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Adenomyosis incidence, prevalence and treatment: United States population-based study 2006–2015

Published:January 15, 2020DOI:https://doi.org/10.1016/j.ajog.2020.01.016

      Background

      Adenomyosis symptoms are disabling. Population-based data on incidence and prevalence of adenomyosis are lacking that could guide future evidence-based treatments and clinical management.

      Objective

      To evaluate the incidence, 10-year secular trends, and prevalence of adenomyosis diagnoses and to describe symptoms and treatment patterns in a large U.S. cohort.

      Study Design

      We performed a retrospective population-based cohort study of women aged 16–60 years in 2006–2015, enrolled in Kaiser Permanente Washington, a mixed-model health insurance and care delivery system. Adenomyosis diagnoses identified by ICD codes from the International Classification of Diseases 9th and 10th editions and potential covariates were extracted from computerized databases. Women with prior hysterectomy, and for incidence estimates women with prior adenomyosis diagnoses, were excluded. Linear trends in incidence rates over the 10-year study period were evaluated using Poisson regression. Rates and trend tests were examined for all women adjusting for age using direct standardization to the 2015 study population, by age groups, and by race/ethnicity. Chart reviews were performed to validate diagnostic accuracy of ICD codes in identifying adenomyosis incidence. Symptoms and treatment patterns at diagnosis and in the following 5 years were assessed.

      Results

      A total of 333,693 women contributed 1,185,855 woman-years (2006–2015) for incidence calculations. Associated symptom-related codes (menorrhagia or abnormal uterine bleeding, dysmenorrhea or pelvic pain, dyspareunia, and infertility) were observed in 90.8%; 18.0% had co-occurrent endometriosis codes and 47.6% had co-occurrent uterine fibroid codes. The overall adenomyosis incidence was 1.03% or 28.9 per 10,000 woman-years, with a high of 30.6 in 2007 and a low of 24.4 in 2014. Overall age-adjusted estimated incidence rates declined during the 10-year study interval (linear trend P < .05). Incidence was highest for women aged 41–45 years (69.1 per 10,000 woman-years in 2008) and was higher for black (highest 44.6 per 10,000 woman-years in 2011) vs white women (highest 27.9 per 10,000 woman-years in 2010). Overall prevalence in 2015 was 0.8% and was highest among women aged 41–45 years (1.5%). Among the 624 potential adenomyosis cases identified by diagnostic codes in 2012–2015 and with sufficient information in the medical record to determine true case status, 490 were confirmed as incident cases, yielding a 78.5% (95% confidence interval, 75.1%, 81.7%) positive predictive value of adenomyosis ICD-9/ICD-10 codes for identifying an incident adenomyosis case. Health care burden was substantial: 82.0% of women had hysterectomies, nearly 70% had imaging studies suggestive of adenomyosis, and 37.6% used chronic pain medications.

      Conclusion

      Adenomyosis burden to the individual and the health care system is high. Incidence rates are disproportionately high among black women. These findings are of concern, as currently available long-term medical therapies remain limited beyond hysterectomy. Our data and methodologies are novel and could serve as a foundation to guide clinicians and health care systems to develop clinical management plans and track outcomes for women with adenomyosis.

      Key words

      Adenomyosis is the aberrant location of endometrial glandular tissue within the uterine myometrium
      • Donnez J.
      • Donnez O.
      • Dolmans M.M.
      Introduction: uterine adenomyosis, another enigmatic disease of our time.
      often associated with cyclical uterine pain, dyspareunia, abnormal uterine bleeding such as menorrhagia, spotting or bleeding before and after menses, and infertility.
      • Gordts S.
      • Grimbizis G.
      • Campo R.
      Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis.
      Adenomyosis may be associated with endometriosis and uterine fibroids.
      • Weiss G.
      • Maseelal P.
      • Schott L.L.
      • Brockwell S.E.
      • Schoken M.
      • Johnston J.M.
      Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN).
      ,
      • Naftalin J.
      • Hoo W.
      • Pateman K.
      • Mavrelos D.
      • Holland T.
      • Jurkovic D.
      How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic.
      Until the last decade adenomyosis was considered a surgical diagnosis made at the time of hysterectomy. But increasingly, imaging studies, particularly pelvic ultrasound, have defined features indicative of adenomyosis, including a globular enlarged uterus, indistinct or irregular endometrial myometrial junction, heterogeneous myometrium, and myometrial cysts.
      • Van den Bosch T.
      • Van Schoubroeck D.
      Ultrasound diagnosis of endometriosis and adenomyosis: state of the art.
      ,
      • Tellum T.
      • Nygaard S.
      • Skovholt E.K.
      • Qvigstad E.
      • Lieng M.
      Development of a clinical prediction model for diagnosing adenomyosis.
      Diagnostic accuracy of ultrasound for adenomyosis is unknown, as prior studies evaluating this outcome were performed in select populations.
      • Van den Bosch T.
      • Van Schoubroeck D.
      Ultrasound diagnosis of endometriosis and adenomyosis: state of the art.

