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Modern Low-Dose Oral Contraceptives Are Very Safe

Professor of Obstetrics and Gynecology Oregon Health Sciences University Portland, Oregon 97201

	Introduction

Top Introduction The recent studies reinforce... References

 
THE 1998 World Health Organization report on cardiovascular disease and steroid hormone contraception concluded that oral contraceptives containing desogestrel or gestodene "probably carry a small risk of venous thromboembolism beyond that attributable to oral contraceptives containing levonorgestrel" (1). I am surprised by this conclusion and disagree with it.

The controversy involving new progestin oral contraceptives began in late 1995, continued through 1996, and began to reach resolution in 1997. Four initial studies comparing users of desogestrel and gestodene products to users of second generation oral contraceptives concluded that the risk of venous thromboembolism was 1.5- to 2.0-fold greater with the newer progestin-containing oral contraceptives (2, 3, 4, 5). An immediate problem with the initial studies was how to reconcile the results with the conventional wisdom that thrombosis is an estrogen dose-related complication. Furthermore, progestational agents, and desogestrel and gestodene in particular, have no significant impact on clotting parameters (6). Therefore, there was inherent biologic implausibility surrounding the new studies. The initial studies were impressive in their agreement. All indicated increased relative risks associated with desogestrel and gestodene compared with levonorgestrel. Nevertheless, all of the early studies, somewhat similar in design, were influenced by the same unrecognized biases. Persistent errors will produce consistent conclusions.

Former users discontinue oral contraceptives for a variety of reasons and often are switched to what clinicians perceive to be "safer" products ("preferential prescribing") (7, 8, 9). Individuals who do well with a product tend to remain with that product. Thus, at any one point in time, individuals on an older product will be relatively healthy and free of side effects ("healthy user effect"). This is also called attrition of susceptibles because higher risk individuals with problems are gradually eliminated from the group (10). Comparing users of older and newer products, therefore, can involve disparate cohorts of individuals.

Because desogestrel- and gestodene-containing products were marketed as less androgenic and therefore better (a marketing claim not substantiated by epidemiologic studies), clinicians chose to provide these products to higher risk patients and older women (7, 8). In addition, clinicians switched patients perceived to be at greater risk for thrombosis from older oral contraceptives to the newer formulations with desogestrel and gestodene. Furthermore, these products were prescribed more often to young women who were starting oral contraception for the first time (these young women will not have experienced the test of pregnancy or previous oral contraceptive use to help identify those who have a congenital predisposition to venous thrombosis). Subsequent studies, correcting for duration of use and focusing on first-time users found no differences between second and third generation oral contraceptives (11, 12, 13, 14).

The apparent differences associated with the new progestins, in my view, were due to two major factors: 1), the marketing and preferential prescribing of new products, and 2), the characteristics of the patients for whom the new products were prescribed. I do not agree with the conclusion by Walker (15) that these explanations do not sufficiently explain the magnitude of the observations. Indeed, I believe this is a reasonable alternative explanation. Most impressive and important is the fact that there is no evidence of an increase in mortality due to venous thromboembolism since the introduction of new progestin oral contraceptives (3, 16).

The new studies on venous thrombosis and recent studies on arterial thrombosis (17, 18, 19, 20, 21, 22, 23, 24) provide an evidence-based formulation that can be summarized as follows:

• Pharmacologic estrogen increases the production of clotting factors.

