1. Women taking newer formulations of combined oral contraceptive pills, with the exception of norgestimate, were more likely to have had a blood clot than those using second-generation drugs.
2. The absolute risk of blood clot remained low, with just 14 additional cases per 10 000 women per year.
Evidence Rating Level: 3 (Average)
Study Rundown: Oral contraceptive pills (OCPs) are some of the most common birth controls used worldwide. Roughly 1 in 10 reproductive-aged women worldwide use them for contraception, dysmenorrhea or endometriosis-related chronic pelvic pain. OCPs are even more common in developed nations. Despite their popularity, OCPs have significant side effects, including increased propensity to form blood clots, which can manifest as deep vein thromboses (DVT) or venous thromboembolism (VTE), which can be fatal. The risk of blood clots is primarily attributed to the estrogen component of oral contraceptives such that women with a history of DVT, cancer or other thrombogenic conditions are recommended against estrogen replacement therapy or oral contraceptives containing estrogen. Progesterone, the other component in oral contraceptives, is also thought to contribute to clot risk by leading to venous stasis via progesterone-mediated vascular smooth muscle relaxation. Previous studies have confirmed that higher estrogen doses are associated with increased risk of clot. Numerous, recent studies have demonstrated an association of higher VTE risk with use of newer (third or fourth generation) formulations of progesterone. However, these studies have been metholodologically compromised or failed to include all the newest formulations of progesterone such as drospirenone. In this large, nationally representative United Kingdom study, researchers sought to compare whether the incidence of blood clot varies as a result of the generation and dose of progestin and/or dose of estrogen.
Findings highlight an increased odds of blood clot among women on newer generation progestins (drospirenone, gestodene, desogestrel, cyproterone) with the exceptoon of norgestimate, which had a similar risks as the lower-risk second-generation formulations (levonorgestrel, norethisterone). Of note, among women on newer generation progestins, the absolute risk of blood clot was objectively low (14 cases per 10 000 women) and remains lower than that of a pregnant woman’s risk of clot. A strength of this study was the large, nationally representative cohort; however, the study was limited by potential selection bias as exposure to OCPs was ascertained by filled prescriptions. Future, prospective studies comparing prescription data to self-reported use could help account for this limitation and support the findings of this study. Furthermore, this study did not identify a difference in risk by estrogen concentration, which is known to increase clot risk.
In-Depth [case-control study]: From 2 large primary care databases from the UK, researchers collected data on women with a first diagnosis of VTE (n = 10 562) and compared them to up to 5 matched controls. Odds ratios for incidence of VTE with use of combined oral contraceptives in the previous year were calculated, adjusting for smoking status, alcohol use, ethnic group, BMI, comorbidities and use of other contraceptive drugs.
Compared to healthy controls, women who experienced blood clot were more likely to use any combined OCP within the past year (aOR = 2.97, 95%CI 2.78-3.17). With the exception of norgestimate (a third-generation progestin), exposure to other newer-generation progestins like desogestrel, gestodene, drospirenone, and cyproterone, was associated with a significantly higher risk of VTE compared to second-generation formulations (levonorgestrel, norethisterone). An estimated 14 additional cases of VTE per 10 000 women will be diagnosed due to the use of desogestrel and cyproterone compared to 8 out of 10 000 women due to levonorgestrel and norgestimate.
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