Dr. Levine of the SUNY Health Science Center at Brooklyn has received honorariums from Genentech for service on a scientific advisory committee and a research grant from Genentech as a principal investigator.)
Since their introduction, hormonal contraceptives have been associated with an increased risk of stroke. With newer formulations, however, the magnitude of that risk has become less clear. In this article, the authors discuss data regarding risk of stroke associated with different types of oral contraceptives. The article also includes an expanded explanation of the possible pathophysiology of hormonal contraceptive-related stroke. Special risk groups, including women who smoke, are migraineurs, or who have arterial hypertension are specifically considered as well. In addition, a brief discussion is included regarding stroke risks associated with the ovarian hyperstimulation syndrome and stroke risks among transsexuals.
• Oral contraceptives may increase the risk of ischemic stroke, but the absolute risk remains very small.
• Oral contraceptives do not seem to increase the risk of hemorrhagic stroke in the general population.
• Oral contraceptives should not be offered to women with migraine with aura.
Historical note and terminology
Shortly after the introduction of oral contraceptives, strokes associated with their use were first reported (Lorentz 1962). Numerous studies have since estimated the risk of stroke, with varying results (Inman and Vessey 1968; Sartwell et al 1969; Vessey and Doll 1969; Anonymous 1973; Jick et al 1978; Mettinger et al 1984; Chang et al 1986). Several factors have contributed to the difficulties in accurately validating this risk. One major issue is that formulations of oral contraceptives vary considerably, and moreover, they have changed remarkably over the years. When originally introduced, oral contraceptives contained doses of ethinyl estradiol as high as 150 mcg. Presently, no formulations have more than 50 mcg of ethinyl estradiol, and most have as little as 20 to 35 mcg. Also, multiple types of progestins are available in different combinations with various ethinyl estradiol doses.
Lack of consistent system of categorization of different formulations of oral contraceptives has made comparison between studies rather difficult. Some studies have evaluated all types of oral contraceptives; others have attempted to address the risk associated specifically with either changes in estrogen or progestins dose. Additionally, some studies have compared current users of oral contraceptives to women who have never used them, whereas other studies have compared current users to noncurrent users. Still other studies have compared those who have ever used oral contraceptives to women who have never used them.
Moreover, stroke subtype has not been consistent between studies. Some studies evaluated all stroke types, whereas some only selected certain categories, such as ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, cerebral venous thrombosis, or transient ischemic attacks.
Likewise, differences in the rate and control of vascular risk factors could contribute to diverse results reported. Inherited prothrombic conditions may increase the risk of oral contraceptive-associated strokes (Slooter et al 2005).
Furthermore, research on oral contraceptive-associated stroke has been mainly observational design, either as case-control or cohort studies. Limitations of observational studies include unknown differences between study groups, recall bias, and appropriateness of control groups.
However, there is general agreement that there is a small but significant increased risk of stroke among women who use oral contraceptives, but the overall risk and the particular risk in selected populations remains uncertain.
Worldwide, more than 100 million women either ever used or are currently using oral contraceptive medications (Blackburn et al 2000). There are approximately 40 brands of oral contraceptives in the United States and 21 brands of emergency contraceptive pills (Table 1). Physicians must consider type of estrogen, estrogen dose, progestin type, progestin dose, routes of administration (oral, vaginal, patches), and other relative potencies of different oral contraceptive formulations. Risk of serious side effects is higher among women who take more than 50 mcg of estrogen. Thus, many physicians recommend estrogen of 35 mcg or less. Therefore, the ideal drug is one with the lowest estrogen and progestin doses that will be effective in preventing pregnancy while minimizing adverse effects ( American College of Obstetricians and Gynecologists ).
Table 1. Hormonal Contraception
Methods of administration
• Combined ethinyl estradiol plus progestin
• Types of progesterone include chlormadinone, cyproterone acetate, dienogest, desogestrel, drospirenone, gestodene, levonorgestrel, norethindrone, norgestimate, nomegestrol, and norgestrel
• Types of estrogen: ethinyl estradiol, estradiol valerate, estradiol
• Progestin only
• Long-acting reversible contraception
• Combined oral contraceptives (1st, 2nd, 3rd, 4th generations)
• Transdermal patch
• Vaginal ring
• Oral contraceptive pill or “mini pill”
• Injectable - depox medroxyprogesterone acetate
• Subdermal implant (etonogestrel)
• Levonorgestrel intrauterine device
• Copper intrauterine device
This article considers the evidence for stroke risk associated with use of currently available oral contraceptives. Most oral contraceptives are combined formulations of ethinyl estradiol or any of the several different progestins. Doses of estrogen vary from 20 to 50 mcg. Formulations containing progesterone only, in oral and injectable forms, are specifically referred to as such in this article. Transdermal hormonal contraception is discussed briefly. Implantable forms of hormonal contraception are not discussed in detail (see clinical vignette #3). Estrogen and progesterone preparations used in hormone replacement therapy also are not addressed in this article.
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