or characteristics consistent with adenomyosis at or prior to the incident 290
diagnosis date. 291
STRUCTURED DISCUSSION/COMMENT 292
Principal findings: The incidence of adenomyosis in this relatively large population-293
based cohort was estimated to be 1.03% or 28.9 per 10,000 women-years in a 10-year 294
interval (2006-2015); 90.8% had associated clinical symptoms. Incidence decreased 295
over time and peaked in 2007 at 30.6 per 10,000 women-years. Incident and prevalent 296
cases were most common among women ages 41-45 years. Black women were more 297
15
likely, and Asian women were less likely, than Non-Hispanic white women to have an 298
incident diagnosis of adenomyosis. The overall prevalence of adenomyosis in 2015 299
was 0.8% with a high of 1.5% among women ages 41-45; 34.0% of prevalent cases 300
were over 50. 301
Results: To our knowledge, recent reliable incidence and prevalence estimates 302
from a large population-based study such as these have not been previously 303
described,[3, 9] nor has anyone reported on adenomyosis by race/ethnicity. One Italian 304
study of women ages 15-50 reported age-specific adenomyosis incidence based on 305
adenomyosis diagnosis at hysterectomy identified by automated inpatient hospital 306
discharge records as 0.023% over 3 years (2011-2013), or an average of 0.0077% 307
annually, [11] much lower than our estimates. Adenomyosis prevalence estimated from 308
incidence with various assumptions was 0.13%.[12] Given the disease is cured with 309
hysterectomy, and all cases in this study were identified at hysterectomy, the incidence 310
should have approximated the prevalence estimates. 311
Others have reported 10-57% of women undergoing hysterectomy were 312
diagnosed with adenomyosis.[3, 13-16] Among symptomatic women undergoing a 313
pelvic ultrasound in a general gynecology clinic 21% had an imaging diagnosis of 314
adenomyosis.[4] These reported proportions of women with adenomyosis, where the 315
denominator consists of all women who had hysterectomy or ultrasound, are commonly 316
mistaken for population-based prevalence estimates and if used clinically result in 317
misinformation to patients. 318
16
Concomitant diagnoses of endometriosis (18.0%) or uterine fibroids (47.6%) 319
among our incident adenomyosis cases was common and higher than other reports: 320
endometriosis 3-10%[3, 4, 14, 16, 17] and uterine fibroids 23-37%.[3, 4, 16] 321
A definitive diagnosis of adenomyosis has historically been made surgically, but 322
our study suggested that almost a third of women with a surgical diagnosis of incident 323
adenomyosis had pre-operative imaging findings compatible with adenomyosis. Nearly 324
70% of all confirmed incident adenomyosis cases had imaging with adenomyosis 325
characteristics prior to or on the incident diagnosis date. Recent studies suggest that 326
an imaging diagnosis of adenomyosis may be more accurate than a tissue diagnosis.[5, 327
18] Correlation of imaging diagnosis with tissue diagnosis has been described as 328
moderate, κ= 0.62 (95% CI 0.32-0.91).[4] Imaging studies are increasingly important for 329
the diagnosis of adenomyosis. 330
Clinical Implications: Adenomyosis symptoms can be disabling and despite no FDA 331
approved therapies, medical management is first line therapy, particularly for younger 332
women. [1, 7,19, 20] . Controversy over ideal medical management exists[1, 7, 19] and 333
characterizing medication utilization patterns in a population-based cohort is of 334
importance. Health care utilization was high in our study - 82% of incident adenomyosis 335
cases underwent hysterectomy and nearly 40% used pain medication for over 6 336
months. Hormonal medication use was modest (16%). Women in their early 40s, and 337
