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Contraception Corner

Combination Oral Contraceptives and Migraine: Is There an Increased Risk for Ischemic Stroke?*

E. Anne MacGregor, MFFP; Barbara Clark, RN, MSN, MPH

Migraines can be debilitating and, in a minority of women who use estrogen-progestin combination oral contraceptives (COCs), they can be life-threatening. Indeed, evidence shows that women with a history of migraine who use COCs are at increased risk for ischemic stroke. But how great is this risk? And is the risk affected by age, the presence/absence of migraine aura, or other stroke risk factors (eg, smoking)? Are there viable contraceptive alternatives to COCs for these women? Answers to these questions are crucial because of the prevalence of migraine; it has been established that in a given year, 16% of women (11% without aura and 5% with aura) experience migraine headache.¹ This article examines recent research on migraine, COCs, and the risk of ischemic stroke.²

MIGRAINE PATTERNS

Migraines can occur with or without aura„ie, prodromal symptoms that often involve visual or other sensory disturbances. Migraine without aura, accounting for 70% to 80% of migraines, is also called a common or simple migraine or a ñsick headache.î³ Migraine without aura is generally unilateral and recurrent; it usually lasts for 4 to 72 hours and is accompanied by nausea and intolerance to light and noise.

Migraine with aura, also called focal or classical migraine, comprises 20% to 30% of migraines, but in 1% of cases there is no headache. This type of migraine is also recurrent and is usually characterized by focal neurologic symptoms (99% visual) that develop gradually over 5 to 20 minutes and last for less than 1 hour.³ In a study of 4,000 subjects from the general population, Russell and Olesen⁴ found that 163 had migraine with aura. Of these, 99% had visual symptoms, 31% sensory, 18% aphasic, and 6% motor. Visual aura was present in nearly all attacks in those with several types of aura symptoms, while sensory, motor, and aphasic aura were present only in a small number of attacks. With motor aura, the hand and arm were affected but rarely the leg.

Patients usually describe the aura as starting from a small, paracentral bright spot and enlarging to a bright, curved, zig-zag line (scintillation).⁵ The scintillations make map-like ñfortificationî figures that flicker with the brilliant intensity of a fluorescent bulb.⁶ Within these lines, vision is dark and obstructed (scotoma). This process takes 10 to 20 minutes, and then the image disappears. After the aura subsides, a typical migraine headache ensues, although sometimes the headache that follows is not a migraine-type headache, or there is no headache.

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MIGRAINE, STROKE, AND COMBINATION ORAL CONTRACEPTIVES

For the majority of women„including those with migraine„COCs are a highly effective and safe means of contraception. Some women even take COCs to help treat migraine occurring in association with menstruation. However, the effects of COCs on migraine vary, including no change, improvement in migraine (typically without aura), recurrence of migraine without aura in the pill-free interval, more severe or frequent migraine (typically with aura), and onset of migraine with aura.^7,8 Yet for a minority of women with certain risk factors, COCs are associated with an unacceptable increase in the risk of stroke. At baseline, a woman with no risk factors is 1.5 times more likely to have an ischemic stroke if she uses COCs. Smoking and hypertension constitute additional, independent risk factors.⁹ And now, through a case study, MacGregor² has shown that migraine with aura also represents a risk factor for ischemic stroke in women who use COCs (Figure 1).

Figure not available online

FIGURE 1. Case Report: development of migraine with aura and ischemic stroke associated with combination oral contraceptive use.2 COCs = combination oral contraceptives.

Several case-control studies have shown that both migraine without aura and especially migraine with aura are risk factors for ischemic stroke. Tzourio et al¹⁰ studied 72 women younger than 45 years of age with ischemic stroke and 173 controls, and found that ischemic stroke is strongly associated with both migraine without aura (odds ratio [OR] 3.0, 95% confidence interval [CI] 1.5-5.8) and migraine with aura (OR 6.2, 95% CI 2.1-18.0). Chang et al¹¹ reported similar findings from a case-control study of 291 patients aged 20 to 44 years who had a stroke compared with 736 matched controls; for patients who had migraine without aura the OR was 2.97 with a 95% CI of 0.66-13.5, and for those who had migraine with aura the OR was 3.81 with a 95% CI of 1.26-11.5. In a study of 308 patients aged 15 to 44 years with either transient ischemic attack or stroke and 591 matched controls, Carolei et al12 found that both migraine without aura (OR 1.0, 95% CI 0.5-2.0) and migraine with aura (OR 8.6, 95% CI 1-75) were associated with strokes.

Several studies have looked at the relationship of migraine, COCs, and stroke.^{10, 11} As shown in Figure 2, the risk of ischemic stroke in women who have migraine increases significantly when other risk factors„eg, COC use, smoking, smoking plus COC use„are added (Figure 2).^{10, 11}

Figure not available online

FIGURE 2. Return to fertility after single-rod implant removal.

