period. Modern COCs are associated with about a 2- to 4-fold higher risk of VTE than non-use. The route of administration of EE does not appear to influence VTE risk, as EE/progestin-containing contraceptive vaginal rings and contraceptive patches have the same or even higher risk of VTE than COCs. Pregnancy is associated with about a 4.3-fold increase in risk of VTE. It has been estimated that at least 300 to 400 healthy young women die each year in the United States due to VTE caused by EE-containing birth control pills. Modern COCs contain 10 to 35 μg EE, but typically 20, 30, or 35 μg. The initial formulations of COCs that were introduced in the 1960s contained 100 to 150 μg EE. However, it was soon found that EE is associated with increased risk of VTE and that the risk is dose-dependent. Following these events, the dose of EE was greatly reduced, and is now always less than 50 μg. These lower doses have a significantly reduced risk of VTE with no loss of contraceptive effectiveness. Gerstman et al. (1991) found that COCs containing more than 50 μg EE had 1.7-fold and COCs containing 50 μg EE 1.5-fold the risk of VTE of COCs containing less than 50 μg. A 2014 Cochrane review found that COCs containing 50 μg EE with levonorgestrel had 2.1- to 2.3-fold the risk of COCs containing 30 μg or 20 μg EE with levonorgestrel, respectively. COCs containing 20 μg EE are likewise associated with a significantly lower risk of cardiovascular events than COCs containing 30 or 40 μg EE. However, discontinuation of COCs is more common with doses of EE from 10 to 20 μg due to problematic changes in bleeding patterns. Women with thrombophilia have a dramatically higher risk of VTE with EE-containing contraception than women without thrombophilia. Depending on the condition, risk of VTE can be increased 5- to 50-fold relative to non-use in such women. Sex hormone-binding globulin (SHBG) levels indicate hepatic estrogenic exposure and may be a surrogate marker for coagulation and VTE risk with estrogen therapy, although this topic has been debated. SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold with levonorgestrel, 2.5- to 4-fold with desogestrel and gestodene, 3.5- to 4-fold with drospirenone and dienogest, and 4- to 5-fold with cyproterone acetate. Contraceptive vaginal rings and contraceptive patches likewise have been found