The American Journal of Medicine
Volume 123, Issue 7 , Pages 612-624, July 2010

Migraine Headache and Ischemic Stroke Risk: An Updated Meta-analysis

  • June T. Spector, MD, MPH

      Affiliations

    • Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md
    • ,
  • Susan R. Kahn, MD, MSc

      Affiliations

    • Department of Medicine, McGill University Division of Internal Medicine, and Center for Clinical Epidemiology & Community Studies, Jewish General Hospital, Montreal, QC, Canada
    • ,
  • Miranda R. Jones, BA

      Affiliations

    • Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md
    • ,
  • Monisha Jayakumar, BDS, MPH

      Affiliations

    • Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md
    • ,
  • Deepan Dalal, MBBS, MPH

      Affiliations

    • Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md
    • ,
  • Saman Nazarian, MD

      Affiliations

    • Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md
    • Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md
    • Corresponding Author InformationRequests for reprints should be addressed to Saman Nazarian, MD, Division of Cardiac Arrhythmia, Johns Hopkins Hospital, Carnegie 592C, 600 N. Wolfe Street, Baltimore, MD 21287

published online 20 May 2010.

Article Outline

Abstract 

Background

Observational studies, including recent large cohort studies that were unavailable for prior meta-analysis, have suggested an association between migraine headache and ischemic stroke. We performed an updated meta-analysis to quantitatively summarize the strength of association between migraine and ischemic stroke risk.

Methods

We systematically searched electronic databases, including MEDLINE and EMBASE, through February 2009 for studies of human subjects in the English language. Study selection using a priori selection criteria, data extraction, and assessment of study quality were conducted independently by reviewer pairs using standardized forms.

Results

Twenty-one (60%) of 35 studies met the selection criteria, for a total of 622,381 participants (13 case-control, 8 cohort studies) included in the meta-analysis. The pooled adjusted odds ratio of ischemic stroke comparing migraineurs with nonmigraineurs using a random effects model was 2.30 (95% confidence interval [CI], 1.91-2.76). The pooled adjusted effect estimates for studies that reported relative risks and hazard ratios, respectively, were 2.41 (95% CI, 1.81-3.20) and 1.52 (95% CI, 0.99-2.35). The overall pooled effect estimate was 2.04 (95% CI, 1.72-2.43). Results were robust to sensitivity analyses excluding lower quality studies.

Conclusions

Migraine is associated with increased ischemic stroke risk. These findings underscore the importance of identifying high-risk migraineurs with other modifiable stroke risk factors. Future studies of the effect of migraine treatment and modifiable risk factor reduction on stroke risk in migraineurs are warranted.

Keywords: Cerebral ischemia, Epidemiology, Meta-analysis, Risk factors, Stroke

 

Stroke is the second highest cause of disability in developed countries and the second most common cause of death globally, surpassed only by coronary heart disease.1 A recent review of population-based studies of stroke incidence and mortality indicates that the burden of stroke is likely to increase, primarily due to the advancing age of the population and disease-promoting lifestyle factors.2 Migraine headache also is associated with significant morbidity. Migraine occurs in 17% of women and 6% of men each year and can be incapacitating.3, 4

Clinical Significance

 


•A history of migraine headache is associated with a 2-fold increased risk of ischemic stroke.

•Ischemic stroke risk might be further increased in migraineurs with aura and in women.

•Risk factor reduction should be considered in high-risk migraineurs with other modifiable stroke risk factors.

Migraine has been proposed as an ischemic stroke risk factor in addition to traditional risk factors such as atherosclerosis and atrial fibrillation.5 Several prior systematic reviews have reported an increased risk of stroke in certain migraineur populations.6, 7 Ischemic stroke accounts for over 80% of all strokes,8 and migraine is a potentially modifiable risk factor. Therefore, better understanding of the association between migraine and ischemic stroke is important.

Since the reporting of 2 prior systematic reviews of predominantly case-control studies,6, 7 4 large cohort studies9, 10, 11, 12 containing a combined total of more than 300,000 patients have been published. Here we provide an updated systematic review and meta-analysis, utilizing the most recent Cochrane Collaboration guidelines for systematic reviews,13 to determine the strength of the association of migraine and ischemic stroke.