Extrapolating from several studies, Becker¹³ estimated the expected incidence of ischemic stroke per 100,000 women for COC users and non-COC users aged 25 to 34 years and 35 to 44 years. Figure 3 shows the additive effect of migraine (with and without aura), COC use, and age.¹³ Additional data from a multicenter, case-control study on the relationship of migraine and ischemic stroke in women aged 20 to 44 years may help to provide a marker for ischemic stroke.¹⁴ Results indicated that the adjusted risk of ischemic stroke was significantly associated with a history more than 12 years since onset of aura (OR 6.42, 95% CI 1.31-31.5), initial migraine with aura (OR 8.37, 95% CI 2.33-30.1), and migraine with aura initially occurring more than 12 times per year (OR 10.4, 95% CI 2.18-49.4).

Kruit et al¹⁵ compared the prevalence of white-matter infarcts in people who had migraine with those who did not have migraine. In a cross-sectional study, the researchers studied Dutch adults aged 30 to 60 years, including 161 patients with migraine with aura, 134 patients with migraine without aura, and 140 group-matched controls. Infarcts and white-matter lesions were rated from 3-mm magnetic resonance imaging sections. Results showed no significant difference between patients with migraine and controls in overall infarct prevalence, but there was a difference in posterior circulation infarcts. People with migraine had a 5.4% prevalence of infarcts, while controls had a 0.7% prevalence (P = .02). Those with migraine with aura had an 8.1% prevalence, while controls had a 2.2% prevalence (P = .03). The highest risk„9.3 times higher than in controls„was in patients with migraine with aura who had one or more attacks per month.

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GUIDELINES

In evaluating whether it is appropriate to prescribe COCs for a woman with migraine, it is important to determine the type of migraine she has. Patients should be questioned about the presence and duration of visual disturbances before the headache.¹⁶ If migraine with aura is confirmed, the physician should assess the womanÍs history to determine whether COCs are appropriate (Table).

Table not available online

TABLE. Prescribing Guidelines

For women with migraine with aura for whom COC use is deemed inadvisable, other effective contraceptive choices are available. One option is a daily estrogen-free pill that contains 75 mcg of desogestrel and has an anovulant action and efficacy similar to COCs. Progestogen-only contraception has not been associated with an increased risk of ischemic stroke.^10,17,18

If migraine occurs during the pill-free interval, it is typically without aura and occurs about 3 days after pill use stops (ie, the migraine is associated with estrogen withdrawal). Using tricyclic/ continuous COCs or natural estrogen supplements during the pill-free interval can often prevent this type of migraine.

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CONCLUSION

Studies have shown that migraine is an independent risk factor for ischemic stroke in young women. Women who have migraine without aura and take COCs are at increased risk, and the risk is still higher for women who have migraine with aura. Even though the evidence is based on case-control studies that are vulnerable to recall, observation, and selection bias, it deserves serious consideration. Only the degree of risk is open to question. However, for women with migraine who should not take COCs, effective contraceptive alternatives are available.

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E. Anne MacGregor, MFFP, is director of clinical research, The City of London Migraine Clinic, England; Barbara Clark, RN, MSN, MPH, is a freelance writer in Arlington, Va.

References

1. Rasmussen BK. Epidemiology of headache. Cephalalgia. 1995;15(1): 45-68.
2. MacGregor EA (Burnhill Lectureship). Migraine, aura and combined oral contraceptives. Presented at the Annual Meeting of the Association of Reproductive Health Professionals, Washington DC, September 8-11, 2004.
3. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 2nd ed. Cephalalgia. 2004;24(Suppl 1):9-160.
4. Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain. 1996;119(Pt 2):355-361.
5. Airy H. On a distinct form of transient hemiopsia. Phil Trans Roy Soc Lond (Biol Sci). 1870;160:247-264.
6. Lashley KS. Patterns of cerebral integration indicated by scotomas of migraine. Arch Neurol Psych. 1941; 46:333.
7. Bickerstaff ER. Neurological Complications of Oral Contraceptives. Oxford, England: Oxford University Press; 1975.
8. Granella F, Sances G, Pucci E, Nappi RE, Ghiotto N, Napp G. Migraine with aura and reproductive life events: a case control study. Cephalalgia. 2000;20(8):701-707.
9. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1996;348 (9026):498-505.
10. Tzourio C, Tehindrazanarivelo A, Iglesias S, et al. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ. 1995;310 (6983):830-833.
11. Chang CL, Donaghy M, Poulter N. Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ. 1999; 318(7175):13-18.
12. Carolei A, Marini C, De Matteis G. History of migraine and risk of cerebral ischaemia in young adults. The Italian National Research Council Study Group on Stroke in the Young. Lancet. 1996;347(9014):1503-1506.
13. Becker WJ. Migraine and oral contraceptives. Can J Neurol Sci. 1997; 24(1):16-21.
14. Donaghy M, Chang CL, Poulter N; European Collaborators of The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Duration, frequency, recency, and type of migraine and the risk of ischaemic stroke in women of childbearing age. J Neurol Neurosurg Psychiatry. 2002; 73(6):747-750.
15. Kruit MC, van Buchem MA, Hofman PA, et al. Migraine as a risk factor for subclinical brain lesions. JAMA. 2004; 291(4):427-434.
16. Gervil M, Ulrich V, Olesen J, Russell MB. Screening for migraine in the general population: validation of a simple questionnaire. Cephalalgia. 1998; 18(6):342-348.
17. Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception. 1998;57(5):315-324.
18. Heinemann LA, Assmann A, DoMinh T, Garbe E. Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Eur J Contracept Reprod Health Care. 1999;4(2):67-73.

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