• Progestins have no significant impact on clotting factors. • Past users of oral contraceptives do not have an increased incidence of cardiovascular disease. • All low-dose oral contraceptives, regardless of progestin type, have an increased risk of venous thromboembolism. The actual risk of venous thrombosis with low-dose oral contraceptives is lower in the new studies compared with previous reports. Some have argued that this is due to preferential prescribing and the healthy user effect. However, it is also logical that the lower risk reflects better screening of patients and lower estrogen doses. • Smoking has no effect on the risk of venous thrombosis. • Smoking and estrogen have an additive effect on the risk of arterial thrombosis. • Hypertension is a very important additive risk factor for stroke in oral contraceptive users. • Low-dose oral contraceptives (less than 50 µg ethinyl estradiol) do not increase the risk of myocardial infarction or stroke in healthy, nonsmoking women, regardless of age. • Almost all myocardial infarctions and strokes in oral contraceptive users occur in users of high-dose products, or in users with cardiovascular risk factors over the age of 35. • Arterial thrombosis (myocardial infarction and stroke) has a dose-response relationship with the dose of estrogen, but there are insufficient data to determine whether there is a difference in risk with products that contain 20, 30, or 35 µg ethinyl estradiol.

The recent studies reinforce the belief that the risks of arterial and venous thrombosis are a consequence of the estrogen component of combination oral contraceptives. Current evidence does not support an advantage or disadvantage for any particular formulation, except for the greater safety associated with any product containing less than 50 µg ethinyl estradiol. Although it is logical to expect the greatest safety with the lowest dose of estrogen, the rare occurrence of arterial and venous thrombosis in healthy women makes it unlikely that there will be any measurable differences in the attributable incidence of clinical events with all low-dose products.

Top Introduction The recent studies reinforce... References

 
The new studies emphasize the importance of good patient screening. The occurrence of arterial thrombosis is essentially limited to older women who smoke or have cardiovascular risk factors, especially hypertension. The impact 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, 25). Although the risk of venous thromboembolism is slightly increased, the actual incidence is still relatively rare, and the mortality rate is about 1% (probably less with oral contraceptives, because most deaths from thromboembolism are associated with trauma, surgery, or a major illness). The minimal risk of venous thrombosis associated with oral contraceptive use does not justify the cost of routine screening for coagulation deficiencies. Nevertheless, the importance of this issue is illustrated by the increased risk of a very rare event, cerebral sinus thrombosis, in women who have an inherited predisposition for clotting and who use oral contraceptives (26, 27). If a patient has a close family history (parent or sibling) or a previous episode of idiopathic thromboembolism, an evaluation to search for an underlying abnormality in the coagulation system is warranted.

Combination oral contraception is contraindicated in women who have a history of idiopathic venous thromboembolism, and also in women who have a close family history (parent or sibling) of idiopathic venous thromboembolism. These women will have a higher incidence of congenital deficiencies in important clotting measurements, especially antithrombin III, protein C, protein S, and resistance to activated protein C. Such a patient who screens negatively for an inherited clotting deficiency might still consider the use of oral contraceptives, but this would be a difficult decision with unknown risks for both patient and clinician, and it seems more prudent to consider other contraceptive options. Other risk factors for thromboembolism that should be considered by clinicians include an acquired predisposition, such as the presence of lupus anticoagulant or malignancy, and immobility or trauma. Varicose veins are not a risk factor unless they are very extensive.

Low-dose oral contraceptives are very safe for healthy, young women. By effectively screening for the presence of smoking and cardiovascular risk factors, especially hypertension, in older women, we can limit, if not eliminate, any increased risk for arterial disease associated with low-dose oral contraceptives. And it is very important to emphasize that there is no increased risk of cardiovascular events associated with duration (long-term) use. In the 1970s, as epidemiological data first became available, we emphasized in our teaching and in our communication with patients the risks and dangers associated with oral contraceptives. In the 1990s, with better patient screening and epidemiologic data documenting the effects of low-dose products, we appropriately emphasized the benefits and safety of modern oral contraceptives. In the new millennium, we can with confidence promote the idea that the use of oral contraceptives yields an overall improvement in individual health, and from a public health point of view, the collection of effects associated with oral contraceptives leads to a decrease in the cost of health care.

	References

Top Introduction The recent studies reinforce... References

 

1. World Health Organization. 1998 Cardiovascular Disease and Steroid Hormone Contraception. WHO Technical Report Series, No. 877.
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