      Why was the study conducted?

      Adenomyosis symptoms are disabling. Population-based cohort studies of incidence, prevalence, trends, and treatment of adenomyosis are lacking.

      Key findings

      Overall incidence among 333,693 women aged 16–60 years (2006–2015) was 1%; incidence was higher for black vs white women and highest for ages 41–45. Ninety-one percent of incident cases had ICD-9 symptom-related codes. Adenomyosis co-occurrence with endometriosis and uterine fibroids was 18% and 47%, respectively. Eighty-two percent of women had hysterectomies, almost 70% had imaging studies suggestive of adenomyosis, and 38% used chronic pain medications.

      What does this add to what is known?

      Women in their early 40s are at highest risk for symptomatic adenomyosis. Incidence rates are disproportionately high among black women. Co-occurrence with uterine fibroids and endometriosis is high. Health care burden is substantial.
      Adenomyosis symptoms can be disabling and have been treated medically, despite no U.S. Food and Drug Administration–approved therapies,
      • Donnez J.
      • Donnez O.
      • Dolmans M.M.
      Introduction: uterine adenomyosis, another enigmatic disease of our time.
      and surgically.
      • Vannuccini S.
      • Luisi S.
      • Tosti C.
      • Sorbi F.
      • Petraglai F.
      Role of medical therapy in the management of uterine adenomyosis.
      Better data on efficacy of medical treatment would assist women who prefer not to have hysterectomy. Tools that can track adenomyosis incidence, prevalence, and treatment response will be important as new therapies targeted at the pathogenesis of the disease—sex steroid regulation, inflammation, apoptosis, and neuroangiogenesis manipulation
      • Vannuccini S.
      • Luisi S.
      • Tosti C.
      • Sorbi F.
      • Petraglai F.
      Role of medical therapy in the management of uterine adenomyosis.
      ,
      • Garcia-Solares J.
      • Donnez J.
      • Donnez O.
      • Dolmans M.M.
      Pathogenesis of uterine adenomyosis: invagination or metaplasia?.
      —are developed. Despite considerable public health burden, associated costs of care, and impacts on the lives of many women, reliable population-based incidence estimates of adenomyosis do not exist
      • Weiss G.
      • Maseelal P.
      • Schott L.L.
      • Brockwell S.E.
      • Schoken M.
      • Johnston J.M.
      Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN).
      and studies on prevalence vary widely.
      • Cunningham R.K.
      • Horrow M.M.
      • Smith R.J.
      • Springer J.
      Adenomyosis: a sonographic diagnosis.
      To address this gap, we conducted a retrospective cohort study using electronic health records (EHR) to estimate the incidence of symptomatic adenomyosis over a 10-year period (2006–2015) and symptomatic adenomyosis prevalence (2015) in a U.S. population. Secondary aims were to estimate incidence rates by age and by race/ethnicity, to evaluate trends, and to describe symptoms and treatment practice patterns. Furthermore, we performed chart reviews to assess the accuracy of diagnosis codes in identifying incident adenomyosis. We also estimated the proportion of cases that had imaging changes prior to their diagnosis that could be indicative of adenomyosis, thus estimating the proportion of women that might benefit from medical therapies.

      Methods

      Study setting and cohort

      This retrospective cohort study was conducted at Kaiser Permanente Washington (KPWA), a mixed-model health insurance and care delivery system based in Seattle, Washington. KPWA provides comprehensive care on a prepaid basis to approximately 650,000 individuals in 22 Washington counties. It contracts with the KP Physicians group to provide care within an integrated group practice division (GPD) for approximately 70% of enrollees. The remaining 30% are insured by this health plan and receive care from non-KP provider networks located in geographic areas not served by KPWA medical centers. The KPWA population generally reflects the underlying community it serves with respect to age, race, and sex.
      • Yu O.
      • Scholes D.
      • Schulze-Rath R.
      • Grafton J.
      • Hansen K.
      • Reed S.D.
      A US population-based study of uternine fibroid diagnosis incidence, trends and prevalence: 2005 through 2014.
      The cohort consisted of all women aged 16–60 years in 2006–2015 enrolled at KPWA for a minimum of 2 years with at least 1 health care utilization at KPWA in the 2 years before cohort entry on January 1, 2006, through December 31, 2015. We further restricted to women who did not have a record of hysterectomy at least 61 days (or 2 months) prior to cohort entry. All study methods received approval from KPWA’s Human Subjects Institutional Review Board.

