Abstracts & Commentary
Synopsis: The increased risks of venous and arterial thrombosis is significantly affected by the estrogen dose and the duration of use of oral contraceptives.
Sources: Lidegaard Ø, et al. Contraception. 2002;65: 187-196; Lidegaard Ø, Kreiner S. Contraception. 2002; 65:197-205.
Øjvind Lidegaard is an obstetrician-gynecologist in Denmark who has become an epidemiologist. His case-control studies using the Denmark Registry are recognized as being as good as can be. Lidegaard and colleagues have now published 5-year case-control studies of OCs and venous thromboembolism, and cerebral thrombosis. The study of venous thromboembolism (VTE) included 987 cases and 4054 controls. The risk of VTE was increased with current use of OCs and declined with increasing duration of use. Correcting for confounding factors, the risk decreased with decreasing estrogen dose, and the risk was slightly greater with second-generation progestins (levonorgestrel or norgestimate) compared with third-generation progestins (desogestrel or gestodene). Correction for duration of use and estrogen dose, the risk was 33% greater with third-generation progestins.
The study of cerebral thrombosis (cerebral infarction and transitory ischemic attacks) included 626 cases and 4054 controls. The odds ratio (relative risk) of cerebral thrombosis decreased from a high of 4.5 (CI = 2.6-7.7) with 50 mg pills to 1.6 (CI = 1.3-2.0) with 30-40 mg pills and the same 1.7 (CI = 1.0-3.1) with 20 mg pills. There was a slight decline in risk with increasing duration of use. Second generation products with less than 50 mg estrogen had a 61% higher risk compared with third-generation, low-dose estrogen products.
Comment by Leon Speroff, MD
Denmark provides a unique opportunity for epidemiologists. Every person in Denmark has a personal identification number, given at birth and collected in a register that is updated daily. In addition, every hospital discharge diagnosis is registered electronically (and has been since 1977). Germane to the OC controversy comparing second- and third-generation progestins is the fact that there was no controversy in Denmark. In response to the British-initiated publicity, the Danish Health Board concluded that there was no reason to change OC prescribing practices, and, therefore, the market share of third-generation products remained stable and still accounts for about two thirds of current users. Lidegaard et al argue that this absence of a controversy or a change in Denmark’s prescribing of OCs minimizes any bias due to "preferential prescribing," providing perceived safer products to higher risk patients.
The conclusions reached in these case-control studies, with the exception of the effects of high-dose estrogen products, were not large. Problems, biases, and confounders could, therefore, account for the results. The method depended upon questionnaires to retrieve the data. Even though the return rate was remarkable (87.2% in the VTE study and 88.1% in the cerebral thrombosis study), categories with small changes in the odds ratios could have been influenced by those who did not participate or those who did not provide accurate information. Furthermore, critics claim that any study using hospital admissions overestimates the VTE risk of OCs.1
The studies contained nuggets of information that are clinically useful:
The VTE Study
The following conditions increased the risk of VTE:
- Smoking more than 10 cigarettes per day, BMI greater than 25 (a BMI greater than 30 increased the risk 5-fold), a family history of VTE, and the presence of an inherited coagulation defect (more than a 30-fold increase);
- These are the first epidemiologic data to indicate that OCs with 20 mg estrogen have a lower risk of VTE than products with 30-40 mg;
- Progestin-only contraceptive products did not have a statistically significant increase in the risk of VTE;
- These conditions did not increase the risk of VTE: hypertension, diabetes, migraine, and hyperlipidemia;
- Based on the Denmark data, the incidence rate of VTE is 10 per 100,000 users per year in women younger than age 30, and 23 per 100,000 women per year in women 30-44 years old. The mortality rate is low, 0.6 per million in the younger women and 1.7 per million in the older women.
The Cerebral Thrombosis Study
- Hypertension increased the risk of cerebral thrombosis 5-fold, migraine 3.2 times, and diabetes 5.6 times. Hyperlipidemia and coagulation disorders increased the risk about 12-fold. A family history of arterial or venous thrombosis increased the risk by about 50-60%;
- The risk of cerebral thrombosis was the same comparing products with 20 mg estrogen with 30-40 mg products;
- Based on the Denmark data, the incidence rate of thrombotic stroke is 3 per 100,000 users per year in women younger than age 30, and 15 per 100,000 women per year in women 30-44 years old. The mortality rate is 2.2 per million in the younger women and 2.3 per million in the older women.
The risk of VTE associated with modern OCs is increased but manifested primarily in the first years of use. The risk is influenced in a major way by the estrogen dose, and the difference between second-generation and third-generation progestin products is small (either real and not meaningful clinically or a reflection of biases and confounders). Previous studies have indicated that smoking is only a risk factor for arterial thrombosis, but this study indicates that the risk is dose-related (no increase in risk when smoking less than 10 cigarettes per day). Nevertheless, the effect of smoking on the risk of VTE is less than that on the risk of arterial thrombosis.
Why did American researchers not find an increase risk for arterial thrombosis in users of low-dose oral contraceptives?2 The difference may be due to the intensity and quality of patient screening. The occurrence of arterial thrombosis is essentially limited to older women who smoke or have cardiovascular risk factors, especially hypertension. The effect of good screening is evident in the repeated failure to detect an increase in mortality due to myocardial infarction or stroke in several studies.3,4
Screening women for inherited clotting disorders is not cost effective. Only a small number of women even with the Leiden mutation (less than 1 in 1000) have a clinical event (99.85% of the women who test positively will not have a clinical event!). The finding of a positive screening test, especially considering the high rate of false-positive tests, would be a barrier to the use of oral contraceptives, and a subsequent increase in unwanted pregnancies (which has an even greater risk of venous thromboembolism) would likely follow. Most experts believe that screening for inherited disorders should be pursued only in women with a previous episode of idiopathic venous thromboembolism or in women with a close positive family history (parent or sibling) of venous thrombosis. If a diagnosis of a congenital deficiency is made, screening should be offered to other family members.
These studies are consistent with the literature of the last 5 years, documenting that low-estrogen dose OCs are very safe for healthy women younger than age 35, and safe for women older than 35 who do not smoke or have hypertension.
Dr. Speroff is Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland.
1. Heinemann LAJ, et al. Contraception. 2002;65: 207-214.
2. Schwartz SM, et al. Stroke. 1998;29:2277-2284.
3. Jick H, et al. Lancet. 1995;348:1589-1593.
4. Petitti DB, et al. Stroke. 1997;28:280-283.