Venous Thromboembolism Risk Is Sharply Elevated For Users of Combined Pills

T. Lane

First published online:

Women who use oral contraceptives containing progestin and a low dose of estrogen have an increased risk of venous thromboembolism—a blood clot that forms in the veins of the legs and may detach and travel to the lungs.1 In a population-based case-control study conducted in California, women who currently used this type of pill had odds of venous thromboembolism that were four times those of women who did not; their odds were three times those of women who had never used such pills. The risk of disease was elevated among current users, regardless of the progestin type (odds ratios, 3.4–5.1).

To investigate the link between combined pills containing fewer than 50 mcg of estrogen and the risk of venous thromboembolic disease, researchers identified women aged 18–44 who were members of the Kaiser Permanente Medical Care Program and, according to medical records and claims data, had been treated for a possible episode of venous thromboembolism between March 1998 and June 2000. The researchers held interviews with the women to collect information on pill use, demographic characteristics, height and weight, medical history, family history of venous thromboembolism, any prolonged periods of immobilization in the previous six months (e.g., overnight hospitalization or an airplane ride lasting four hours or longer), smoking, and use of alcohol, aspirin and vitamins. The study also included randomly selected women from the same medical program as controls.

In all, 196 interviewees in the study group had had a probable and first-time case of venous thromboembolism, were not pregnant, were fecund and were not using an oral contraceptive containing 50 mcg or more of estrogen. Some 44% of these women and 18% of the 746 controls were currently using combined pills that contained a low dose of estrogen. The average duration of pill use was roughly five years for both groups of women. Some 51% of women in the study group were obese (body mass index of more than 30 kg/m2), compared with 28% of controls.

After adjustment for age, multivariate logistic regression analysis revealed that the higher a woman's body mass index, the higher her risk of venous thromboembolism: Women with a body mass index of at least 25 kg/m2 were more likely than others to have had a venous thromboembolism (odds ratios, 1.8–3.5); in general, odds were elevated by 8% per kg/m2. Odds of venous thromboembolism also were positively associated with current use of pills and having a family history of the disorder, as well as having experienced prolonged immobilization and having had a possible predisposing health problem (e.g., stroke, heart attack or a clotting disorder) in the previous six weeks (1.7–5.9). In contrast, the odds of venous thromboembolism decreased by 2% per year of age and 6% per year of pill use. Odds also were negatively associated with being a current smoker, regular physical activity, vigorous physical activity at least once a week, being Hispanic or Asian, being or having been married, having an annual income of at least $20,000, having used aspirin in the previous week and having had at least one child (0.2–0.7).

After adjustment for age, race and ethnicity, income and body mass index, women who currently used the pill were significantly more likely than those who did not to have had a venous thromboembolism (odds ratio, 4.1). Current users were also more likely to have had this condition than were women who had never used the pill (3.2). The odds of venous thromboembolism were elevated regardless of the duration of current pill use: The odds ratio was 5.4 for women who had used the pill for fewer than 12 months, 5.7 for those who had used it for 12–59 months and 3.1 for those who had used it for 60 months or more. However, women who had ever used the pill were as likely as those who had never done so to have developed a venous thromboembolism.

In additional adjusted analyses, the increase in odds of venous thromboembolism associated with current pill use was significantly higher among women with a body mass index of more than 30 kg/m2 than among others (odds ratios, 6.0 vs. 3.3), and among women who did not have a predisposing medical condition than among those who did (7.8 vs. 1.9)—a somewhat surprising finding, according to the analysts. However, the increase in the risk of venous thromboembolism associated with current pill use among women who used pills containing norethindrone was similar to that among women who used pills containing levonorgestrel (3.4 and 5.1).

The researchers comment that their findings are consistent with those of other studies showing a 300–400% increase in the risk of venous thromboembolism among current users of pills with a low estrogen concentration, especially in the first year of use. Furthermore, noting that roughly half of the women who had had a venous thromboembolism were obese, the analysts conclude that the interaction between obesity and pill use is particularly "noteworthy" in light of the current epidemic of obesity in the United States.

—T. Lane


1. Sidney S et al., Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives, Contraception, 2004, 70(1):3–10.