      Data collection

      We utilized KPWA electronic health care data sources. A notable feature of KPWA is the depth and longevity of its multiple computerized databases, extensively used for patient care and research for nearly 50 years. Information on enrollment, demographics, health care utilization, height and weight, diagnoses, procedures, pharmacy dispensings, and radiology and laboratory results have been maintained in automated databases since 1977. A fully integrated EHR that documents all patient care and contacts, including clinic notes and phone and e-mail communications, in KPWA-owned clinics began in 2005. All automated data sources are linked using the member’s unique health record number.
      Race/ethnicity data were not complete in all years and for women who were not enrolled in the GPD. As a result, the analyses by race/ethnicity were restricted to GPD enrollees. To obtain more complete race/ethnicity data on women enrolled in the GPD, we augmented race/ethnicity data from the EHR with data extracted via Natural Language Processing. Our prior research showed a reduction from 19% to 13% in women with unknown race/ethnicity using these methods.
      • Grafton J.
      • Yu O.
      • Carrell D.
      • et al.
      Identifying race/ethnicity data via natural language processing among women in a uterine fibroid cohort study.

      Identification of adenomyosis cases and potentially associated symptoms

      We identified incident adenomyosis cases by selecting all women with International Classification of Diseases, 9th revision (ICD-9) diagnosis code 617.0 or 10th revision (ICD-10) code N80.0. We restricted the analyses of potential incident cases to women without an adenomyosis diagnosis in the 2 years prior to study entry. To assess the current burden of disease, we estimated adenomyosis prevalence among women enrollees in 2015 regardless of their history of adenomyosis diagnosis.
      Symptoms and 2 conditions potentially associated with adenomyosis were identified from ICD-9 diagnosis codes (Table 1).
      Table 1ICD-9 diagnosis codes for symptoms and conditions associated with adenomyosis
      ICD-9 codes
      Symptoms
       Menorrhagia or abnormal uterine bleeding626.2 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 pain625.3 dysmenorrhea, painful menstruation

      625.9 pelvic pain

      626.4 irregular periods

      626.6 metrorrhagia, bleeding between menses
       Dyspareunia625.0 pain with sex (dyspareunia)
       Infertility628.0 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
       Uterine fibroids218 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
       Endometriosis
      ICD-9/ICD-10 codes.
      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
      Yu et al. Adenomyosis incidence, prevalence, trends, and treatment. Am J Obstet Gynecol 2020.
      a ICD-9/ICD-10 codes.

      Description of treatment and utilization patterns

      We assessed treatment and utilization patterns on the incident diagnosis date and in the following 5 years among women who had an ICD-9 adenomyosis code in 2006–2010. Four treatments were of interest: (1) hysterectomy (61 days prior to diagnosis through 5 years postdiagnosis) as identified by procedure codes, (2) laparoscopy and/or laparotomy from procedure codes, (3) dispensing of pain medications including opioid and nonsteroidal antiinflammatory drugs in the pharmacy data, and (4) dispensing of hormone medications including progesterone, oral contraceptives, danazol, progesterone intrauterine devices, and gonadotropin-releasing hormone antagonists. For pain medication use, we further identified chronic users as women who had at least 7 fills of opioid and/or nonsteroidal antiinflammatory drugs, which equated to approximately 7 months of use. For hormone medication use, we defined chronic users as those women who had at least 3 fills of oral progesterone and/or oral contraception, at least 3 fills of danazol, at least 3 injectable progesterone fills, any implant progesterone, any progesterone intrauterine devices, or gonadotropin-releasing hormone injections which equated to over 6 months of use.

      Case validation

      Two trained abstractors and a study clinician (S.D.R.) reviewed medical records of enrollees with adenomyosis diagnosis codes in years 2012–2015. True incident cases identified at chart review were women who had surgical or imaging diagnosis of adenomyosis in the index period (defined as 60 days before and 60 days after the automated index diagnosis date) without a prior adenomyosis code and without prior imaging studies with possible or probable adenomyosis. By definition, incident cases diagnosed by imaging had the word “adenomyosis” in the body or in the impression of the imaging report. Cases defined by imaging could include words like “possible,” “probable,” or “unable to rule out” adenomyosis. Incident cases may have had prior imaging with characteristics suggestive of adenomyosis but without the word “adenomyosis” in the imaging report.

