SAN DIEGO—Among women with migraine, low-dose combined estrogen–progestin contraceptives do not increase the risk of stroke, and continuous hormonal contraceptive use may reduce menstrual migraine, according to a lecture delivered at the 58th Annual Scientific Meeting of the American Headache Society.
High doses of combined oral contraceptives do increase stroke risk, and migraine with aura confers an independent increased risk of stroke, said Anne H. Calhoun, MD, Professor of Anesthesiology and Psychiatry at the University of North Carolina in Chapel Hill and partner and cofounder of the Carolina Headache Institute in Durham. Evidence does not suggest, however, that low-dose hormonal contraceptive use together with history of migraine confers additive risk, she said.
Over the last several decades, various combined oral contraceptive regimens (eg, triphasic, extended cycle, and continuous) with a range of estrogen doses have been developed. “They are all over the place, and we really need to know what we are dealing with,” Dr. Calhoun said. Risks of combined oral contraceptives, including myocardial infarction and stroke, are almost exclusively seen with smoking and high-dose pills, she said.
Dr. Calhoun prefers to prescribe pills that inhibit ovulation while using 20 μg or less of the synthetic estrogen ethinyl estradiol (EE) for women at increased risk of stroke. The highest dose pill in the United States contains 50 μg of estrogen. The lowest dose pill contains 10 μg.
Placebo Side Effects
In hormonal contraception, headache often develops during the placebo week. A typical contraceptive regimen includes 21 active pills and seven placebo pills. Sulak et al found that 70% of women taking birth control pills had headache during the placebo week, and peak incidence of headache was on the third day of the placebo week. “When you eliminated the placebo week, it improved mood scores, improved headache scores, there was less dysmenorrhea and pelvic pain,” Dr. Calhoun said.
When estrogen concentrations decrease upon taking placebo, 5HT concentration in the CNS declines, serotonin synthesis declines, monoamine oxidase and calcitonin gene-related peptide concentrations increase, and beta endorphins decline. “All pain is perceived as more intense,” she said. Furthermore, flow-mediated vasodilation parallels estrogen levels.
“You would think looking at all this, in a field where most of the patients are women, and the majority of them have menstrual migraine, and all of these things happen when estrogen falls, that headache specialists would be really interested in preventing estrogen from declining every month,” Dr. Calhoun said.
In 2012, Dr. Calhoun and colleagues published a retrospective database review that identified 23 women in a subspecialty menstrual migraine clinic who had migraine with aura, a confirmed diagnosis of menstrual-related migraine, and who received treatment with extended-cycle dosing of a transvaginal ring contraceptive containing 0.120 mg of etonogestrel and 15 μg of EE for at least a month. The women were treated with the transvaginal ring for the purpose of migraine prevention, and not to prevent pregnancy. Participants were observed for an average of eight months. Women used the ultralow-dose ring contraceptive continuously. Instead of using the ring for three weeks followed by one week without the ring, women replaced the ring every three weeks. “With that, you stop ovulation with a level of estrogen that is lower than your own natural menstrual cycle. You do not have the high ovulatory peaks or even the peaks of the luteal phase,” she said.
At baseline, subjects experienced a median of 3.2 auras per month. With treatment, the median number of auras per month decreased to 0.2. Frequency of aura decreased from baseline for each participant, and menstrual migraine was eliminated in 91.3% of patients. Such use of hormonal contraceptives for the prevention of migraine is off label, Dr. Calhoun noted.
Risk of Stroke
How oral contraceptives affect risk of stroke has been studied for decades. In a 1975 study in JAMA, researchers looked at 140 cases of stroke in young women and compared them with hospital controls. There was a 4.6 times increased risk of stroke if a woman was taking high-dose oral contraceptives.
Hannaford et al in 1994 published a nested case–control analysis using data mainly from the 1970s and 1980s. They found that high-dose oral contraceptive use was associated with a sixfold increased risk of first stroke. Low-dose pills—including 30-μg and 35-μg pills, “which I do not think of as particularly low dose these days”—did not significantly increase risk, Dr. Calhoun said. However, the risk with these moderate-dose pills is usually around 1.2 to 2.5 times greater and is significant in some studies, she noted. Today’s “low-dose” pills (≤ 20 μg EE) are the best for decreasing risk.
In 1996, a study by Petitti et al looked at risk of stroke with “low-dose” (at that time meaning simply < 50 μg EE) hormonal contraceptives in the US. They identified 408 strokes in 3.6 million women-years and concluded that stroke is rare in this population. Low-dose pills did not increase the risk. At that time, 99.4% of prescriptions for hormonal contraception in the US contained less than 50 μg of estrogen.