Risk factors for and outcomes of ring expulsions with a one year contraceptive vaginal system

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Article (peer-reviewed)

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Background: The FDA-approved, segesterone acetate/ethinyl estradiol, ring-shaped contraceptive vaginal system, known was Annovera (Sever Pharma Solutions/QPharma, Malmö, Sweden inserted and removed under a woman’s control for a 21 day in/7 day out regimen for up to 13 cycles of use. Objectives: We aimed to describe patterns of ring expulsion over time, identify potential predictors of expulsion and evaluate the impact of expulsions on method discontinuation and pregnancy risk. Study Design: Using data from 2064 participants in two multinational Phase 3 clinical trials of this contraceptive vaginal system we examined data from participants’ daily diaries for documentation of complete ring expulsion. We modeled the odds of reported expulsions over time, adjusting for background and demographic characteristics, using mixed-effects logistic regression models with random intercepts. We compared probability of continuation between those who did and did not report expulsions in the first cycle of use using survival analysis and hazards modeling. To determine if expulsions during the first cycle of use affected risk of pregnancy, we calculated Pearl Indices. Results: Most participants (75%) never experienced any expulsions during any cycle of use, with 91-97% not experiencing an expulsion during any one cycle. The incidence of expulsion was highest in Cycle 1 (9%). The odds of experiencing expulsions decreased by half in cycles 2-8 3 vs cycle 1 (0.48 95% CI 0.40-0.58) and in in cycles 9-13 expulsions were about a third that in cycle 1 (0.32 95% CI 0.26-0.41). Of those who did experience expulsions, most (62-84%) experienced ≤2 expulsions per cycle. Participants from study sites in Latin America vs U.S. had higher odds of not experiencing an expulsion (OR 1.95, 95% CI 1.45-2.63). Women with more education had higher odds of experiencing an expulsion. Notably, parity, age and BMI were not associated with expulsion. Participants who did experience any expulsions in Cycle 1 were more likely to discontinue early hazards ratio 1.28, 95% CI (1.14, 1.43) compared to participants who had an expulsion. The Pearl Index for participants who had expulsions during Cycle 1 was 3.99 (95% CI: 1.29-9.31), higher than among participants who reported no expulsions (PI 2.39, 95% CI: 1.61-3.41) but the overlapping confidence intervals indicate there is not sufficient evidence to demonstrate an association between expulsions and pregnancy risk. Conclusions: Expulsions were infrequent overall, decreased with subsequent cycles of use and were not associated with BMI or parity. Early discontinuation of product use was higher among participants who experienced an expulsion during Cycle 1. While it is unclear whether pregnancy risk is associated with expulsions, early recognition of expulsions among users may identify those at higher risk for discontinuation and may highlight, where enhanced anticipatory counselling and guidance may be advantageous.