      Statistical analyses

      Women contributed person-time from the date when they became eligible for the study through the earliest date of disenrollment from KPWA (their 61st birthday, date of hysterectomy (if it occurred after study entry), or study end date of December 31, 2015. Annual incidence rates of adenomyosis were calculated for all women (16–60 years), age-adjusted using direct standardization to the 2015 study population. Linear trends in annual adenomyosis incidence rates over the 10-year study period (2006–2015) were evaluated using Poisson regression. Rates and linear trends were also examined for each 5-year age group (16–20 years through 56–60 years).
      We examined annual adenomyosis incidence rates by race/ethnicity among women enrollees in GPD only (owing to more complete race/ethnicity capture). Groups included Hispanic; non-Hispanic groups: black, white, Asian, Hawaiian/Pacific Islander, and Native American; and other or unknown race/ethnicity. Annual incidence rates were calculated for all women in each race/ethnicity group, age-adjusted using direct standardization to the 2015 race/ethnicity-specific study cohort.
      We estimated the overall and age-specific prevalence of adenomyosis for the most recent study year (2015). The denominator consisted of all women who contributed any person-time in 2015; women who also received an adenomyosis diagnosis during or before 2015 comprised the numerator.
      Among women with an incident adenomyosis diagnosis in 2006–2010, the proportions with symptoms potentially associated with adenomyosis in the 2 years prior to and 5 years following the diagnosis were calculated. We also estimated the proportion of incident cases that had an ICD-9 code for uterine fibroids or endometriosis. Treatment and utilization patterns were assessed by determining the proportions of women who experienced a surgical procedure or had a medication fill on the day of diagnosis or in the following 5 years.
      To determine the accuracy of ICD codes in identifying incident cases of adenomyosis, positive predictive values (PPV) were calculated from chart review (proportion of true cases among all potential cases identified by ICD codes). We estimated the proportion of incident cases that had prior ultrasounds with characteristic features of adenomyosis, but without the word “adenomyosis” in the imaging report. The proportion of cases identified by imaging with surgical confirmation was estimated.