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Methods 

Search Strategy 

We performed a systematic literature search of MEDLINE (using PubMed) and EMBASE for relevant published reports from the beginning of indexing for each database through February 2009. We also searched the National Library of Medicine's Health Services Research Projects in Progress, National Institute of Health's clinical trials registry, World Health Organization's International Clinical Trials Registry Platform, Cochrane Central Register of Controlled Trials, Open System for Information on Grey Literature in Europe, and the New York Academy of Medicine Grey Literature through February 2009 for unpublished reports. PubMed was searched using the following combination of exploded Medical Subject Heading (MeSH) terms and text words: [“migraine disorders” or “migrain*” in all search fields] and [“cerebrovascular disorders,” within which the term “stroke” is fully embedded]. The EMBASE search was conducted using the following combination of exploded terms and synonyms for terms: [“migraine” or “migraine*”] and [“stroke” or “brain infarction” or “brain ischemia” or “cerebrovascular accident”]. The PubMed and EMBASE searches were limited to English language studies in human subjects, and the EMBASE search was additionally limited to studies that had available abstracts. As we focused on original studies, review articles in both searches were excluded. Databases of unpublished studies were searched using the simple keywords “migraine” and “stroke.” After retrieval of articles from the search, the reference lists of selected articles were checked for other potentially relevant articles.

Study Selection 

Pairs of reviewers independently evaluated articles for selection criteria using article titles, abstracts, and full texts. Prespecified selection criteria included: inclusion of studies with case-control or cohort study design; inclusion of studies with reported or extractable adjusted quantitative estimates of the risk of ischemic stroke in migraineurs compared with nonmigraineurs; exclusion of studies of transient stroke-like syndromes only, concurrent ischemic stroke and migraine (migrainous infarctions), or silent infarcts, in which the temporal relationship between migraine and stroke is difficult to determine; exclusion of studies in which stroke outcomes were defined as mixed (eg, hemorrhagic and ischemic stroke); and exclusion of studies of rare genetic syndromes characterized by both migraine and stroke14, 15 or of pregnant patients; and exclusion of studies not in the English language. In cases where an article was based on overlapping data from the same cohort and reported the same type of effect estimate, we selected the largest and most complete article from each cohort to avoid duplicate inclusion of data. Articles that did not have available full text (for example, meeting abstracts with no existing full article) were excluded.

Based on the prespecified selection criteria, all studies that were included in the prior meta-analysis by Etminan et al7 were included in the present study, with the exception of 2 studies that did not meet our inclusion criteria.16, 17 Nine additional studies,9, 10, 11, 12, 18, 19, 20, 21, 22 which were either not captured in the Etminan study7 or were subsequently published, were included in the present study.

Data Extraction 

Pairs of reviewers independently abstracted data and information on study quality from eligible articles using standardized abstraction tables. Study quality was assessed according to published guidelines for assessing bias in observational studies.13, 23, 24, 25 Valid definitions of migraine and stroke included use of the International Headache Society's Headache Classification26 and the National Institute of Neurological Disorders and Stroke classification27 or the Acute Ischemic Cerebrovascular Syndrome classification,28 respectively, or reasonable variations on these accepted definitions. Although infrequent, disagreement during the abstraction process was resolved by consensus discussion between all study authors.

Data Synthesis 

Odds ratios (OR), relative risks (RR), hazard ratios (HR), and incidence rate ratios were used to estimate effect sizes. To estimate overall effect sizes, each natural log effect was weighted by the inverse of its variance, and the weighted natural log effect estimate summed across samples and then divided by the sum of the weights.13

In accordance with the Cochrane Collaboration Guidelines for systematic reviews,13 clinical, methodological, and statistical heterogeneity of included studies was assessed. Clinical heterogeneity was examined by determining whether studies addressed similar populations, exposures, and outcomes; and methodological heterogeneity was addressed by comparing methodology and quality across studies. Statistical heterogeneity was assessed using the I2 statistic to quantify the proportion of variability in effect estimates due to heterogeneity between studies versus sampling error within studies. I2 values >50% were considered to denote substantial heterogeneity.13

For each effect type of estimate, studies without substantial heterogeneity were pooled using a random effects model. A random effects model was chosen because of the high likelihood of between-study variance in observational studies. An overall pooled effect estimate across different effect estimate types also was computed for comparison. A priori subgroup analyses by type of migraine (with aura vs without aura) and sex, factors reported to be associated with ischemic stroke risk,7 were performed. These subgroup analyses also were used to investigate heterogeneity, if present.

