Literature search
The process of literature identification and inclusion was shown in Figure 1. Initially, 15,087 articles were identified with the search terms previously described, of which 10,705 non-repeated articles remained after duplicates articles were removed. We excluded 10,624 reports according to the title and abstract as the contents of these articles did not correspond with our research topic. Among the remaining 81 articles, 62 were further excluded for various reasons: 28 were comments, reviews, meta-analysis, conference abstract/summary, erratum, and note, etc.; 14 were the case-control, retrospective cohort, or cross-sectional design; 2 evaluated other types of headache, but not migraine; 6 reported hospitalization rate or stroke-related mortality rate, but not the incidence of stroke; 8 did not report required extractable data on the variables of interest; 4 studies reported earlier results and overcome by larger ones(supplementary table 2). Eventually, 19 studies published between 1995 and 2019 were eligible for our final review and meta-analysis.
Characteristics of the included studies
The basic characteristics of the 19 selected studies were represented in Table 1. The 19 studies included for the analysis were published from 1995 to 2019 and came from six different countries. The follow-up period varied from 17 months up to around 20 years. The cohort size ranged from 917 to 1,411,306 and enrolled a total of 3,523,235 participants. These studies included 661,057 migraineurs and 2,755,670 non-migraineurs, and reported 32,379 stroke events in total.
Out of the 19 studies, 6 studies reported the outcome of total stroke only15,19,20,21,22,23, 3 study reported the outcome of ischemic stroke only24,25,26, and 2 study reported the outcome of hemorrhagic stroke only27,28. 2 studies reported the outcome of both ischemic and hemorrhagic stroke29,30, 1 study reported the outcome of both total and ischemic stroke16, 5 studies reported the outcome of total stroke, ischemic and hemorrhagic stroke31,32,33,34,35. Notably, the study cohort of the Women’s Health Study updated the outcome of hemorrhagic stroke in 2010 separately after the initial report of all stroke outcome in 200527,33. Similarly, the outcome of the Physician’s Health Study reported all outcomes in one publication except the subsequent renewal of ischemic stroke24,31.
Out of all the studies, 2 studies included only male participates24,31, 4 studies included only female participates22,23,27,33, and the leaving 13 studies included both male and female participates. The information on the method of migraine assessment and the definition of stroke by each study was available in supplementary table 3.
Quality assessment
The quality of 19 included studied were evaluated by the Newcastle-Ottawa Quality Assessment Scale, the results of which were summarized in Table 2. Sixteen studies scored more than 7 points and ranked high quality, while the other three studies were rated as moderate quality with a score of fewer than 7 points15,23,34. Eighteen out of the 19 studies made adjustments for at least three variables for statistical analysis except for only one study34. Some commonly adjusted variables included age (18 studies), sex (11 studies), body mass index (BMI) (12 studies), history of smoking (12 studies), hypertension (16 studies), diabetes mellitus (16 studies), hyperlipidemia (15 studies), and aspirin medication (8 studies) (supplementary table 4).
Association between migraine and stroke risk
Figure 2A shows the relationship of migraine status with the risk of total stroke events. Among all the 12 studies, 8 studies found a positive correlation, while the other 4 studies attained no statistical significance. The pooled adjusted effect size for the outcome of total stroke events was 1.69 with 95% CI from 1.36 to 2.11 and substantial heterogeneity (I2 = 86.0%, Q-statistic P-value <0.001). Figure 2B demonstrates the correlation of migraine status with the ischemic stroke risk. Out of the 11 studies, six studies reported a positive correlation, and the other 5 studies found no statistical significance. The pooled RR was 1.46 with 95% CI from 1.14 to 1.87 (I2 = 95.8%, p < 0.001). Figure 2C shows the correlation of migraine status with hemorrhagic stroke risk. Among all the 8 studies, 2 showed a positive association and the other 6 studies had no statistical significance. The pooled RR was 1.37 with 95%CI ranging from 1.04 to 1.81 (I2 = 85.9%, p < 0.001). Overall, our results founded that migraine was associated with an elevated risk of total, ischemic, and hemorrhagic stroke.
Subgroup and sensitivity analyses
Results separately for different effect estimates did not illustrate any statistically significant differences (supplementary figure 1). Similarly, the sensitivity analysis limited to high-quality studies did not alter the pooled effect sizes substantially (supplementary figure 2). Besides, there existed no significant differences in the direction of effect size when any one study was excluded from the analysis (supplementary figure 3). Although some studies declared that only with enough long follow-up time, there existed a significant relationship between migraine and hemorrhagic stroke 27, the results from our meta-regression analyses indicated that the age at baseline, the midpoint of the recruitment time, and length of follow-up period accounted for no significant statistical heterogeneity.
Of the 19 studies included in the analysis, 7 reported the effect size representing the association between different migraine subtypes and ischemic stroke16,25,26,29,30,33,35, and 5 reported that value for hemorrhagic stroke27,28,29,30,35. The prespecified subgroup analysis showed that migraine with aura was related to an elevated risk of ischemic stroke (the pooled RR 1.75, 95%CI 1.35 to 2.29, P<0.001, I2=81.7%), while we found no significant relationship between migraine without aura and ischemic stroke risk (the pooled RR 1.17, 95%CI 0.94 to 1.46, P<0.001, I2=86.7%) (figure 3A). This was also true for hemorrhagic stroke: there was evidence of the association between migraine with aura and an elevated risk of hemorrhagic stroke (the pooled RR 1.63, 95%CI 1.26 to 2.10, P=0.266, I2=23.2%), while no positive relation was found between migraine without aura and hemorrhagic stroke (the pooled RR 1.32, 95%CI 0.99 to 1.74, P=0.012, I2=69.1%) (figure 3B). The statistical heterogeneity concerning the outcome of hemorrhagic stroke was improved when the subgroup analysis stratifying for the aura status was performed.
Due to the lack of data, subgroup analysis stratifying for different age subgroups could not be performed. Subgroup analysis stratifying for sex did not show any difference for ischemic stroke. Both female and male migraineurs showed an elevated risk of ischemic stroke (For female: the pooled effect size 1.29, 95%CI 1.13 to 1.47, P=0.748, I2=0.0%; For male: the pooled effect size 1.24, 95%CI 1.01 to 1.52, P=0.224, I2=33.1%) (figure 4A). Some interesting statistics results were found for subgroup analysis for hemorrhagic stroke. The results from the pooled analysis showed that female migraineurs were not at a higher risk of hemorrhagic stroke (the pooled RR 1.44, 95%CI 0.74 to 2.81, P=0.034, I2=77.8%), while the prevalence of hemorrhagic stroke in male migraineurs increased significantly(the pooled effect size 2.31, 95%CI 1.68 to 3.17, P=0.388, I2=0.0%)(figure 4B).
Evaluation of publication bias
For total, ischemic, and hemorrhagic stroke groups, the visual inspection of the funnel plot (supplementary figure 4) or the Egger’s test (P=0.366 for total stroke, P=0.631 for ischemic stroke, P=0.672 for hemorrhagic stroke, respectively) both indicated no publication bias.