      Results

      Adenomyosis incidence and prevalence

      A total of 333,693 women without an adenomyosis diagnosis in the past 2 years contributed 1,185,855 woman-years during the 10-year study period. Of these, 3425 women received a first diagnosis of adenomyosis and were considered potential incident cases. Mean age at study cohort entry was 41.5 years for case women and 37.5 years for non-case women (Table 2). Women with adenomyosis diagnoses were more likely to be non-Hispanic black. Among 3425 women with an incident diagnosis of adenomyosis, 1633 (47.7%) received the diagnosis during an inpatient stay and 1380 (40.3%) during an outpatient visit. On the date of adenomyosis diagnosis, 18.0% were also diagnosed with endometriosis and 47.6% were also diagnosed with uterine fibroid(s).
      Table 2Study cohort characteristics by incident adenomyosis case status in 2006–2015 defined by ICD-9/10 adenomyosis diagnosis codes
      Adenomyosis diagnosis
      Yes (n = 3425)No (n = 330,268)
      N%N%
      Age at study entry
      Study entry was the earliest date when women met the study eligibility criteria: (1) aged 16–60 years in 2006–2015, (2) had 2 years of prior enrollment at Kaiser Permanente Washington, and (3) had 1 health care utilization at Kaiser Permanente Washington in the past 2 years
       Mean age (SD), years41.5(7.7)37.5(14.3)
       Median age, years4239
       16–20 years34153,80416.3
       21–25 years421.225,9977.9
       26–30 years2116.232,7849.9
       31–35 years4451332,6829.9
       36–40 years71020.732,4359.8
       41–45 years93627.334,84410.6
       46–50 years67319.638,63311.7
       51–55 years2898.441,30512.5
       56–60 years852.537,78411.4
      Race/ethnicity
      Race/ethnicity distribution among women enrollees in group practice division (1898 cases and 220,532 non-cases)
       Hispanic1276.713,6486.2
       Non-Hispanic white131669.3136,40461.9
       Asian151821,8519.9
       Native American552.938791.8
       Non-Hispanic black1467.711,3215.1
       Hawaiian/Pacific Islander160.826411.2
       Other/unknown874.630,78814
      Diagnosis year
       200637110.8n/a
       200738011.1
       20083329.7
       20093209.3
       201036410.6
       201135110.2
       201237110.8
       201337210.9
       20142898.4
       20152758
      Visit setting at diagnosis
       Inpatient163347.7n/a
       Emergency department110.3
       Urgent care110.3
       Outpatient138040.3
       Radiology641.9
       Other care3269.5
      Other ICD-9/10 diagnosis codes on adenomyosis diagnosis date (not mutually exclusive)
      Endometriosis
      ICD-9/ICD-10 codes.
      61718.0n/a
       617.1/N80.1 Ovary2758.0
       617.2/N80.2 Fallopian tubes702.0
       617.3/N80.3 Pelvic peritoneum34410.0
       617.4/N80.4 Vagina20.1
       617.5/N80.5 Intestine290.8
       617.6/N80.6 Scar of skin30.1
       617.8/N80.8 Other sites401.2
       617.9/N80.9 Unspecified44112.9
      Uterine fibroids 218.0, 218.1, 218.2, 218.9163047.6
      Data are n and % unless indicated otherwise.
      n/a, not available; SD, standard deviation.
      Yu et al. Adenomyosis incidence, prevalence, trends, and treatment. Am J Obstet Gynecol 2020.
      a Study entry was the earliest date when women met the study eligibility criteria: (1) aged 16–60 years in 2006–2015, (2) had 2 years of prior enrollment at Kaiser Permanente Washington, and (3) had 1 health care utilization at Kaiser Permanente Washington in the past 2 years
      b Race/ethnicity distribution among women enrollees in group practice division (1898 cases and 220,532 non-cases)
      c ICD-9/ICD-10 codes.
      The overall incidence of adenomyosis was 1.03% or 28.9 per 10,000 woman-years, with a high of 30.6 per 10,000 woman-years in 2007 and a low of 24.4 in 2014 (Figure 1). Incidence was highest for women aged 41–45 years and peaked at 69.1 per 10,000 woman-years in 2008. Adenomyosis incidence was significantly lower among Asian women in 2010, 2012, and 2015, and higher among non-Hispanic black women in 2008, 2009, 2011, and 2013 (highest, 44.6 per 10,000 woman-years in 2011) compared with Non-Hispanic white women (highest, 27.9 per 10,000 woman-years in 2010) (Figure 2). Incidence rates declined significantly over the 10-year study interval overall, and among women aged 36–40 years (P values for linear trend < .05). Adenomyosis diagnosed during an inpatient visit decreased over time (from 70% in the first 3 years of the study to 25% in the last 3 years of the study), while diagnosis during an outpatient visit increased.
      Figure thumbnail gr1
      Figure 1Adenomyosis incidence by age, 2006–2015. X-axis: time (years); Y-axis: number of incidence cases per 10,000 woman-years
      Yu et al. Adenomyosis incidence, prevalence, trends, and treatment. Am J Obstet Gynecol 2020.
      Figure thumbnail gr2
      Figure 2Adenomyosis incidence by race/ethnicity, 2006–2015. X-axis: time (years); Y-axis: number of incidence cases per 10,000 woman-years
      Yu et al. Adenomyosis incidence, prevalence, trends, and treatment. Am J Obstet Gynecol 2020.
      A total of 135,162 women aged 16–60 years contributed person-time in 2015, with 1068 having a previous adenomyosis diagnosis. Thus, the prevalence of adenomyosis in 2015 was 0.8%; it was highest among women aged 41–45 years, at 1.5% (Figure 3).
      Figure thumbnail gr3
      Figure 3Adenomyosis prevalence, 2015. X-axis: Age group in 5-year intervals; Y-axis: percent prevalence
      N, number of adenomyosis cases.
      Yu et al. Adenomyosis incidence, prevalence, trends, and treatment. Am J Obstet Gynecol 2020.

      Symptoms and treatments

      Among 1768 incident adenomyosis cases diagnosed from 2006 to 2010, ICD-9 codes consistent with 4 potential adenomyosis symptom groups (menorrhagia or abnormal uterine bleeding, dysmenorrhea or pelvic pain, dyspareunia, and infertility) were noted in 90.8% of cases. Over half of women experienced at least 2 symptoms, with abnormal bleeding or menorrhagia being the most common (78.9%), followed by dysmenorrhea or pelvic pain (63.0%).
      Almost all women (96.3%) received at least 1 of the 4 treatments of interest. Overall, 82.0% of incident cases underwent hysterectomy, and 21.7% had a laparoscopy or laparotomy (Table 3). In over 72% of adenomyosis cases women used pain medications; 37.6% were chronic users. Less than 20% used hormone medications; 10.4% were chronic users. Hysterectomy occurred more often among older women (46–60 years), while laparoscopy/laparotomy was more common in younger women (16–45 years). Hormone therapy was more common among younger women and use was often long term. There was no difference in pain medication use between younger and older women. However, there were slightly more chronic pain medication users among younger women.
      Table 3Treatments
      Treatments were not mutually exclusive.
      in the 5 years following incident adenomyosis diagnosis among women aged 16–60 years in 2006–2010, overall and by age group
      Aged 16–60 (n = 1768)Aged 16–45 (n = 920)Aged 46–60 (n = 848)P value
      N%N%N%
      Hysterectomy144982.072779.072285.1<.001
      Laparoscopy/laparotomy38421.724326.414116.6<.001
      Pain medications128272.567773.660571.3.29
       Chronic user66537.637440.729134.3.006
      Hormone medications28916.318620.210312.1<.001
       Chronic user18410.411912.9657.7.0003
      Yu et al. Adenomyosis incidence, prevalence, trends, and treatment. Am J Obstet Gynecol 2020.
      a Treatments were not mutually exclusive.

