Delayed start of estetrol drospirenone versus ethinyl estradiol gestodene for ovulation inhibition in a noninferiority randomized controlled trial

Delayed-start contraception may reduce the risk of unintended pregnancy; however, data on newer formulations, such as estetrol (E4)-containing pills are limited. Therefore, this study aimed to evaluate the effectiveness of delayed start combined oral contraceptives (COCs) containing 15 mg E4 and 3 mg drospirenone (E4/DRSP). In this randomized, single-blind, non-inferiority trial, 36 healthy women aged 18-45 years with regular menstrual cycles were assigned to receive either E4/DRSP or 20 µg ethinyl estradiol/75 µg gestodene (EE/GS), starting treatment between cycle day 7 and 9. The primary outcome was ovulation inhibition, assessed using the modified Hoogland score. The secondary outcomes included cervical mucus changes and adverse effects. Baseline characteristics did not differ significantly between the groups. The mean age and menstrual cycle length were 38.75 ± 5.8 years and 28.67 ± 1.96 days, respectively. More than half (55.56%) of the participants began COC use on day 9, with 50% of them showing active follicular development at baseline (Hoogland score of 4). Ovulation was inhibited in 61.11% of participants in both groups (adjusted relative risks: 0.95, 95% confidence interval [CI]: 0.56-1.59, p = 0.841, and absolute risk difference: -0.03, 95% CI: -0.39 to 0.33). Approximately half of the participants who ovulated showed ovarian activity that was not associated with theoretical pregnancy risk. Cervical mucus profiles and adverse events, including unscheduled bleeding, did not differ significantly between the groups. Initiating E4/DRSP on cycle day 7-9 appears comparable to that of EE/GS for ovulation inhibition; however, high ovulation rates limit the confirmation of non-inferiority.Clinical trial registration: ClinicalTrials.gov Registration on April 25, 2024 (ID: NCT06396221; https://clinicaltrials.gov/study/NCT06396221 ).