The Risks of Oral Contraceptive Pills

Helen C. Pymar, M.D., Mitchell D. Creinin, M.D.; Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Women's Research Institute, Pittsburgh, Pennsylvania.

Semin Reprod Med. 2001;19(4) 

In This Article

The Risk of Venous Thromboembolic Disease Associated With the Use of Oral Contraceptive Pills

Use of oral contraceptive pills has been found to increase the risk of VTE. This risk appears to be proportional to estrogen dose.[4] More recently, it has been suggested that the type of progestin may also influence the risk of VTE.[18,19,20,21,22] Although many of these studies attempted to control for bias and confounding, the nature of the study designs left doubt about the true impact of the new progestins on thromboembolic risk.

Based on a study of over 400,000 woman-years performed in the Netherlands, women aged 15 to 49 years who are factor V Leiden-negative and not pregnant or using oral contraceptive pills have an incidence of venous thrombosis of 8/100,000/year.[23] Pregnancy, however, is associated with a much higher risk of VTE. In a recent cohort study of almost 400,000 women in the United Kingdom who had live births with pregnancies of 24 or more weeks of gestation, the incidence of VTE was 85/100,000 women.[24] Whenever considering the increased risks of VTE associated with the oral contraceptive pills, it is important to keep in mind the baseline and pregnancy-associated incidence rates.

An estimate of the risk of VTE associated with birth control pill use was calculated in a study by Gerstman et al[4] in 1991. His calculations were based upon a cohort study from 1980 through 1986 of oral contraceptive users between the ages of 15 and 44 years in the Michigan Medicaid population. The majority of oral contraceptive pill users had daily estrogen doses of less than 50 µg. Over 230,000 women received prescriptions for oral contraceptive pills. The unadjusted rates of deep venous thromboembolic disease in users of less than 50 µg, 50 µg, and greater than 50 µg oral contraceptive pills were 4.2, 7.0, and 10.0 per 10,000 woman-years, respectively. When diagnostically confirmed cases of VTE were used, there was a trend toward higher relative risk for the intermediate dose formulations (2.0; 95% CI, 0.9 to 4.0) and a statistically significant increased risk for the high-dose formulations (3.2; 95% CI, 2.4 to 4.3). Thus, there appears to be a dose-response relationship between estrogen dose and VTE risk. Given a risk of 1 per 10,000 of VTE in the general population,[23] the estimated attributable risk of oral contraceptives currently used in the United States would be 3 per 10,000. This risk should still be considered acceptably low.

In 1995, studies performed by the World Health Organization[18] and Jick et al[21] suggested that oral contraceptive pills containing desogestrel (and gestodene, which is not available in the United States) could be associated with higher risks of VTE than those pills containing the older progestins. The research performed by the World Health Organization was a hospital- and community-based, multinational, case-control study. Levonorgestrel- or desogestrel-containing oral contraceptive pills were used by 182 of the women diagnosed with VTE. When the results from all centers were calculated, the odds ratios of VTE for users of oral contraceptives containing desogestrel and levonorgestrel were 8.3 (95% CI, 4.3 to 15.9) and 3.4 (95% CI, 2.5 to 4.7), respectively, compared with nonusers of oral contraceptives. The adjusted odds ratio for VTE in the users of desogestrel compared with levonorgestrel oral contraceptive pills was 2.4 (95% CI, 1.3 to 4.6). In this study, odds ratios were mainly adjusted for alcohol use and body mass index. In the Oxford region of the United Kingdom, 28/35 desogestrel- and 40/137 levonorgestrel-associated cases were identified. In this site, with almost equal numbers of hospital and community controls, there was an insignificantly increased odds ratio of 1.8 (95% CI, 0.7 to 4.8) in desogestrel compared with levonorgestrel oral contraceptive pill users.

Jick et al[21] performed a population-based and nested case-control study of women under the age of 40 years in the United Kingdom. Women who received a prescription for oral contraceptives containing less than 35 µg of ethinyl estradiol and levonorgestrel or desogestrel were included. The risk of death due to pulmonary thromboembolism was 1.6/100,000 and 0.7/100,000 woman-years for users of oral contraceptive pills containing levonorgestrel and desogestrel, respectively. There were 80 cases of nonfatal VTE in the group, of which 51 (64%) were confirmed and the remainder were possible cases. The incidence rates of nonfatal VTE were 16/100,000, and 29/100,000 in users of oral contraceptive pills containing levonorgestrel and desogestrel, respectively. The relative risk of VTE comparing desogestrel with levonorgestrel and adjusted for age and calendar year was 1.9 (95% CI, 1.1 to 3.2).

