By Rebecca H. Allen, MD, MPH
Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck, and has served as a consultant for Bayer and Pharmanest.
SYNOPSIS: In this case-control study, women with migraines with aura using combined hormonal contraception had six times the odds of experiencing ischemic stroke compared to women without migraines not using combined hormonal contraception. Use of combined hormonal contraception among women with migraines without aura was not associated with an increased risk of stroke over baseline.
SOURCE: Champaloux SW, Tepper NK, Monsour M, et al. Use of combined hormonal contraceptives among women with migraines and risk of ischemic stroke. Am J Obstet Gynecol 2016; Dec 26. doi: 10.1016/j.ajog.2016.12.019 [Epub ahead of print].
This is a case-control study of women aged 15-49 years whose data were collected in a U.S. national database of health claims and prescription drug claims entitled MarketScan Research Databases, Commercial Claims, and Encounters. Between 2006 and 2012, women with inpatient ischemic stroke codes were identified. Four controls were randomly selected for each case and matched by age in 2006. Both cases and controls had to be enrolled continuously in private insurance from Jan. 1, 2004, to the index date of the first stroke diagnosis. This ensured that adequate capture of migraine history and prior strokes was obtained. Women with pregnancy codes within six weeks prior to the index date of the stroke were excluded, as well as women with hysterectomy or sterilization from 2004 up to the index date. Migraine headaches were identified with both inpatient and outpatient codes, and migraine history had to be present before the index date. Current combined hormonal contraception (CHC) use was defined as a filled prescription for combined oral contraceptives, patch, or ring within 90 days prior to the index date. The number of women using the contraceptive patch and ring was too small for separate analyses. Other risk factors for ischemic stroke were identified, including age, obesity, smoking, diabetes, hypertension, ischemic heart disease, and valvular heart disease.
From 2006 to 2012, in the entire cohort, there were 25,887 ischemic strokes among 33,218,977 women. The overall average yearly cumulative incidence of stroke was 11 strokes per 100,000 women. Younger women had a lower incidence of stroke (1 per 100,000 women aged 15-19 years) compared to older women (30 per 100,000 women aged 45-49 years). After applying inclusion and exclusion criteria, there were 1,884 cases matched to 7,536 controls. After adjusting for hypertension, diabetes, obesity, smoking, ischemic heart disease, and valvular heart disease, compared to women with neither migraine nor CHC use, the odds ratio (OR) of ischemic stroke was highest among women with migraine with aura using CHCs (adjusted OR, 6.1; 95% confidence interval [CI], 3.1-12.1). The odds of ischemic stroke also was elevated among women with migraine with aura not using CHCs (adjusted OR, 2.7; 95% CI, 1.9-3.7), women with migraine without aura using CHCs (adjusted OR, 1.8; 95% CI, 1.1-2.9), and women with migraine without aura not using CHCs (adjusted OR, 2.2; 95% CI, 1.9-2.7).
COMMENTARY
Although the absolute risk of ischemic stroke is low in women of reproductive age, as evidenced in the study discussed here, migraine with aura is an independent risk factor for stroke. Most studies have noted that women who have migraine with aura have a higher stroke risk than those who have migraine without aura.1,2 The assumption is that aura is associated with vascular changes.3 Use of combined hormonal contraception also increases the risk of stroke in women, although the absolute risk is still low.4 The elevated risk of ischemic stroke likely is due to the hypercoagulable state caused by estrogen’s effect on liver metabolism. The risk of stroke among women using combined hormonal contraception rises with increasing age, from 3.4 per 100,000 women-years in adolescents to 64.4 events per 100,000 women-years among women aged 45-49 years.5
The authors conducted this study to elucidate the risk of stroke among women using CHCs according to migraine type. The investigators found that CHC use by women with migraines with aura synergistically increases the risk of stroke. In contrast, use of CHC by women with migraines without aura did not increase the risk. This conclusion supports the 2016 recommendation of the Centers for Disease Control and Prevention’s U.S. Medical Eligibility Criteria for Contraceptive Use (USMEC).6 The USMEC states that estrogen-containing contraceptives are contraindicated for women with migraine with aura given the devastating consequences of stroke. For women with migraine without aura, the USMEC recommends that the benefits of using CHCs outweigh the risks. Progestin-only methods and intrauterine devices also are safe for women with migraines of any type.
