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.