      Accuracy of adenomyosis diagnosis codes

      Chart review was completed on 642 potential incident adenomyosis cases identified by ICD-9/ICD-10 codes in 2012–2015. There were 152 (23.7%) of the 642 women who did not have a current diagnosis of adenomyosis confirmed at surgery or with “adenomyosis” diagnosis on imaging report: 18 (2.8%) had insufficient information in the chart, 7 (1.1%) had sufficient information but no rationale for an assigned adenomyosis ICD code, 47 (7.3%) were diagnosed outside of the index period, 55 (8.6%) were diagnosed with endometriosis and not adenomyosis, and 25 (3.9%) women had “other,” likely miscoded diagnoses.
      Among the 624 potential adenomyosis cases identified by diagnostic codes with sufficient information in the EHR to determine true case status, 490 were confirmed as incident cases, yielding a 78.5% (95% confidence interval, 75.1%, 81.7%) PPV of adenomyosis ICD-9/ICD-10 codes for identifying an incident adenomyosis case.

      Adenomyosis and imaging

      Of the 490 women with incident adenomyosis confirmed on chart review, 482 (98.4%) had surgical confirmation during or after the index period; the remaining 8 (1.6%) were diagnosed by imaging only. Nearly one third of the 482 women with a surgical diagnosis of incident adenomyosis also had preoperative imaging findings compatible with adenomyosis (149, or 30.9%). Of the 490 women with incident adenomyosis, 180 (36.7%) had prior imaging during the study period with characteristics of adenomyosis,
      • Van den Bosch T.
      • Van Schoubroeck D.
      Ultrasound diagnosis of endometriosis and adenomyosis: state of the art.
      ,
      • Tellum T.
      • Nygaard S.
      • Skovholt E.K.
      • Qvigstad E.
      • Lieng M.
      Development of a clinical prediction model for diagnosing adenomyosis.
      but the word “adenomyosis” was not found in the report. Thus, nearly 70% of confirmed incident adenomyosis cases had imaging diagnoses or characteristics consistent with adenomyosis at or prior to the incident diagnosis date.

      Comment

      Principal findings

      The incidence of adenomyosis in this relatively large population-based cohort was estimated to be 1.03% or 28.9 per 10,000 woman-years in a 10-year interval (2006–2015); 90.8% had associated clinical symptoms. Incidence decreased over time and peaked in 2007 at 30.6 per 10,000 woman-years. Incident and prevalent cases were most common among women aged 41–45 years. Black women were more likely, and Asian women were less likely, than non-Hispanic white women to have an incident diagnosis of adenomyosis. The overall prevalence of adenomyosis in 2015 was 0.8%, with a high of 1.5% among women aged 41–45; 34.0% of prevalent cases involved women over 50.

