Venous thromboembolism with combined oral contraceptives based on estrogen and progestin content: a disproportionality analysis of the United States Food and Drug Administration Adverse Event Reporting System database

BACKGROUND: Disproportionality analyses using pharmacovigilance databases permit comparisons between products for rare outcomes, such as venous thromboembolism with combined oral contraceptives. OBJECTIVE: To compare the proportionality reporting rate of venous thromboembolic adverse events in the Food and Drug Administration Adverse Reporting System database between 2 body-identical estrogen combined oral contraceptives available in the United States, 17β-estradiol valerate/dienogest and estetrol/drospirenone, and combined oral contraceptives containing ethinyl estradiol. STUDY DESIGN: We extracted individual case safety reports and adverse events from the Food and Drug Administration Adverse Reporting System database from its inception to October 2024. We performed a proportionality reporting rate analysis of venous thromboembolic events associated with various combined oral contraceptives as compared to reference standards of ethinyl estradiol/levonorgestrel combined oral contraceptives and the entire therapeutic class. Secondarily, we assessed the proportionality reporting rate with drospirenone-only pills and norethindrone-only pills. RESULTS: Compared to ethinyl estradiol/levonorgestrel, we found lower proportionality reporting rates with estetrol/drospirenone (0.54; 95% confidence interval, 0.30-0.99) and 17β-estradiol valerate/dienogest (0.79 [5]; 95% confidence interval, 0.65-0.97), which were similar to the proportionality reporting rates for drospirenone-only pills (0.64; 95% confidence interval, 0.55-0.74) and norethindrone-only pills (0.69; 95% confidence interval, 0.60-0.79). Ethinyl estradiol/drospirenone had the highest proportionality reporting rate at 5.18 (95% confidence interval, 4.95-5.42). Using the entire therapeutic class as reference, we similarly found lower proportionality reporting rates with estetrol/drospirenone (0.17; 95% confidence interval, 0.09-0.31) and 17β-estradiol valerate/dienogest (0.25; 95% confidence interval, 0.21-0.30), both of which were similar to the proportionality reporting rate observed for drospirenone-only pills (0.20; 95% confidence interval, 0.17-0.23) and norethindrone-only pills (0.21; 95% confidence interval, 0.19-0.24); the highest proportionality reporting rate, for ethinyl estradiol/drospirenone, was 4.52 (95% confidence interval, 4.41-4.63). CONCLUSION: Combined oral contraceptives containing body-identical estrogens, estetrol, and 17β-estradiol have lower proportions of venous thromboembolism reports than ethinyl estradiol-based pills and are similar to progestin-only pills. These findings suggest a potentially safer thrombotic profile of body-identical estrogen-based combined oral contraceptives.