Incidence and factors associated with premature ovarian insufficiency: a population-based cohort study

STUDY QUESTION: What is the incidence of premature ovarian insufficiency (POI) and its associated factors in Ontario, Canada, between 1995 and 2019? SUMMARY ANSWER: The incidence of POI increased after 2011, driven primarily by non-iatrogenic POI, and was highest among women with a history of endometriosis. WHAT IS KNOWN ALREADY: Recent estimates suggest a global POI prevalence of ∼3.7%, with increasing rates over time. POI has heterogeneous etiologies, including genetic, autoimmune, infectious, and iatrogenic causes; however, the cause remains unknown in ∼70% of non-iatrogenic cases. Existing incidence estimates are limited by recall bias, cross-sectional designs, small sample sizes, and limited assessment of associated factors. STUDY DESIGN, SIZE, DURATION: This population-based cohort study included all women aged ≤ 39 years residing in Ontario between 1995 and 2019. Follow-up continued until POI diagnosis, age 40 years, death, loss of provincial health insurance, or end of the study period. PARTICIPANTS/MATERIALS, SETTING, METHODS: POI was defined using administrative health data as a diagnosis occurring before age 40 years identified by either (i) surgical menopause or (ii) ≥1 physician consultation coded as menopause (ICD-9 627). Annual incidence rates (IRs) were calculated using census data, with the Ontario female population aged ≤ 39 years as the denominator. POI was classified as non-iatrogenic, surgical, post-chemotherapy and/or radiotherapy, or combined surgical with chemotherapy and/or radiotherapy. Associations between clinical factors and POI were estimated using age-adjusted modified Poisson regression to derive incidence rate ratios (IRRs). MAIN RESULTS AND THE ROLE OF CHANCE: Among 3 635 702 eligible women, 168 173 developed POI from any etiology (IR 389.4 per 100 000 person-years). Median follow-up was 11 years (IQR 6-18), and median age at POI diagnosis was 31 years (IQR 25-36). IRs were 351.4 per 100 000 person-years for non-iatrogenic POI, 30.2 for surgical POI, 5.5 for post-chemotherapy and/or radiotherapy POI, and 2.3 for combined surgical with chemotherapy and/or radiotherapy POI. Overall POI incidence declined between 2002 and 2008, followed by a sustained increase through 2019, largely attributable to non-iatrogenic POI. The incidence of surgically induced POI decreased from 60 per 100 000 person-years in 1995 to 20 in 2019, while combined surgical with chemotherapy and/or radiotherapy POI increased steadily over the study period. Factors associated with higher POI incidence included endometriosis (IRR 3.45, 95% CI 3.39, 3.52), cancer treated with chemotherapy or radiotherapy (IRR 2.01, 95% CI 1.89, 2.14), drug or tobacco use (IRR 1.59, 95% CI 1.51, 1.67), chromosomal disorders (IRR 1.50, 95% CI 1.42, 1.59), and autoimmune diseases (IRR 1.19, 95% CI 1.17, 1.22). LIMITATIONS, REASONS FOR CAUTION: Use of administrative health data may result in outcome misclassification and limited availability of detailed clinical and demographic information. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide contemporary population-based estimates of POI incidence and identify endometriosis as a major associated factor. The marked decline in surgically induced POI over time suggests increased adoption of ovarian-preserving surgical approaches, while rising non-iatrogenic POI incidence underscores the need for improved risk stratification, counselling, and further studies to elucidate underlying mechanisms and modifiable risk factors. FUNDING: Canadian Menopause Society. DISCLOSURES: Nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.