      Results

      To our knowledge, recent reliable incidence and prevalence estimates from a large population-based study such as these have not been previously described,
      • Weiss G.
      • Maseelal P.
      • Schott L.L.
      • Brockwell S.E.
      • Schoken M.
      • Johnston J.M.
      Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN).
      ,
      • Cunningham R.K.
      • Horrow M.M.
      • Smith R.J.
      • Springer J.
      Adenomyosis: a sonographic diagnosis.
      nor has anyone reported on adenomyosis by race/ethnicity. One Italian study of women aged 15–50 years reported age-specific adenomyosis incidence based on adenomyosis diagnosis at hysterectomy, identified by automated inpatient hospital discharge records, as 0.023% over 3 years (2011–2013), or an average of 0.0077% annually,
      • Grafton J.
      • Yu O.
      • Carrell D.
      • et al.
      Identifying race/ethnicity data via natural language processing among women in a uterine fibroid cohort study.
      much lower than our estimates. Adenomyosis prevalence estimated from incidence with various assumptions was 0.13%.
      • Morassutto C.
      • Monasta L.
      • Ricci G.
      • Barbone F.
      • Ronfani L.
      Incidence and estimated prevalence of endometriosis and adenomyosis in northeast Italy: a data linkage study.
      Given that the disease is cured with hysterectomy, and all cases in this study were identified at hysterectomy, the incidence should have approximated the prevalence estimates.
      Others have reported 10–57% of women undergoing hysterectomy were diagnosed with adenomyosis.
      • Weiss G.
      • Maseelal P.
      • Schott L.L.
      • Brockwell S.E.
      • Schoken M.
      • Johnston J.M.
      Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN).
      ,
      • Bergholt T.
      • Eriksen L.
      • Berendt N.
      • Jacobsen M.
      • Hertz J.B.
      Prevalence and risk factors of adenomyosis at hysterectomy.
      • Vercellini P.
      • Parazzini F.
      • Oldani S.
      • Panazza S.
      • Bramante T.
      • Crosignani P.G.
      Adenomyosis at hysterectomy: a study on frequesncy distribution and patient characteristics.
      • Shrestha A.
      • Shrestha R.
      • Sedhai L.B.
      • Pandit U.
      Adenomyosis at hysterectomy: prevalence, patient characteristics, clinical profile and histopatholgical findings.
      • Shaikh H.
      • Khan K.S.
      Adenomyosis in Pakistani women: four year experience at the Aga Khan University Medical Centre, Karachi.
      Among symptomatic women undergoing a pelvic ultrasound in a general gynecology clinic, 21% had an imaging diagnosis of adenomyosis.
      • Naftalin J.
      • Hoo W.
      • Pateman K.
      • Mavrelos D.
      • Holland T.
      • Jurkovic D.
      How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic.
      These reported proportions of women with adenomyosis, where the denominator consists of all women who had hysterectomy or ultrasound, are commonly mistaken for population-based prevalence estimates and, if used clinically, result in misinformation to patients.
      Concomitant diagnoses of endometriosis (18.0%) or uterine fibroids (47.6%) among our incident adenomyosis cases was common and higher than other reports: endometriosis 3–10%
      • Weiss G.
      • Maseelal P.
      • Schott L.L.
      • Brockwell S.E.
      • Schoken M.
      • Johnston J.M.
      Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN).
      ,
      • Naftalin J.
      • Hoo W.
      • Pateman K.
      • Mavrelos D.
      • Holland T.
      • Jurkovic D.
      How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic.
      ,
      • Vercellini P.
      • Parazzini F.
      • Oldani S.
      • Panazza S.
      • Bramante T.
      • Crosignani P.G.
      Adenomyosis at hysterectomy: a study on frequesncy distribution and patient characteristics.
      ,
      • Shaikh H.
      • Khan K.S.
      Adenomyosis in Pakistani women: four year experience at the Aga Khan University Medical Centre, Karachi.
      ,
      • Parazzini F.
      • Verecellini P.
      • Panazza S.
      • Chatenout L.
      • Olidani S.
      • Crosignani P.G.
      Risk factors for adenoymosis.
      and uterine fibroids 23–37%.
      • Weiss G.
      • Maseelal P.
      • Schott L.L.
      • Brockwell S.E.
      • Schoken M.
      • Johnston J.M.
      Adenomyosis a variant, not a disease? Evidence from hysterectomized menopausal women in the Study of Women's Health Across the Nation (SWAN).
      ,
      • Naftalin J.
      • Hoo W.
      • Pateman K.
      • Mavrelos D.
      • Holland T.
      • Jurkovic D.
      How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic.
      ,
      • Shaikh H.
      • Khan K.S.
      Adenomyosis in Pakistani women: four year experience at the Aga Khan University Medical Centre, Karachi.
      A definitive diagnosis of adenomyosis has historically been made surgically, but our study suggested that almost a third of women with a surgical diagnosis of incident adenomyosis had preoperative imaging findings compatible with adenomyosis. Nearly 70% of all confirmed incident adenomyosis cases had imaging with adenomyosis characteristics prior to or on the incident diagnosis date. Recent studies suggest that an imaging diagnosis of adenomyosis may be more accurate than a tissue diagnosis.
      • Van den Bosch T.
      • Van Schoubroeck D.
      Ultrasound diagnosis of endometriosis and adenomyosis: state of the art.
      ,
      • Exacoustos C.
      • Zupi E.
      A new era in diagnosing adenomyosis is coming.
      Correlation of imaging diagnosis with tissue diagnosis has been described as moderate, κ = 0.62 (95% confidence interval, 0.32–0.91).
      • Naftalin J.
      • Hoo W.
      • Pateman K.
      • Mavrelos D.
      • Holland T.
      • Jurkovic D.
      How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic.
      Imaging studies are increasingly important for the diagnosis of adenomyosis.