particularly black women, who have painful menses or abnormal uterine bleeding 338
deserve pelvic ultrasound evaluation for adenomyosis. Characteristics of adenomyosis 339
on ultrasound likely represent a true diagnosis. Risk of concomitant uterine fibroids or 340
endometriosis is higher than previously recognized. 341
17
Research Implications: Using the methodologies described here, women with 342
diagnostic codes and ultrasound findings suggestive of adenomyosis[5, 18], could be 343
identified in large organizations with EHRs to target therapies, develop practice 344
guidelines, recruit for clinical trials, and evaluate factors associated with adenomyosis 345
(e.g. cancers).[21, 22] Adenomyosis diagnoses could be reliably identified using 346
adenomyosis ICD-9/ICD-10 codes (nearly 80% PPV for new cases). 347
Strengths and Limitations: Our study has multiple strengths. It is population-based 348
and a relatively large cohort, with a chart validation component. Importantly, estimates 349
are not limited to access-to-care issues since all women were insured. Generalizability 350
is unknown as the study was limited to one region of the U.S. with lower prevalence of 351
non-Hispanic black women than other regions in the U.S. Case validation was restricted 352
to a recent 4-year period. The incidence rates that changed over time could be 353
attributed to changes in hysterectomy patterns[23], changes in coding practices or 354
changes in practice patterns (e.g. more therapeutic options and improved diagnostic 355
imaging capabilities in latter study years). 356
Conclusions: Adenomyosis burden to the individual and the health care system is 357
high. Incidence rates are disproportionately high among black women. These findings 358
are of concern, as currently available long-term medical therapies remain limited 359
beyond hysterectomy. Our data and methodologies are novel and serve as a 360
foundation to potentially guide clinicians and health care systems to develop and test 361
treatment plans for women with adenomyosis. Nearly 70% of the incident adenomyosis 362
cases confirmed at chart review in our study had had a prior ultrasound that either 363
diagnosed or was suggestive of adenomyosis – these are the patients who could be 364
18
targeted for treatment interventions and management of this relatively understudied but 365
common gynecologic condition. 366
19
Acknowledgements 367
We appreciate the chart review performed by KPWA employees Ms. Jennifer Covey 368
and Ms. Ann Kelly and the redcap database management by Ms. Jennifer Covey for the 369
case validation. 370
20
References 371
1. Donnez J, Donnez O, Dolmans MM. Introduction: Uterine adenomyosis, another 372
enigmatic disease of our time. Fertil Steril 2018 Mar;109(3):369-70. 373
2. Gordts S, Grimbizis G, Campo R. Symptoms and classification of uterine 374
adenomyosis, including the place of hysteroscopy in diagnosis. Fertil Steril 2018 375
Mar;109(3):380-8e1. 376
3. Weiss G, Maseelal P, Schott LL, Brockwell SE, Schoken M, Johnston JM. 377
Adenomyosis a variant, not a disease? Evidence from hysterectomized 378
menopausal women in the Study of Women's Health Across the Nation (SWAN). 379
Fertil Steril 2009 Jan;91(1):201-6. 380
4. Naftalin J, Hoo W, Pateman K, Mavrelos D, Holland T, Jurkovic D. How common 381
is adenomyosis? A prospective study of prevalence using transvaginal 382
ultrasound in a gynaecology clinic. Hum Reprod 2012 Dec;27(12):3432-9. 383
5. Van den Bosch T, Van Schoubroeck D. Ultrasound diagnosis of endometriosis 384
and adenomyosis: State of the art. Best Pract Res Clin Obstet Gynaecol 2018 385
Aug;51:16-24. 386
6. Tellum T, Nygaard S, Skovholt EK, Qvigstad E, Lieng M. Development of a 387
clinical prediction model for diagnosing adenomyosis. Fertil Steril 2018 388
