The Impact of Evolving Endometriosis Guidelines on Diagnosis and Observational Health Studies

Abstract

Study question: Do recent changes in European Society of Human Reproduction and Embryology (ESHRE) clinical guidelines result in more comprehensive diagnosis of women with endometriosis?

Summary answer: The latest shift in clinical guidelines results in diagnosis of more women with endometriosis but current ESHRE diagnostic criteria do not capture a sizable percentage of women with the disease.

What is known already: Historically, laparoscopy was the gold standard for diagnosing endometriosis, a complex gynecological condition marked by a heterogeneous set of symptoms that vary widely among women. More recently, changes in clinical guidelines have shifted to incorporate imaging-based approaches such as transvaginal sonography and magnetic resonance imaging.

Study design size duration: Retrospective, observational cohort study of women aged 15-49 years diagnosed with endometriosis in the United States (US) between January 1, 2013, and December 31, 2023.

Participants/materials setting methods: Data sources include US insurance claims data from the Merative^™ MarketScan^® Commercial Database (CCAE), Merative^™ MarketScan^® Multi-State Medicaid Database (MDCD), Optum^® de-identified Electronic Health Record dataset (Optum^® EHR), and electronic health record (EHR) data from a large academic medical center in New York City (CUIMC EHR). To examine the potential impact of expanding clinical criteria for the diagnosis of endometriosis, we validated and compared five cohort definitions based on different sets of diagnostic guidelines involving combinations of surgical confirmation, diagnostic imaging, guideline-recognized symptoms, and other symptoms commonly reported among women with endometriosis. We performed pairwise comparisons between cohorts and applied Bonferroni corrections to account for multiple comparisons.

Main results and the role of chance: We identified 491,048 women with a diagnosis of endometriosis across the CCAE, MDCD, Optum EHR, and CUIMC EHR datasets. Each cohort definition demonstrated strong positive predictive value (0.84-0.96), yet only 15-20% of cases were identified by all 5 cohort definitions. Women diagnosed with endometriosis based on imaging and symptoms were three years younger, on average, than women with a diagnosis based on surgical confirmation (mean age = 35 years [SD = 9] vs 38 years [SD = 8]; p<0.001). Women in cohorts based only on symptoms were two years younger than those based on surgery (36 years [SD = 8] vs 38 years [SD = 8]; p<0.001). More than one-fourth of cases presented with endometriosis-related symptoms but lacked surgical or imaging-related documentation required by ESHRE guideline criteria. Pain was reported among nearly all women with endometriosis. Abdominal pain and pain in the pelvis were the most prevalent (ranging from 69% to 90% of women in each cohort). Among approximately 2-5% of all endometriosis cases (14,795 total), women presented with pelvic and/or abdominal pain but none of the other symptoms noted in clinical guidelines.

Limitations reasons for caution: Our study has potential biases associated with documentation practices and secondary data use of insurance claims and EHR data. Further, the phenotyping algorithms used rely on clinical codes that do not necessarily capture all ESHRE diagnostic criteria for endometriosis and may not be generalizable to women with atypical presentation of endometriosis.

Wider implications of the findings: High positive predictive value among all five cohort definitions despite poor overlap among cases identified illustrates both the heterogeneous presentation of the disease and importance of expanding diagnostic criteria. For example, cohorts derived from updated guidelines identified younger patients at time of diagnosis. Women diagnosed based on imaging had higher rates of emergency room visits while patients diagnosed via laparoscopy had a larger number of hospitalizations. The substantial number of cases with pelvic and/or abdominal pain but none of the other symptoms noted in clinical guidelines underscores the continued need for improved access to timely and appropriate care, particularly among those with non-classical symptoms, different care-seeking patterns, or lack of available surgical intervention.

Keywords: clinical guidelines; diagnosis; endometriosis; imaging; laparoscopy.

Figure 1a-d.. Patient Set Overlap Among Study Cohorts in Optum EHR Dataset.

a) UpSet plot illustrating intersections among patients identified across all cohorts. b) Venn diagram of patients in Cohorts A, B, and C. c) Venn diagram of patients in Cohorts A, D, and E. d) Venn diagram of patients in Cohorts C, D, and E. Cohort A: Surgical confirmation phenotype; Cohort B: Imaging and guideline-recognized symptoms phenotype; Cohort C: Guideline-recognized symptoms only phenotype; Cohort D: Guideline-recognized symptoms and/or pelvic pain phenotype; Cohort E: Guideline-recognized symptoms, pelvic pain, and/or abdominal pain phenotype. Abbreviations: EHR, Electronic Health Record.