The study team chose to pool adjusted rather than crude measures of effect given the significant threat of confounding to the validity of unadjusted results of observational studies. However, recognizing that different observational studies may address confounding and other sources of bias differently, a sensitivity analysis was performed to quantify the effect on summary results of including only studies with a low risk of bias. Low-risk-of-bias studies were defined as those with poor methodological quality in fewer than 3 areas in the standardized study quality abstraction tables. Biases whose existences were deemed by consensus to be uncertain in particular studies were not included in the assessment of low-risk-of-bias studies. We also examined the degree to which excluding single studies, one by one, influenced summary results. Finally, the possibility of publication bias was assessed by inspecting funnel plots. All statistical analyses were performed using Stata version 9.2 (StataCorp, College Station, Tex).

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Results 

Literature Search 

The search strategy retrieved 2287 citations: 1275 from PubMed, 1009 from EMBASE, and 3 from the Grey Literature (Figure 1). Hand searching of bibliographic references identified 2 additional articles, leaving 1799 unique articles for screening of titles or abstracts. Of 35 articles evaluated by full-text review, 21 studies were eligible for final inclusion in the meta-analysis.

Study Characteristics 

Characteristics of the 21 selected studies are shown in Table 1, Table 2.9, 10, 11, 12, 18, 19, 20, 21, 22, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 There were 13 case-control (Table 1) and 8 cohort studies (Table 2). The studies were drawn from developed countries and were published between 1975 and 2007. Sample sizes of case-control studies ranged from about 250 to 4500, and sample sizes of cohort studies ranged from about 12,000 to 260,000, for a total of 622,381 participants in the meta-analysis. Two studies included only men,11, 30 one study included both men and women but only reported a measure of association for men,34 and 9 studies included only women.10, 18, 20, 29, 32, 33, 37, 38, 40 Most studies were of middle-aged adults, with average ages of participants in the range of 30-50 years.

