Thromboembolic safety of norethisterone vs levonorgestrel in combined oral contraceptive users: a pooled analysis of 4 large prospective cohort studies

BACKGROUND: Norethisterone (acetate) and levonorgestrel are marketed globally as components of combined oral contraceptives. Although guidelines recommend both as first-line combined oral contraceptives, no direct, comparative safety studies are available. OBJECTIVE: We directly compared the thromboembolic event risk associated with the use of norethisterone acetate-containing and levonorgestrel-containing combined oral contraceptives. STUDY DESIGN: Data regarding the cohorts of interest, norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg) and levonorgestrel (ethinylestradiol ≤30 µg), were retrieved from a pooled dataset comprising 4 prospective, noninterventional, active-surveillance cohort studies in 14 European countries, the United States, and Canada, with similar study design but differing medication cohorts. Baseline characteristics and parameters of reproductive, contraceptive, and medical history were summarized using descriptive statistics. Propensity score subclassification was applied to balance baseline parameters between cohorts. Time-to-event analysis of venous thromboembolic events was performed on the basis of the extended Cox model to calculate crude and adjusted hazard ratios, including 95% confidence intervals. The time of venous thromboembolic events was censored at the end of the observation period for women who did not have an event. Women who dropped out or were lost to follow-up without reported venous thromboembolic events were censored at the time they last confirmed that they did not have an event. RESULTS: The pooled dataset included 235,437 combined oral contraceptive users who were followed up for a total of 571,163 women years. Among these, 40,142 women were users of norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg), and 39,098 women were users of levonorgestrel (ethinylestradiol ≤30 µg), contributing 61,976 and 84,816 women years of observation, respectively. The observed prevalence of prognostic factors at baseline showed typical features of US and European combined oral contraceptive users. Both cohorts showed a similar, low rate of thromboembolic events, and we could exclude a 1.5-fold increased venous thromboembolism risk for norethisterone/norethisterone acetate relative to levonorgestrel (adjusted hazard ratio, 0.73; 95% confidence interval, 0.48–1.11). CONCLUSION: These data confirm the similar risk profiles of norethisterone/norethisterone acetate and levonorgestrel regarding thromboembolic events in routine combined oral contraceptive use of around 80,000 women from Europe and the United States/Canada. The analysis provides reassurance for both combined oral contraceptive users and clinicians regarding the safety of oral contraceptives and potentially opens discussion on norethisterone acetate as a potential gold standard therapy in clinical and postmarket research alongside levonorgestrel-combined oral contraceptives.