Figure 2a-d.. Age at Diagnosis of Endometriosis in the Optum EHR Dataset.

On average, women in Cohort A were diagnosed with endometriosis at an older age than women in Cohorts B-E (mean age difference Cohort A vs Cohorts C-E = 2 years; p<0.001 for all comparisons). a) Age at diagnosis among patients in Cohorts A and B. b) Age at diagnosis among patients in Cohorts A and C. c) Age at diagnosis among patients in Cohorts A and D. d) Age at diagnosis among patients in Cohorts A and E. Cohort A: Surgical confirmation phenotype; Cohort B: Imaging and guideline-recognized symptoms phenotype; Cohort C: Guideline-recognized symptoms only phenotype; Cohort D: Guideline-recognized symptoms and/or pelvic pain phenotype; Cohort E: Guideline-recognized symptoms, pelvic pain, and/or abdominal pain phenotype. Abbreviations: EHR, Electronic Health Record.

Figure 3a-d.. Differences in Cohort Entry Dates in the Optum EHR Dataset.

Among most women identified by more than one phenotype definition, there was little to no difference in date of cohort entry (e.g., median difference in entry date between Cohort A and B = 0 days, interquartile range [IQR] = 0–45 days). a) Differences in cohort entry dates among patients identified by both cohort definitions A and B. b) Differences in cohort entry dates among patients identified by both cohort definitions A and C. c) Differences in cohort entry dates among patients identified by both cohort definitions A and D. d) Differences in cohort entry dates among patients identified by cohort definitions A and E. Cohort A: Surgical confirmation phenotype; Cohort B: Imaging and guideline-recognized symptoms phenotype; Cohort C: Guideline-recognized symptoms only phenotype; Cohort D: Guideline-recognized symptoms and/or pelvic pain phenotype; Cohort E: Guideline-recognized symptoms, pelvic pain, and/or abdominal pain phenotype. Abbreviations: EHR, Electronic Health Record.

Figure 4a-b.. Condition Concepts in the Optum EHR Dataset with the Largest Differences in Prevalence Between Endometriosis Cohorts Based on Surgical Diagnosis (Cohort A) and Imaging and/or Symptoms-based Diagnosis (Cohorts B and E).

Compared to Cohort A, localized pain (e.g., abdominal, pelvic, genitourinary), dysmenorrhea, and dysuria were consistently more common in Cohorts B and E. Lesions, masses, and neoplasms (e.g., abdominal, pelvic, uterine) were more common in Cohort A. Cohort A: Surgical confirmation phenotype; Cohort B: Imaging and guideline-recognized symptoms phenotype; Cohort E: Guideline-recognized symptoms, pelvic pain, and/or abdominal pain phenotype. Abbreviation: EHR: electronic health record.

Figure 5a-b.. Medication Concepts in the Optum EHR Dataset with the Largest Differences in Prevalence Between Endometriosis Cohorts Based on Surgical Diagnosis (Cohort A) and Imaging and/or Symptoms-based Diagnosis (Cohorts B and E).

Nonsteroidal anti-inflammatory and antirheumatics, other analgesics, corticosteroids, and drugs for gastrointestinal disorders were more common in Cohort A. Hormones, antidepressants, anxiolytics, and antibacterials were more common in Cohorts B and E. *Denotes medications included among ESHRE treatment endometriosis guidelines. Cohort A: Surgical confirmation phenotype; Cohort B: Imaging and guideline-recognized symptoms phenotype; Cohort E: Guideline-recognized symptoms, pelvic pain, and/or abdominal pain phenotype. Abbreviation: EHR: electronic health record.

Figure 6a-b.. Procedure Concepts in the Optum EHR Dataset with the Largest Differences in Prevalence Between Endometriosis Cohorts Based on Surgical Diagnosis (Cohort A) and Imaging and/or Symptoms-based Diagnosis (Cohorts B and E).

Among differences found, women with a diagnosis of endometriosis based on surgical confirmation (Cohort A) were more likely to have received laparoscopy with total hysterectomy or surgical pathology with microscopic evaluation. Cohort A: Surgical confirmation phenotype; Cohort B: Imaging and guideline-recognized symptoms phenotype; Cohort E: Guideline-recognized symptoms, pelvic pain, and/or abdominal pain phenotype. Abbreviation: EHR: electronic health record.