Table 1. Summary of 13 Case-Control Studies in the Meta-analysis
SourceCountryAge, Mean (Range), YearsFemale, %Sources of Cases/ControlsType of Effect EstimateEffect Estimate of Migraine (95% CI)Total Number: Number with Migraine
AnyWith AuraWithout AuraParticipants with StrokeParticipants without Stroke
Carolei et al, 199631ItalyCases: 36
Controls: 36		47Hospital cases/hospital and population controlsOR1.7(1.1-2.8)†
1.9(1.1-3.1)⁎		8.60(1.0-75.0)⁎1.0(0.5-2.0)⁎308:46591:54
Chang et al, 199932Five European Countries (WHO Collaboration)Cases: 36
Controls: 36(20-44)		100Hospital cases/hospital controlsOR3.54(1.30-9.61)⁎3.81(1.26-11.5)⁎2.97(0.66-13.5)⁎86:26220:26
Collaborative Group, 197529USN/A (15-44)100Hospital cases/hospital, neighborhood controlsOR2.0(1.2-3.3)⁎N/AN/A140:48451:106
Donaghy et al, 200233Five European Countries (WHO Collaboration)Cases: 36
Controls: 36(20-44)		100Hospital cases/hospital controlsOR1.9(0.48-7.43)⁎N/AN/A86:26214:26
Haapaniemi et al, 199734FinlandMale cases: 49
Female cases: 45
Male and female controls: 43(16-60)		31Hospital cases/hospital controlsRRMen: 2.12(1.05,2.95)⁎N/AN/ATotal: 506:86
Men: 366:43		Total: 345:42
Men: 219:14
Henrich and Horwitz, 198935USCases: 58
Controls: 56		37Hospital cases/hospital controlsOR1.8(0.9-3.6)⁎2.6(1.1,6.6)⁎1.30(0.90,3.6)⁎89:17178:20
Lidegaard, 199537DenmarkN/A (15-44)100Registry of Hospitals/National RegisterOR2.9(N/A, P <.01)†
2.8(N/A, P <.01)⁎		N/AN/A497:641370:66
Lidegaard and Kreiner, 200220DenmarkN/A (15-44)100Registry of Hospitals/National RegisterOR3.2(2.5-4.2)⁎N/AN/A626:1074054:258
MacClellan et al, 200718US38(15-49)100Hospital cases/community controlsORN/A1.3(0.9,1.8)⁎N/A386:145 with aura (35 without aura)614:175 with aura (79 without aura)
Naess et al, 200419NorwayN/A (15-49)41Hospital cases/county controlsOR1.7(0.9-3.2)⁎N/AN/A187:33217:25
Nightingale and Farmer, 200438UKN/A (15-49)100General practitioner database cases/general practitioner database controlsOR2.35(1.29-4.30)†
2.33(1.04-5.21)⁎		N/AN/A190:161129:44
Tzourio et al, 199339FranceMale cases: 56
Female cases: 57
Male and female controls: 56(18-80)		35Hospital cases/hospital controlsOR1.3(0.8-2.3)⁎1.3(0.5-3.8)⁎0.8(0.4,1.5)⁎212:41(9 with aura)212:34(7 with aura)
Tzourio et al, 199540FranceCases: 36
Controls: 35		100Hospital cases/hospital controlsOR3.5(1.8-6.4)⁎6.2(2.1-18)⁎3.0(1.5,5.8)⁎72:43(10 with aura, 33 without aura)173:52(10 with aura, 42 without aura)

CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; N/A = not available; OR = odds ratio; RR = relative risk; UK = United Kingdom; US = United States; WHO = World Health Organization.

⁎Adjusted.

†Unadjusted.

Table 2. Summary of 8 Cohort Studies in the Meta-analysis
SourceCountry/CohortAge, Mean (Range), YearsFemale, %Follow-up, Mean (Max), Mo. Unless SpecifiedType of Effect EstimateEffect Estimate of Migraine (95% CI)Total No.:No. with Stroke
AnyWith AuraWithout AuraWith MigraineWithout Migraine
Becker et al, 200712UK/General Practice Research DatabaseN/A (<79)72N/ARR2.85(1.88-4.30)⁎N/AN/A51,688:N/A51,688:N/A
Buring et al, 199530US/Physicians' Health Study53(40-84)060(77)RR1.98(1.20-3.28)†
2.00(1.10-3.64)⁎		N/AN/A1479:1720,481:154
Hall et al, 20049UK/General Practice Research DatabaseN/A (0-over 70)74Migraine: 36
No migraine: 33		HR2.49(1.62-3.83)⁎N/AN/A63,575:7177,239:31
Kurth et al, 200510US/Women's Health StudyNo migraine: 55 migraine with and without aura: 531009 years; 353,170 person-yearsHR1.31(0.94,1.83)†
1.36(0.97-1.92)⁎		1.72(1.11-2.67)†
1.73(1.10-2.71)⁎		1.02(0.64-1.63)†
1.11(0.69-1.78)⁎		5173:41 (2059:22 with aura, 3114:19 without aura)32,425:252
Kurth et al, 200711US/Physicians' Health StudyNo migraine: 58
Migraine: 57(40-84)		015.7 years; 316,076 person-yearsHR1.09(0.82,1.44)†
1.12(0.84-1.50)⁎		N/AN/A1449:5118,635:699
Merikangas et al, 199736US/National Health and Nutrition Examina-tion SurveyN/A (25-74)60N/AOR2.1(1.5-2.9)‡N/AN/A1108:4610,982:375
Stang et al, 200521US/Athero-sclerosis Risk In Commun-ities Study60(45-64)56N/AORN/A2.68(1.58-4.57)§
2.81(1.60-4.92)⁎		0.79(0.40-1.55)§
0.82(0.39-1.69)⁎		1015:N/A (345:N/A with aura, 670:N/A without aura)11,735
Velentgas et al, 200422US/United Health CareMigraine: 38
No migraine: 38		761.4 years, 353,190 total person-yearsIRR1.67(1.31-2.13)⁎N/AN/A130,411:216130,411:98

CI = confidence interval; HR = hazard ratio; IRR = incidence rate ratio; N/A = not available; OR = odds ratio; RR = relative risk; UK = United Kingdom; US = United States.

