Oral contraceptives increase the risk of stroke, according to a broad analysis by UC San Francisco researchers, but the risk of stroke is so low in women during their reproductive years to begin with that the added risk is generally miniscule, the researchers say. The analysis, which evaluated 16 earlier studies, indicated that the low dose oral contraceptives generally prescribed in the United States today nearly double the risk of stroke. The risk doubled yet again with higher estrogen doses.
However, says the senior author of the study, S. Claiborne Johnston, MD, UCSF assistant professor of neurology, "the risk is so low to begin with that even when the risk doubles it remains low. Statistically speaking, it would take 24,000 women, being treated for one year with low dose preparations, before a single additional stroke occurred due to the pill.
"So even though there's a significant elevated relative risk, it probably shouldn't influence most women's decision about whether they use oral contraceptives," he added.
The study is reported in the July 5 issue of Journal of the American Medical Association.
The researchers reviewed 73 investigations into the risk of stroke from oral contraceptive use, and culled from this group 16 studies that met rigorous inclusion criteria.
The studies, conducted at different times between 1960 and 1999, reflected different risk factors for stroke. When the pill was first introduced, women were given much higher doses of the drug and many of these women smoked; today, most oral contraceptive users do not smoke, and those with other risk factors for stroke, such as high blood pressure, are generally discouraged from using oral contraceptives. The UCSF analysis took into account possible weaknesses of the studies, including the account of risk factors, and attempted to compensate for them.
In their study, the researchers found that in women taking low dose oral contraceptives, the risk of stroke was just under double what it would otherwise have been, leading to a relative risk of 1.93 based on the most carefully conducted studies. The overall risk among all current users, which included women taking various doses of the drug, more than doubled the risk of stroke, to 2.75. The risk doubled yet again in women taking high-dose estrogen contraceptives, to 4.53.
Surprisingly, results of the study indicated that smoking, high blood pressure, migraines and age did not increase the relative risk of stroke associated with oral contraceptives. However, the researchers cautioned that these results might be misleading.
The findings may well reflect the fact that physicians today are less likely to prescribe oral contraceptives to women who smoke, have high blood pressure or are older, they say.
"It's possible we're underestimating the relative risk of low dose oral contraceptives in our study because fewer high risk women are being prescribed the drug and some studies do not take this into account," says Claiborne. Moreover, he warned, smoking and high blood pressure are independent risk factors for stroke, and doubling the stroke risk by taking an oral contraceptive will have a greater impact in those who begin with higher stroke risk.
Furthermore, it is not yet clear whether smoking and high blood pressure contribute to the risk of other forms of clotting in oral contraceptive users, such as clotting occurring in leg veins and in the large blood-draining structures of the brain. The latter condition, known as cerebral venous sinus thrombosis, is a rare cause of strokes. Two recent studies suggest that oral contraceptive use elevates the risk of the condition. In their analysis, the researchers found a markedly elevated risk for the condition in current oral contraceptive users.
"If high risk of cerebral venous sinus thrombosis with oral contraceptive is confirmed, undiagnosed cerebral venous sinus thrombosis may account for a significant portion of ischemic strokes attributed to oral contraceptives," says Johnston.
Thus, it may still be appropriate, the researchers cautioned, to avoid oral contraceptive prescriptions for smokers and those with high blood pressure. Oral contraceptives are prescribed to more than 10 million women in the United States, and 78.5 million worldwide. Concerns about safety have persisted since their introduction in 1960. Some studies have suggested that oral contraceptive use is associated with increased risk of stroke and numerous other blood clotting conditions, such as deep venous thrombosis, pulmonary embolism, myocardial infarction, cerebral venous sinus thrombosis, and hemorrhage due to aneurysms. However, the risk of stroke has been particularly concerning because of its devastating effects.
"If we were to remove oral contraceptives from the market in the United States and replace them with condoms, we would expect about 400 fewer strokes each year, but the cost would be 690,000 additional unintended pregnancies," Johnston says. "Oral contraceptives certainly aren't perfect, but they work very well."
Co-authors of the study were Leslie Allison Gillum, BA, a medical student at UCSF, and Sai Kumar Mamidipudi, MBBS, a research assistant in Johnston's lab. The study was funded by the National Stroke Association and by the National Institutes of Health's National Institute of Neurological Disorders and Stroke.
Journal
JAMA