Progress in Reproductive Health Research |
Venous Thromboembolism
The first epidemiological evidence implicating use of combined oral contraceptives with an increased risk of venous thromboembolism (blood clots in veins) appeared in 1967. All of the studies conducted since then have found that current users of combined oral contraceptives have a higher risk of venous thromboembolic disease than women not using oral contraceptives. In most studies the relative risks were statistically significant.The consistency of the findings, the size of the relative risks, and the lack of plausible explanation in terms of bias, confounding or chance, strongly suggest a causal relationship between current use of combined oral contraceptives and venous thromboembolic disease. The absolute risk, however, remains very low.
Earlier studies of use of oral contraception and venous thromboembolism found little change in risk with increasing duration of use. The WHO study (1) showed little evidence overall of an appreciable change in risk with duration of use, although the size of the relative risk diminished slightly during the first few years. A comparison between women who had used combined oral contraceptives for the first time and those who had never used them in the Transnational Study indicated a 10-fold increased risk during the first year of use which fell to a twofold increase in subsequent years. Past users of combined oral contraceptives are not at greater risk of venous thromboembolic disease than women who have never used them. The risk among current users falls to that among non-users within 3 months of stopping oral contraceptives.
The relative risk of venous thromboembolism associated with current use of oral contraceptives does not appear to vary with age. The incidence of venous thromboembolic disease, however, rises with age. This means that the absolute risk of venous thromboembolic disease attributable to oral contraception is higher in older than in younger women. In the WHO study (1), oral contraceptive users who were obese had a higher relative risk than did users who were not obese in both developing and developed countries.
Recent studies have shown that women with hereditary clotting defects are at a much higher risk of venous thromboembolism if they use oral contraceptives (2). Current users of oral contraceptives with factor V Leiden mutation had a relative risk of deep vein thrombosis of 35 compared with non-users without this mutation. Even with such a high relative risk, however, the absolute risk was still low: around three additional cases of venous thromboembolism per year per 1000 users with factor V Leiden mutation compared with users without this defect.
Early studies suggested that reduction in the estrogen content of combined oral contraceptives might lower the risk of deep vein thrombosis and pulmonary embolism; however, the evidence was not entirely consistent. There is no convincing evidence that the risks have declined substantially over time, or with reductions in estrogen content. The influence of the progestogen component of combined oral contraceptives on the risk of venous thromboembolism has, until recently, received comparatively little attention.
Since the end of 1995, four studies ( 3, 4, 5, 6) have reported that users of low-dose (<50 µg of estrogen) combined oral contraceptives containing desogestrel or gestodene have a higher risk of venous thromboembolic disease than users of low-dose contraceptives containing levonorgestrel. Comparison between results has been complicated by the use of different reference groups. The only published study which has reported on the risks of venous thromboembolic disease associated with the use of progestogen-only pills compared these preparations with combined oral contraceptives containing levonorgestrel. The estimated relative risk was 1.3.
The Scientific Group concluded that:
Current users of combined oral contraceptives have a low absolute risk of venous thromboembolism, which is nonetheless 3–6 times that in non-users. The risk is probably highest in the first year of use and declines thereafter, but persists until discontinuation.
After use of combined oral contraceptives is discontinued, the risk of venous thromboembolism drops rapidly to that in non-users.
Among users of combined oral contraceptive preparations containing less than 50 µg of ethinylestradiol, the risk of venous thromboembolism is not related to the dose of estrogen.
Combined oral contraceptives containing desogestrel or gestodene probably carry a small risk of venous thromboembolism beyond that attributable to combined oral contraceptives containing levonorgestrel. There are insufficient data to draw conclusions with regard to combined oral contraceptives containing norgestimate.
The absolute risks of venous thromboembolism attributable to use of oral contraceptives rise with increasing age, obesity, recent surgery, and some forms of thrombophilia. The effects of other risk factors for venous thromboembolism have not been quantified in users of combined oral contraceptives.
Cigarette smoking and raised blood pressure, which are important risk factors for arterial disease, do not appear to elevate the risk of venous thromboembolic disease.
There are insufficient data to conclude whether there is a relation between venous thromboembolism and the use of progestogen-only contraceptives.
The relative risks of venous thromboembolic disease observed in users of combined oral contraceptives in developed countries appear to be applicable to developing countries.
References
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboemolic disease and combined oral contraceptives: results of an international multicentre case–control study. Lancet, 1995, 346:1575–1582.
Vandenbroucke JP et al. Increased risk of venous thrombosis in oral contraceptive users who are carriers of V Leiden mutation. Lancet, 1994, 344:1453–1457.
Spitzer WO et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case–control study. British medical journal, 1996, 312:83–88.
Lewis MA et al. The increased risk of venous thromboembolism and the use of third-generation progestogens: role of bias in observational research. Contraception, 1996, 54:5–13.
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effects of different progestogens in low-oestrogen oral contraceptives on venous thromboembolic disease. Lancet, 1995, 346:1582–1588.
Jick H et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptiveswith differing progestogen components. Lancet, 1995, 346:1589–1593.