⁎Adjusted.

†Unadjusted.

‡Adjusted for age and sex only.

§Adjusted for age, sex, and race only.

Study quality is summarized in Figures 2A and 2B. Study quality was generally good in case-control studies (Figure 2A) and moderate in cohort studies (Figure 2B). All studies addressed the potential confounder of age in effect estimates, and all studies except the Mosek et al41 study addressed sex. Some studies addressed potential confounders of hypertension (19 studies), smoking (16 studies), oral contraceptive use (10 studies), cholesterol (9 studies), cardiac disease (8 studies), family history of migraine or stroke (3 studies), and postmenopausal hormone therapy (2 studies) (Table 3).

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  • Figure 2. 

    (A) Methodological quality summary for 14 case-control studies. Colors in table correspond to reviewers' consensus answers to questions at the top of the figure for each study, with green indciating “yes,” yellow indicating “uncertain,” and red indicating “no.” (B) Methodological quality summary for 8 cohort studies. Colors in table correspond to reviewers' consensus answers to questions at the top of the figure for each study, with green indicating “yes,” yellow indicating “uncertain,” and red indicating “no.” LTFU = loss to follow-up.

Table 3. Confounding Factors and Methods for Addressing Confounders
SourceStudy DesignConfounders AssessedMethod of Addressing Confounders
Carolei et al, 199631Case-ControlAge, sex, hypertension, smoking, cholesterol, diabetes mellitus, obesity, OC use, alcohol, residenceMatching (age, sex, residence), Conditional Logistic Regression
Chang et al, 199932Case-ControlAge, hypertension, education, smoking, family history of migraine, alcohol consumption, social class, admission timeMatching (age, admission time), Conditional Logistic Regression
Collaborative Group, 197529Case-ControlAge, OC use, race, source of control groupMatching (age, race) Stratification (OC use)
Donaghy et al, 200233Case-ControlAge, smoking, hypertension, family history, alcohol use, education, social class, OC use, hospital, date of hospital admissionMatching (age, hospital, date of hospital admission), Conditional Logistic Regression
Haapaniemi et al, 199734Case-ControlAge, sex, smoking, hypertension, cardiac disease, diabetes mellitus, alcohol, BMI, cholesterol, day of onset of symptoms, acuity of diseaseMatching (day of onset of symptoms, acuity of disease), Stratification (sex), Multiple Logistic Regression
Henrich and Horwitz, 198935Case-ControlAge, sex, race, hypertension, diabetes mellitus, smoking, date of hospital dischargeMatching (sex, race, age, date of hospital discharge), Multiple Logistic Regression
Case-ControlAge, hypertension, diabetes mellitus, pregnancy, prior thromboembolic disease, OC useMatching (age), Block Recursive Graphical Log Linear Regression
Lidegaard, 199537
Lidegaard and Kreiner, 200220Case-ControlAge, hypertension, diabetes mellitus, cardiac disease, family history of VTE/stroke/cardiac disease, smoking, education, cholesterol, hypercoagulable state, year, OC useMatching (age, year), Conditional Logistic Regression
MacClellan et al, 200718Case-ControlAge, race, hypertension, diabetes mellitus, geographic region, smoking, cardiac disease, OC use, and study periodMatching (age, geographic region, race), Multiple Logistic Regression
Case-ControlAgeMatching (age)
Mosek et al, 200141
Naess et al, 200419Case-ControlAge, sex, hypertension, cardiac disease, smokingMatching (age, sex), Multiple Logistic Regression
Nightingale and Farmer, 200438Case-ControlAge, hypertension, alcohol intake, smoking status, cardiac disease, history of VTE, OC use, diabetes mellitus, locationMatching (age, location), Conditional Logistic Regression
Tzourio et al, 199339Case-ControlAge, sex, hypertensionMatching (age, sex, hypertension), Multiple Logistic Regression
Tzourio et al, 199540Case-ControlAge, hypertension, OC use, smoking, yearMatching (hospital, year), Multiple Logistic Regression
Becker et al, 200712CohortAge, sex, smoking, BMI, diabetes mellitus, hypertension, cholesterol, location, yearMatching (age, sex, location, year), Conditional Logistic Regression
Buring et al, 199530CohortAge, treatment, smoking, hypertension, cholesterol, diabetes mellitus, cardiac disease (angina), BMI, parental history of MI, alcohol, exercise frequencyCox Regression
Hall et al, 20049CohortAge, sex, hypertension, diabetes mellitus, cardiac disease, obesity, cholesterol, OC use, smoking statusStratification (age, sex), Cox Proportional Hazards Regression
Kurth et al, 200510CohortAge, hypertension, menopausal status, history of OC, alcohol, randomized aspirin assignment, exercise, BMI, smoking, postmenopausal hormone therapy, diabetes mellitus, cholesterolCox Proportional Hazards Regression
Kurth et al, 200711CohortAge, hypertension, diabetes mellitus, smoking, exercise, BMI, alcohol, cholesterol, parental history of premature MI, randomized treatment assignmentsCox Proportional Hazards Regression
Merikangas et al, 199736CohortAge, sexMultiple Logistic Regression
Stang et al, 200521CohortAge, sex, race, parental history of migraine, smoking status, pack-years of smoking, diabetes mellitus, regular aspirin and NSAID use, hypertension medication use, systolic blood pressure, cholesterolMultiple Logistic Regression
Velentgas et al, 200422CohortAge, sex, year of cohort entry, cardiac disease, cerebrovascular disease, peripheral arterial disease, diabetes mellitus, hypertension, lipids, OC use, postmenopausal hormone therapy, health planMatching (age, sex, health plan), Poisson Regression

