Ronni Hayon, MD Jensena Carlson, MD Julia McMillen, MD Sarina Schrager, MD, MS University of Wisconsin, Department of Family Medicine and Community Health sbschrag@wisc.edu
The authors reported no potential conflict of interest relevant to this article.
Risk of ischemic stroke.Unfortunately, there are population data showing that second-generation and, to a smaller degree, third-generation progestins, which include the desogestrel used in the above studies, may increase the risk of ischemic stroke. This is a particular concern in women who experience migraine.29 Second-generation progestins include levonorgestrel, which is in the levonorgestrel IUD; however, there is no direct evidence for increased ischemic stroke in this particular preparation, and the circulating plasma levels are low. Etonorgestrel, the active ingredient in the contraceptive implant, is a third-generation progestin, though there is no direct evidence of increased ischemic stroke with use of the etonorgestrel implant.
There is a 2- to 4-fold increased risk of ischemic stroke in women who experience migraine.1,5,30 As stated above, this risk may be further increased by some progesterone formulations. But there is also a demonstrable increase in ischemic stroke risk with the use of estrogen, particularly at the higher concentrations that have been shown to prevent MRM.31,32 The overall incidence of ischemic stroke in menstrual-age women is low, which has limited the number of studies with enough power to quantify the absolute increased risk of stroke in conjunction with estrogen use. Nevertheless, exogenous estrogen is thought to increase the risk of ischemic stroke an additional 2- to 4-fold.1,5,29,30,32-34
A number of studies have demonstrated a correlation between hypomagnesemia and migraine headaches. The exact mechanism for this relationship is unclear.Women who experience aura.MRM, as it is defined, typically excludes women who experience aura; however, the number of women who experience aura with migraine either in proximity to their menses or throughout the month has not been well documented. The risk of ischemic stroke is higher for women who experience migraine with aura than those with migraine alone, possibly because aura is associated with reduced regional vascular flow leading to hypoperfusion, which sets the stage for a possible ischemic event.4,5,35 The risk of ischemic stroke is amplified further for women who are over 35, who smoke, or who have additional vascular risk factors (eg, uncontrolled hypertension, diabetes, or known vascular or cardiac disease).1,5,34 This array of evidence serves as the basis for the US Medical Eligibility Criteria (USMEC) recommendations36 for hormonal contraceptive use, in particular the absolute contraindication for estrogen use in women who experience migraine with aura (TABLE 336-38).
The risk of stroke is also thought to be heightened possibly during the first 4 years following onset of migraine, especially if associated with aura, with migraines occurring more than 12 times a year, or with a history of migraine spanning more than 12 years.32,34 These factors need further study. Ischemic stroke can be a devastating event, especially in young, otherwise healthy women. Therefore, administration of estrogen to reduce MRM should only be considered in low-risk women who do not experience aura, are under 35, and do not smoke.