Oct;110(5):957-64e3. 389
7. Vannuccini S, Luisi S, Tosti C, Sorbi F, Petraglai F. Role of medical therapy in 390
the management of uterine adenomyosis. Fertil Steril 2018 Mar;109(3):398-405. 391
8. Garcia-Solares J, Donnez J, Donnez O, Dolmans MM. Pathogenesis of uterine 392
adenomyosis: invagination or metaplasia? Fertil Steril 2018 Mar;109(3):371-9. 393
21
9. Cunningham RK, Horrow MM, Smith RJ, Springer J. Adenomyosis: A 394
Sonographic Diagnosis. Radiographics 2018 Sept-Oct;38(5):1576-89. 395
10. Yu O, Scholes D, Schulze-Rath R, Grafton J, Hansen K, Reed SD. A US 396
population-based study of uternine fibroid diagnosis incidence, trends and 397
prevalence: 2005 through 2014. Am J Obstet Gynecol 2018 Dec;291(6):591.e1-398
591.e8. 399
11. Grafton J, Yu O, Carrell D, Reed S, Shulze-Rath R, Hansen K, Scholes D. 400
Identifying Race/Ethnicity data via Natural Language Processing Among Women 401
in a Uterine Fibroid Cohort Study. J Patient Cent Res Rev, 2016;3:226. 402
12. Morassutto C, Monasta L, Ricci G, Barbone F, Ronfani L. Incidence and estimated 403
prevalence of endometriosis and adenomyosis in northeast Italy: a data linkage 404
study. PLoS One 2016 Apr 21;11(4):e0154227. 405
13. Bergholt T, EriksenL, Berendt N, Jacobsen M, Hertz JB. Prevalence and risk 406
factors of adenomyosis at hysterectomy. Hum Reprod 2001 Nov;16(11):2418-21. 407
14. Vercellini P, Parazzini F, Oldani S, Panazza S, Bramante T, Crosignani PG. 408
Adenomyosis at hysterectomy: a study on frequesncy distribution and patient 409
characteristics. Hum Reprod 1995 May;10(5):1160-2. 410
15. Shrestha A, Shrestha R, Sedhai LB, Pandit U. Adenomyosis at hysterectomy: 411
prevalence, patient characteristics, clinical profile and histopatholgical findings. 412
Kathmandu Univ Med J (KUMJ) 2012 Jan-Mar;10(37):53-6. 413
16. Shaikh H, Khan KS. Adenomyosis in Pakistani women: four year experience at 414
the Aga Khan University Medical Centre, Karachi. J Clin Pathol 1990 415
Oct;43(10):817-9. 416
22
17. Parazzini F, Verecellini P, Panazza S, Chatenout L, Olidani S, Crosignani PG. 417
Risk factors for adenoymosis. Hum Reprod 1997 Jun;12(6):1275-9. 418
18. Exacoustos C, Zupi E. A new era in diagnosing adenomyosis is coming. Fertil 419
Steril 2018 Oct;110(5):858-62. 420
19. Vannuccini S, Petraglia F. Recent advances in understanding and managing 421
adenomyosis. F1000 Faculty Rev 2019 Mar 13;8(283):1-10. 422
20. De Wilde RL, Wallwiener M, Di Spiezio Sardo A, Tanos V, Becker S. 423
Adenomyosis and Myomata: Risks, Problems, and Complications in Diagnosis 424
and Therapy of Adenomyosis and Myomata. Biomed Res Int 2018 Aug 6; 425
2018:5952460. 426
21. Yeh CC, Su FH, Tzeng CR, Muo CH, Wang WC. Women with adenomyosis are 427
at higher risks of endometrial and thyroid cancers: A population-based historical 428
cohort study. PLoS One 2018 Mar 9;13(3):e0194011. 429
22. Kok VC, Tsai HJ, Su CF, Lee CK. The Risks for Ovarian, Endometrial, Breast, 430
Colorectal, and Other Cancers in Women With Newly Diagnosed Endometriosis 431
or Adenomyosis: A Population-Based Study. Int J Gynecol Cancer 2015 432
Jul;25(6):968-76. 433
23. Morgan D, Kamdar NS, Swenson CW, Kobemik EK, Sammarco AG, Nallamothu 434
B. Nationwide trends in the utilization of and payments for hysterectomy in the 435
United States among commercially insured women. Am J Obstet Gynecol 2018 436
Apr;218(4):425.e1-425.e18. 437
438
439
23
Table 1. ICD-9 diagnosis codes for symptoms and conditions associated with 440
adenomyosis. 441
ICD-9 codes
Symptoms
Menorrhagia or abnormal uterine
bleeding
626.2 excessive bleeding
626.8 other abnormal bleeding
626.9 abnormal bleeding, unspecified
627.0 premenopausal menorrhagia:
excessive bleeding associated with onset of
menopause
Dysmenorrhea or pelvic pain 625.3 dysmenorrhea, painful menstruation