BMI = body mass index; MI = myocardial infarction; N/A = not available; NSAID = non-steroidal anti-inflammatory drug; OC = oral contraceptives; UK = United Kingdom; US = United States; VTE = venous thromboembolism.

The case-control study by Mosek et al41 was not included in the meta-analysis because it was determined to have significant clinical and methodological heterogeneity. The Mosek et al study focused on a substantially older population than the other studies and, although age-matched, failed to adjust for important potential confounders, including sex and co-morbidities associated with stroke that are known to be prevalent in older age groups.

Risk of Ischemic Stroke in Migraineurs Compared with Nonmigraineurs 

For the association between any migraine and ischemic stroke, the pooled adjusted OR (12 studies) was 2.30 (95% confidence interval [CI], 1.91-2.76), with evidence of low to moderate statistical heterogeneity (I2=32.6%; P for chi-squared test of heterogeneity=.13) (Figure 3A).19, 20, 29, 31, 32, 33, 35, 36, 37, 38, 39, 40 For the 3 studies that presented RRs, the pooled adjusted RR was 2.41 (95% CI, 1.81-3.20), with evidence of low statistical heterogeneity (I2=0.0%; P=.54).12, 30, 34 The pooled adjusted HR (3 studies) was 1.52 (95% CI, 0.99-2.35), with high statistical heterogeneity (I2=78.2%; P=.01).9, 10, 11 The high degree of heterogeneity in studies reporting HRs was likely driven by differences in study population (100% men11 vs 100% women10 in studies by Kurth et al vs 74% women in the Hall et al study9). The overall pooled adjusted effect estimate was 2.04 (95% CI, 1.72-2.43).

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  • Figure 3. 