      Clinical implications

      Adenomyosis symptoms can be disabling and despite no U.S. Food and Drug Administration–approved therapies, medical management is first-line therapy, particularly for younger women.
      • Donnez J.
      • Donnez O.
      • Dolmans M.M.
      Introduction: uterine adenomyosis, another enigmatic disease of our time.
      ,
      • Vannuccini S.
      • Luisi S.
      • Tosti C.
      • Sorbi F.
      • Petraglai F.
      Role of medical therapy in the management of uterine adenomyosis.
      ,
      • Vannuccini S.
      • Petraglia F.
      Recent advances in understanding and managing adenomyosis.
      ,
      • De Wilde R.L.
      • Wallwiener M.
      • Di Spiezio Sardo A.
      • Tanos V.
      • Becker S.
      Adenomyosis and myomata: risks, problems, and complications in diagnosis and therapy of adenomyosis and myomata.
      Controversy over ideal medical management exists
      • Donnez J.
      • Donnez O.
      • Dolmans M.M.
      Introduction: uterine adenomyosis, another enigmatic disease of our time.
      ,
      • Vannuccini S.
      • Luisi S.
      • Tosti C.
      • Sorbi F.
      • Petraglai F.
      Role of medical therapy in the management of uterine adenomyosis.
      ,
      • Vannuccini S.
      • Petraglia F.
      Recent advances in understanding and managing adenomyosis.
      and characterizing medication utilization patterns in a population-based cohort is of importance. Health care utilization was high in our study: in 82% of incident adenomyosis cases women underwent hysterectomy, and nearly 40% used pain medication for over 6 months. Hormonal medication use was modest (16%). Women in their early 40s, and particularly black women, who have painful menses or abnormal uterine bleeding deserve pelvic ultrasound evaluation for adenomyosis. Characteristics of adenomyosis on ultrasound likely represent a true diagnosis. Risk of concomitant uterine fibroids or endometriosis is higher than previously recognized.

      Research implications

      Using the methodologies described here, women with diagnostic codes and ultrasound findings suggestive of adenomyosis
      • Van den Bosch T.
      • Van Schoubroeck D.
      Ultrasound diagnosis of endometriosis and adenomyosis: state of the art.
      ,
      • Exacoustos C.
      • Zupi E.
      A new era in diagnosing adenomyosis is coming.
      could be identified in large organizations with EHRs to target therapies, develop practice guidelines, recruit for clinical trials, and evaluate factors associated with adenomyosis (eg, cancers).
      • Yeh C.C.
      • Su F.H.
      • Tzeng C.R.
      • Muo C.H.
      • Wang W.C.
      Women with adenomyosis are at higher risks of endometrial and thyroid cancers: a population-based historical cohort study.
      ,
      • Kok V.C.
      • Tsai H.J.
      • Su C.F.
      • Lee C.K.
      The risks for ovarian, endometrial, breast, colorectal, and other cancers in women with newly diagnosed endometriosis or adenomyosis: a population-based study.
      Adenomyosis diagnoses could be reliably identified using adenomyosis ICD-9/ICD-10 codes (nearly 80% PPV for new cases).

      Strengths and limitations

      Our study has multiple strengths. It is population-based and a relatively large cohort, with a chart validation component. Importantly, estimates are not limited to access-to-care issues, since all women were insured. Generalizability is unknown, as the study was limited to 1 region of the United States with lower prevalence of non-Hispanic black women than other regions in the United States. Case validation was restricted to a recent 4-year period. The incidence rates that changed over time could be attributed to changes in hysterectomy patterns,
      • Morgan D.
      • Kamdar N.S.
      • Swenson C.W.
      • Kobemik E.K.
      • Sammarco A.G.
      • Nallamothu B.
      Nationwide trends in the utilization of and payments for hysterectomy in the United States among commercially insured women.
      changes in coding practices, or changes in practice patterns (eg, more therapeutic options and improved diagnostic imaging capabilities in latter study years).

      Conclusion

      Adenomyosis burden to the individual and the health care system is high. Incidence rates are disproportionately high among black women. These findings are of concern, as currently available long-term medical therapies remain limited beyond hysterectomy. Our data and methodologies are novel and serve as a foundation to potentially guide clinicians and health care systems to develop and test treatment plans for women with adenomyosis. Nearly 70% of the incident adenomyosis cases confirmed at chart review in our study had had a prior ultrasound that either diagnosed or was suggestive of adenomyosis—these are the patients who could be targeted for treatment interventions and management of this relatively understudied but common gynecologic condition.

      Acknowledgments

      We appreciate the chart review performed by KPWA employees Ms Jennifer Covey and Ms Ann Kelly and the RedCap database management by Ms Jennifer Covey for the case validation.

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