625.9 pelvic pain
626.4 irregular periods
626.6 metrorrhagia, bleeding between
menses
Dyspareunia 625.0 pain with sex (dyspareunia)
Infertility 628.0 infertility, female, associated with
anovulation
628.2 infertility, female, of tubal origin
628.8 infertility, female, of other specified
origin
628.9 infertility, female, of unspecified origin
Related Conditions
24
Uterine fibroids 218 uterine leiomyoma
218.0 submucous leiomyoma of uterus
218.1 intramural leiomyoma of uterus
218.2 subserous leiomyoma of uterus
218.9 leiomyoma of uterus, unspecified
Endometriosis1
617.1 /N80.1 endometriosis, ovary
617.2/N80.3 endometriosis, fallopian tubes
617.3/N80.3 endometriosis, pelvic peritoneum
617.4/N80.4 endometriosis, vagina
617.5/N80.5 endometriosis, intestine
617.6/N80.6 endometriosis in scar of skin
617.8/N80.8 endometriosis, other specified
sites
617.9/N80.9 endometriosis, site unspecified
1 Both ICD-9/ICD-10 codes 442
25
Table 2. Study cohort characteristics by incident adenomyosis case status in 2006-443
2015 defined by ICD-9/10 adenomyosis diagnosis codes. 444
Adenomyosis Diagnosis
Yes
(n=3425)
No
(n=330268)
N % N %
Age at study entry1, years
Mean (SD) 41.5 7.7 37.5 14.3
Median 42 39
16-20 34 1 53804 16.3
21-25 42 1.2 25997 7.9
26-30 211 6.2 32784 9.9
31-35 445 13 32682 9.9
36-40 710 20.7 32435 9.8
41-45 936 27.3 34844 10.6
46-50 673 19.6 38633 11.7
51-55 289 8.4 41305 12.5
56-60 85 2.5 37784 11.4
Race/Ethnicity2
Hispanic 127 6.7 13648 6.2
Non-Hispanic white 1316 69.3
13640
4 61.9
Asian 151 8 21851 9.9
26
Native American 55 2.9 3879 1.8
Non-Hispanic black 146 7.7 11321 5.1
Hawaiian/Pacific Islander 16 0.8 2641 1.2
Other/Unknown 87 4.6 30788 14
Diagnosis year
2006 371 10.8 n/a
2007 380 11.1
2008 332 9.7
2009 320 9.3
2010 364 10.6
2011 351 10.2
2012 371 10.8
2013 372 10.9
2014 289 8.4
2015 275 8
Visit setting at diagnosis
Inpatient 1633 47.7 n/a
Emergency department 11 0.3
Urgent care 11 0.3
Outpatient 1380 40.3
Radiology 64 1.9
Other care 326 9.5
Other ICD-9/10 diagnosis codes on
27
adenomyosis diagnosis date (not mutually
exclusive)
Endometriosis3 617 18.0 n/a
617.1/N80.1 Ovary 275 8.0
617.2/N80.2 Fallopian tubes 70 2.0
617.3/N80.3 Pelvic peritoneum 344 10.0
617.4/N80.4 Vagina 2 0.1
617.5/N80.5 Intestine 29 0.8
617.6/N80.6 Scar of skin 3 0.1
617.8/N80.8 Other sites 40 1.2
617.9/N80.9 Unspecified 441 12.9
Uterine fibroids 218.0, 218.1, 218.2, 218.9 1630 47.6
1 Study entry was the earliest date when women met the study eligibility criteria: 1) aged 445
16-60 years in 2006-2015, 2) had 2 years of prior enrollment at KPWA, and 3) had 1 446
health care utilization at KPWA in the past 2 years. 447
2 Race/ethnicity distribution among women enrollees in GPD (1,898 cases and 220,532 448
non-cases). 449
3 Both ICD-9/ICD-10 codes 450
SD, standard deviation 451
28
Table 3. Treatments1 in the 5 years following incident adenomyosis diagnosis among 452
women ages 16-60 years in 2006-2010, overall and by age group. 453
Age 16-60
(n=1768)
Age 16-45
(n=920)
Age 46-60
(n=848) P-value
N % N % N %
Hysterectomy 1449 82.0 727 79.0 722 85.1 <0.001
Laparoscopy/laparotomy 384 21.7 243 26.4 141 16.6 <0.001
Pain medications 1282 72.5 677 73.6 605 71.3 0.29
Chronic user 665 37.6 374 40.7 291 34.3 0.006
Hormone medications 289 16.3 186 20.2 103 12.1 <0.001
Chronic user 184 10.4 119 12.9 65 7.7 0.0003
1 Treatments were not mutually exclusive. 454
29
Figure Legends 455
Figure 1. Adenomyosis Incidence by Age, 2006-2015 456
X axis: time (years), Y axis: Number of incidence cases per 10,000 women years 457
Figure 2. Adenomyosis Incidence by Race/Ethnicity, 2006-2015 458
X axis: time (years); Y axis: Number of incidence cases per 10,000 women years 459
Figure 3. Adenomyosis Prevalence, 2015 460
X axis: Age group in 5-year intervals; Y axis: Percent prevalence 461
top related