    (A) Adjusted effect estimates of ischemic stroke in participants with any migraine versus no migraine. Size of data markers indicates weight of study. (B) Adjusted effect estimates of ischemic stroke in participants with migraine with aura versus no migraine. Size of data markers indicates weight of study. (C) Adjusted effect estimates of ischemic stroke in participants with migraine without aura versus no migraine. Size of data markers indicates weight of study. (D) Adjusted effect estimates of ischemic stroke in studies of only women participants with any migraine versus no migraine. Size of data markers indicates weight of study. (E) Adjusted effect estimates of ischemic stroke in low bias studies in participants with any migraine versus no migraine. Size of data markers indicates weight of study.

Subgroup Analyses 

There was a stronger association of ischemic stroke and migraine with aura (pooled adjusted OR for 7 studies 2.51; 95% CI, 1.52-4.14)18, 21, 31, 32, 35, 39, 40 (Figure 3B) compared with the association of ischemic stroke and migraine without aura (pooled adjusted OR for 6 studies 1.29; 95% CI, 0.81-2.06)21, 31, 32, 35, 39, 40 (Figure 3C). However, the confidence intervals for the pooled adjusted ORs of ischemic stroke in migraine with aura and migraine without aura overlap, suggesting that there is no statistically significant difference between these subgroups. The pooled adjusted OR for ischemic stroke in studies of only women migraineurs versus nonmigraineurs (7 studies) was 2.89 (95% CI, 2.42-3.45), with evidence of low statistical heterogeneity (I2=0.0%, P=.70)20, 29, 32, 33, 37, 38, 40 (Figure 3D).

Sensitivity Analyses 

In a sensitivity analysis of study quality, 3 studies that were not at low risk of bias (low risk of bias defined as fewer than 3 negatives in the standardized study quality abstraction tables, Figure 2) were removed from the analysis.22, 36, 38 The effect on pooled adjusted RRs, ORs, and HRs was minimal (Figure 3E). In the influence analysis, there was minimal change in the quantitative summary measure of effect or 95% CI, and there was no change in the direction of effect, when any one study was excluded (Figure 4).

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  • Figure 4. 

    Influence of removing studies one by one on adjusted effect estimates of ischemic stroke. Circles are effect estimates and horizontal dotted lines 95% confidence intervals for meta-analysis of the studies listed, excluding the study indicated by the circle. The vertical line in the center is the summary effect estimate including all listed studies.

Publication Bias 

Visual inspection of funnel plots revealed no significant publication bias for studies that provided ORs (Figure 5). There were not enough studies to produce interpretable funnel plots for studies providing RRs, HRs, or incidence rate ratios.

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  • Figure 5. 

    Funnel plot of studies reporting adjusted odds ratios. Plots are log standard error of effect estimate by adjusted effect estimate, centered on the pooled adjusted effect estimate. The pseudo 95% confidence interval corresponds to the expected 95% confidence interval for a given standard error. OR = odds ratio.

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Discussion 

We report the largest meta-analysis to date of the association between migraine and stroke. In this meta-analysis of 21 observational studies of the association of migraine headache and ischemic stroke, migraine was independently associated with a 2-fold increased risk of ischemic stroke.

There are several potential mechanisms for the increased risk of ischemic stroke in migraineurs. Migraine may increase ischemic stroke risk via vasospasm-induced cerebrovascular hypoperfusion,42 platelet activation,43 increased platelet aggregation,44 and increased concentrations and activity of vascular procoagulant factors such as endothelin 1,45 von Willebrand factor,46 prothrombin factor 1.2,47 homocysteine (MTHFR C677T genetic variant),48 and antiphospholipid antibody.49 An increased prevalence of patent foramen ovale (PFO) in patients with migraine also may predispose to embolic stroke via transit of a blood clot from the right- to left-sided circulation through the PFO.50

Comparison with Prior Meta-Analysis 

Our results expand on those of a prior smaller systematic review and meta-analysis by Etminan et al,7 which reported a similar magnitude of ischemic stroke risk in participants with migraine with aura and in women. Important differences among our and Etminan et al's study include temporal inclusion of studies from 1996 to 2004 (vs through 2009 in the current study). Also, Etminan et al assumed ORs approximate RRs.7 This assumption is tenable given the low prevalence of stroke in migraineurs and is supported by the similar magnitudes of pooled ORs and RRs in our meta-analysis. However, newer studies reporting HRs and incidence rate ratios also were included in our study. We therefore preferred not to pool across all effect estimates because of the potential for significant methodological heterogeneity, particularly differences in biases, by type of observational study design. However, we did provide the overall pooled effect estimate for comparison.

