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