The study had several strengths, including use of a national database allowing sufficient cases of ischemic stroke to be identified and the ability to differentiate between migraine types. Nevertheless, even with this national database, the absolute numbers of women who had migraines with aura, took CHCs, and suffered a stroke were very small. Of note, all the women in this study had private insurance, which makes the study less generalizable. In addition, the use of diagnostic codes in large health claims database studies to classify exposures and outcomes can lead to misclassification. The design of this study also limited its ability to capture any information on women who had migraines but did not seek any medical attention. Finally, relying on filled prescriptions for evidence of contraceptive exposure may overestimate use.
Nevertheless, the findings of this study are consistent with the literature and USMEC recommendations, so where do we go from here? Migraine headaches are more common in women than men and peak at a prevalence of 24% among women aged 30-39 years.7 Migraine without aura is the most common subtype, accounting for 75% of cases. Clearly, this is a common problem that obstetrician-gynecologists encounter. Given the USMEC contraceptive recommendations, it is very important for clinicians to be able to distinguish between classic migraines and migraines with aura. Nausea, vomiting, photophobia, phonophobia, or visual blurring occurring before or during a migraine headache do not constitute aura. According to the International Headache Society, an aura is the complex of neurological symptoms that occurs usually before the headache, but it may begin after the headache has begun.8 A typical aura is reversible, lasts less than 60 minutes, and can consist of visual symptoms such as a zigzag figure (fortification spectrum, so named due to its resemblance to the walls of a medieval fortress) spreading across the visual field, sensory symptoms such as pins and needles, speech disturbances, or motor weakness (see Table). It is critical that we are very certain before diagnosing and labeling a woman with migraine with aura. Otherwise, we are reducing her contraceptive options for her entire life.
Table 1: Diagnostic Criteria for Migraine With and Without Aura |
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Migraine without aura Recurrent headache disorder manifesting in attacks lasting 4-72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea and/or photophobia and phonophobia. |
Migraine with aura Migraine headache plus recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory, or other central nervous system symptoms that usually develop gradually and usually are followed by headache and associated migraine symptoms. |
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Diagnostic criteria A. At least five attacks fulfilling criteria B–D B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics:
D. During headache at least one of the
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Diagnostic criteria A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms:
C. At least two of the following four
D. Not better accounted for by another diagnosis, and transient ischemic attack has been excluded. |
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Adapted from: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version) Cephalalgia 2013;33:629-808. |
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REFERENCES
- Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: Systematic review and meta-analysis of observational studies. BMJ 2005;330:63.
- Kurth T, Slomke MA, Kase CS, et al. Migraine, headache, and the risk of stroke in women: A prospective study. Neurology 2005;64:1020-1026.
- Kurth T, Chabriat H, Bousser MG. Migraine and stroke: A complex association with clinical implications. Lancet Neurol 2012;11:92-100.
- Bushnell C, McCullough L. Stroke prevention in women: Synopsis of the 2014 American Heart Association/American Stroke Association guideline. Ann Intern Med 2014;160:853-857.
- Lidegaard O, Lokkegaard E, Jensen A, et al. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012;366:2257-2266.
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-104. http://dx.doi.org/10.15585/mmwr.rr6503a1.
- Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventative therapy. Neurology 2007;68:343.
- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version) Cephalalgia 2013;33:629-808.
In this case-control study, women with migraines with aura using combined hormonal contraception had six times the odds of experiencing ischemic stroke compared to women without migraines not using combined hormonal contraception. Use of combined hormonal contraception among women with migraines without aura was not associated with an increased risk of stroke over baseline.
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