with positive (or unknown) antiphospholipid antibodies Complicated valvular heart disease Except when being used to treat it, EE should be avoided in women with current breast cancer due to a possible worsening of prognosis. EE should also be avoided in breastfeeding women who are less than 21 days postpartum due to an increased risk of VTE. EE use in breastfeeding women who are at least 21 days postpartum should be discussed with a provider and include information on the advantages, disadvantages, and alternatives for using EE. Due to risk of cholestatic hepatotoxicity, it is widely considered that COCs containing EE should be avoided in women with a history of cholestasis of pregnancy, hepatic tumors, active hepatitis, and familial defects in biliary excretion. Side effects The severity of side effects can vary based on the dose and administration route of EE. General side effects of EE are the same as for other estrogens and include breast tenderness, headache, fluid retention (bloating), nausea, dizziness, and weight gain. The estrogen component of oral contraceptives, which is almost always EE, can cause breast tenderness and fullness. In males, EE has additional side effects, including gynecomastia (breast development), feminization in general, hypogonadism, infertility, and sexual dysfunction (e.g., reduced libido and erectile dysfunction). In men who received high-dose estrogen therapy with 200 μg/day oral EE for more than three months, gynecomastia occurred in 98% and decreased libido occurred in 42 to 73%. Long-term effects Blood clots VTE is a blood clot in a vein, and includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Estrogens are known to increase the risk of VTE due to their effects on liver synthesis of coagulation factors. EE carries a greater risk of blood clot formation and VTE than does natural estradiol, which is thought to be due to structural differences between the two compounds and different susceptibilities to liver inactivation. A 2012 meta-analysis estimated that the absolute risk of VTE is 2 per 10,000 women for non-use, 8 per 10,000 women for EE and levonorgestrel-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing EE and a third- or fourth-generation progestin such as desogestrel or drospirenone. For comparison, the absolute risk of VTE is generally estimated as 1 to 5 per 10,000 woman–years for non-use, 5 to 20 per 10,000 woman–years for pregnancy, and 40 to 65 per 10,000 woman–years for the postpartum