Impact of contraceptive initiation on the cervicovaginal mucosa: results from the UMPALA multicentre, partially randomized patient-preference interventional trial

Background Long-acting contraceptives are widely used, providing superior efficacy and systemic safety; however, the impact of contraceptive initiation on female genital tract function and health has been understudied. Methods Non-pregnant, HIV-uninfected women aged 18–50 years were enrolled in a dual-centre partially randomized patient-preference interventional trial (NCT04814927) and allowed to choose one of four contraceptive options, etonogestrel contraceptive implant, depot medroxyprogesterone acetate subcutaneous injection, levonorgestrel intrauterine device, and copper IUD, with a minimum target of 12 participants per arm and site. Sampling took place at baseline, 1 and 3 months after contraceptive initiation, and 1 month post-contraceptive discontinuation. Primary outcomes focused on mucosal function and health, while secondary and tertiary outcomes pertained to systemic and mucosal susceptibility to HIV-1 and HSV-2. Results Cervicovaginal samples from 112 enrolled participants showed transient, statistically significant changes in endpoints comparing baseline vs. 1 and 3 months after contraceptive initiation. Changes in pH, epithelial thickness, E-cadherin expression, antimicrobial peptides, glycogen, and lactic acid varied with contraceptive type and were typically transient. Serum oestradiol level was correlated with cervicovaginal epithelial function and glycogen and lactic acid secretion. Contraceptive initiation did not result in detectable ex vivo or in vitro increase of HIV-1 and HSV-2 susceptibility in cellular and tissue models. Conclusions Contraceptive initiation during the first 3 months of use induced transient and variable changes in mucosal epithelial and immune markers, not leading to persistent alterations of the vaginal milieu or increased susceptibility to viral infections during the 3 months after contraception initiation. Clinical Trial Registration https://clinicaltrials.gov/study/NCT04814927?term=NCT04814927.&viewType=Card&rank=1 , identifier NCT04814927.