Phenome-wide association study of uterine fibroid subtypes reveals symptoms of fibroid severity and subtype-specific comorbidities

Background Uterine leiomyomata (or fibroids) are common benign tumors of the uterus. Fibroids are classified into subtypes by location: submucosal, intramural, subserosal. Although the symptomology and comorbidities associated with fibroids have been extensively assessed, there is less knowledge regarding factors associated with fibroid subtypes. We tested the associations between fibroid subtypes and a broad range of clinical diagnoses to characterize their shared and unique comorbidity profiles. Methods Using billing codes and clinical note text from the Vanderbilt University Medical Center’s electronic health record (EHR) system, we identified individuals with three common fibroid subtypes (cases/controls): submucosal (2,445/28,746), intramural (4,877/20,315), subserosal (3,472/24,447). Using multivariate logistic regression, we performed a phenome-wide association study (PheWAS) for each subtype with over 1,800 constructed clinical diagnoses (phecodes) as predictors. Results We identified 149 significant phecode associations with submucosal fibroids, 218 with intramural fibroids, and 178 with subserosal fibroids. The most significant submucosal fibroid associations were “disorders of menstruation” (odds ratio [OR][95% Confidence Interval] = 5.35[4.79–5.97]) and “iron deficiency anemia secondary to blood loss (chronic)” (OR = 5.20[4.53–5.97]). The most significant association with intramural fibroids was also “disorders of menstruation” (OR = 4.68[4.31–5.08]). The most significant association in the subserosal analysis was with “other benign neoplasm of connective and other soft tissue” (OR = 5.35[4.74–6.04]). We performed sensitivity analyses to narrow down subtype-specific associations. From these, only submucosal fibroids had multiple anemia-, irregular menstruation-, and dysmenorrhea-related phecodes remain significant, and only submucosal and intramural fibroids remained significantly associated with infertility. Conclusions We identified multiple factors that were more strongly or uniquely associated with having a specific fibroid subtype. We demonstrated a greater severity of fibroid symptoms in individuals with a subtype-level fibroid diagnosis.