Stroke Risk in Migraineurs with or without Aura 

We found a greater risk of ischemic stroke in migraine with aura than migraine without aura, although this difference was unlikely to be significant. Migraine with aura is characterized by cortical spreading depression, oligemia, and changes in vascular perfusion.42 Changes in vascular perfusion may be associated with vasospasm, which could lead to cerebral hypoperfusion and ischemic stroke.51 In comparison with our study, the Etminan et al7 study also reported a statistically significant, albeit reduced, risk of stroke for migraine without aura (pooled RR 1.83; 95% CI, 1.06-3.15). This discrepancy is likely the result of differential inclusion in our meta-analysis of a large study by Stang et al,21 which reported a negative association with ischemic stroke in migraine patients without aura.

Stroke Risk in Female Migraineurs 

The association between migraine and stroke was strongest in studies of women. However, no direct comparison of effect estimates between men and women could be made as no studies of both men and women presented data separately by sex. This finding could represent a true increased risk, or it could be the consequence of residual or unmeasured confounding. Important potential confounders include those that reflect hormone status in women, including pregnancy52 and oral contraceptive53 and postmenopausal hormone use,54 and factors such as smoking that may interact with these risk factors to further increase the risk of ischemic stroke.53 Increased estrogen levels might increase the risk of ischemic stroke via their affect on endothelial function, coagulation factors, and inflammation.55

Although we excluded studies solely of pregnant participants, few studies in our meta-analysis that included women adjusted for pregnancy status. In addition, not all studies adjusted for oral contraceptive or postmenopausal hormone use, which is likely to confound the relationship between migraine in women and ischemic stroke, as estrogen-containing therapies have been used to treat certain types of migraines.56, 57 Finally, migraine is more common in women,3, 4 and vasoactive medications used to treat migraines, such as triptans, may predispose to ischemic stroke.42, 51

Limitations 

Potential limitations of this meta-analysis must be considered. First, our review was subject to language bias, as we included articles only in the English language. However, a secondary search of PubMed and EMBASE using the same strategy, but without the English language limitation, yielded no additional articles that would have met our selection criteria. Second, the meta-analysis was limited by limitations in its included studies. Certain data from individual studies, for example, subgroup data or information about potential confounders such as PFO prevalence or vasoactive medication use, were often not available or not reported. We did not attempt to procure this information or impute data. Third, this meta-analysis might not be generalizable to all populations. Included studies were from the US, UK, and Europe and consisted of largely white populations. Finally, although our results strongly suggest that migraine and stroke are associated, they do not shed light on whether this represents a true etiological association or rather an epiphenomenon whereby migraine and stroke are both manifestations of a shared, underlying propensity to cerebral vascular dysfunction.

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Conclusion 

Migraines appear to be independently associated with a 2-fold increased risk of ischemic stroke. Migraine is a potentially modifiable risk factor that can be treated,58 and stroke risk can be reduced through reduction of other risk factors.5 Therefore, further study is warranted to assess the effects of migraine control and stroke risk factor reduction on the risk of ischemic stroke in migraineurs.

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 Funding: Dr. Kahn is a recipient of a National Career Scientist Award from the Fonds de la Recherche en Santé du Québec. Dr. Nazarian is funded by the Johns Hopkins Richard S. Ross Clinician Scientist Award, the PJ Schafer Memorial Research Award, and the National Institutes of Health Clinical Research Scholars Program (1KL2RR025006-01). We did not receive any additional funding, including pharmaceutical industry funds, for the preparation of this manuscript or any related research.

 Conflict of Interest: All authors report no conflicts of interest.

 Authorship: All authors had access to the data and a role in writing the manuscript.

PII: S0002-9343(10)00129-4

doi:10.1016/j.amjmed.2009.12.021

The American Journal of Medicine
Volume 123, Issue 7 , Pages 612-624, July 2010

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