In 1996, a community- and hospital-based case-control study by Spitzer et al[22] again suggested a small but significant increase in risk of VTE with desogestrel compared with levonorgestrel or norethindrone oral contraceptive pills. Cases were females aged 16 to 44 years who had VTE diagnosed at 10 centers in Germany and the United States. In the study 183 cases of pulmonary embolism with four fatal events and 288 cases of deep venous thrombosis alone were reported. The odds ratios were adjusted for linear age, smoking, alcohol, study center, body mass index, and duration of exposure to oral contraceptives prior to current contraceptive. The adjusted odds ratio for VTE with desogestrel- compared with the levonorgestrel- or norethindrone-containing oral contraceptive pills was 1.5 (95% CI, 1.1 to 2.2). In a further analysis of this study data, Suissa et al[25] found that first-time users of oral contraceptive pills had an increased risk of VTE during the first year of use. This rate was increased by about 10 times for oral contraceptive pills with all types of progestins compared with nonusers in the first year and decreased to around a 2 times elevated risk after 2 years of use. However, this comparison was based on only 26 and 39 cases of VTE in first-time users of levonorgestrel and norethindrone or desogestrel and gestodene oral contraceptive pills, respectively. Women at higher risk for VTE may have been preferentially prescribed a newer progestin oral contraceptive pill. Although studies have attempted to control for this effect, it is an inherent problem in a case-control or cohort study.

A study performed in the United Kingdom by Farmer et al[20] suggested that a prescribing bias may have affected the rate of deep venous thrombosis in desogestrel or gestodene oral contraceptive users. There were almost 500,000 women included in the study with 234,899 woman-years of exposure to hormonal contraception. There was a trend present in prescribing patterns of oral contraceptive pills: women given desogestrel or gestodene oral contraceptive pills tended to be older than those prescribed levonorgestrel or norethindrone pills. Additionally, women prescribed the formulation of 20 mg of ethinyl estradiol with 150 mg desogestrel were significantly older than those prescribed the 30 mg ethinyl estradiol and 150 mg desogestrel combination. The rate of VTE in levonorgestrel or norethindrone oral contraceptive pills, desogestrel plus 30 mg ethinyl estradiol, and desogestrel plus 20 mg ethinyl estradiol was 3.10, 3.99, and 11.53/10,000 woman-years, respectively. After excluding the 20 mg ethinyl estradiol plus desogestrel oral contraceptive pill, there were no significant differences between any of the combination oral contraceptive pill formulations with respect to VTE risk. However, the combination of desogestrel and 20 mg of ethinyl estradiol had a significantly increased adjusted odds ratio for VTE compared with levonorgestrel and norethindrone oral contraceptive pills (3.49; 95% CI, 1.21 to 10.12). These calculations were adjusted for age, body mass index, concurrent disease, and hormone use. It seems biologically implausible that an oral contraceptive pill with a lower dose of estrogen and an identical amount of progestin would have a higher risk of VTE. As such, it is likely that there are biases inherent to new oral contraceptive pills that are not adequately adjusted for using logistic regression methods. It is logical to question previous studies that also show small but significant increases in VTE risk for newer oral contraceptive pills.

Using the same General Practice Research Database,[20] Jick et al[26] came to the conclusion that women using oral contraceptives containing desogestrel or gestodene had twice the risk of VTE as those containing levonorgestrel. Farmer et al and Jick et al reviewed the database between 1991 and 1995, and 1993 and 1999, respectively. Jick et al maintain that their conclusions were different from those of Farmer et al because of better validation of the diagnosis of VTE and better controlling for confounding factors in their study. Thus, the newer analysis of the data continues to suggest a small but significant increase in VTE in users of desogestrel and gestodene containing oral contraceptives.

In summary, oral contraceptive pills produce a small but significant increase in risk of VTE. However, the risk of VTE is further increased for women who become pregnant. The studies suggesting increased risks of VTE in desogestrel-containing oral contraceptives may be due to biases and confounding that are not adequately adjusted for using standard statistical methods. However, a recent study suggests that the risk of oral contraceptive pills containing desogestrel or gestodene have twice the risk of thromboembolism as those containing levonorgestrel.[26] Regardless, even if true, the attributable risk would be around 1 to 2 per 10,000 woman-years of use.[20,21]

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