A total of 3051 publications were retrieved of which 60 studies were included (Figure 1).[3–7,13,17–70] Study characteristics are summarized in Table S1. An overview of reported symptoms in included studies is given in Table S2. The 60 studies[3–7,13,17–70] included a total of 582 844 patients (50% women). The median age was 74 years for women (interquartile range, 69–75) and 69 years for men (interquartile range, 64–70). Eighteen studies included ischemic strokes with a total of 51 824 patients (49% women),[5,7,19,22,23,27,29,30,32,40,41,49,52,54,56,62,65,68] 4 studies included TIAs with 8004 patients (50% women),[3,31,38,50] 3 studies included both ischemic strokes and TIAs with 5130 patients (45% women),[6,51,63] and 3 studies included 842 patients (46% women) with ICH without data available on possible inclusion of SAH.[20,48,53] Twenty-four[7,17,19,20,24,27,31,36,38,43,45,48,49,51,53,54,58,59,63,65,66,68,69,71] of these 60 studies (68 958 patients) reported on nonfocal symptoms. Fourteen studies[25,26,29,30,32,35,37,39–41,46,47,61,64] (18 299 patients) assessed focal symptoms. Twenty-two studies reported on both nonfocal and focal symptoms (496 187 patients).[3–6,13,18,21–23,28,33,34,42,44,50,52,55,56,60,62,67,70] Thirty-three studies (56%) were multicenter cohorts.[3–5,7,13,17,19,20,22–25,27,28,33,34,36,39,42,46,48–51,55,56,58–60,63,65,66,69] The total number of patients per study ranged from 59 to 398 798.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of inclusion of studies.
Risk-of-bias Assessment of Included Studies
Most studies contained 1 or 2 sources of bias, and no study fulfilled our criteria of high methodological quality. Therefore, the outcomes of our risk-of-bias assessment were not suitable to perform a subgroup analysis with studies containing low or relatively low risk of bias.
Fifty-one studies confirmed stroke through clinical evaluation and neuroimaging and were classified as having low risk of bias.[3,5–7,13,17–23,25,27–36,39–49,52–54,56–61,63–70] Other articles assessed stroke through the International Classification of Diseases, Tenth Revision, codes (n=2)[4,50] and medical records (n=5).[24,26,38,55,62]
Only 2 of the 60 studies provided both crude and age-adjusted comparisons between men and women.[36,62] In total, 31 studies included all subtypes of stroke and imposed no selection criteria for their patient population and, therefore, had a low risk of bias.[4,13,17,18,20,24,25,28,33–37,39,41–43,45–47,55,57–61,64,66,67,69,70] Moreover, 2 studies that included hemorrhagic stroke did not make a clear distinction between ICH and SAH.[48,53] The remaining studies were classified as having high risk of bias. The results of the risk-of-bias assessment and the funnel plots are presented in Table S3 and Figure S8.
Meta-Analysis for any Type of Stroke
The overall pooled OR of occurrence of nonfocal symptoms in women versus men was 1.24 (95% CI, 1.16–1.33) with a summary incidence of 27% for men versus 31% (95% CI, 30%–33%) for women and considerable heterogeneity (I2=91.9%). Headache including migraine (OR, 1.24 [95% CI, 1.11–1.39]; summary incidence: 16% for men versus 19% [95% CI, 17%–21%] for women; I2=75.2%; 30 studies; 47 254 patients), minor change in level of consciousness or mental status change (GCS score, ≤14; OR, 1.38 [95% CI, 1.19–1.61]; summary incidence: 17% for men versus 22% [95% CI, 20%–25%] for women; I2=95.0%; 17 studies; 122 465 patients), and coma or stupor (GCS score, ≤8; OR, 1.39 [95% CI, 1.25–1.55]; summary incidence: 6% for men versus 8% [95% CI, 7%–9%] for women; I2=27.0%; 13 studies; 37 196 patients) occurred more frequently in women compared with men. However, aspecific neurological or other neurological symptoms occurred less frequently in women (OR, 0.96 [95% CI, 0.94–0.97]; summary incidence: 32% for men versus 31% [95% CI, 31%–31%] for women; I2=0.1%; 5 studies; 409 464 patients; Figure 2; Figure S1). Because 1 study with risk of bias on the domain validation of diagnosis had a very large sample size (398 798 patients; 68% of the total number of patients), we chose to assess impact of this study on the association between aspecific neurological or other neurological symptoms and female sex. A post hoc sensitivity analysis was, therefore, performed by excluding this study, which showed no significant differences between women and men in occurrence of aspecific neurological or other neurological symptoms (OR, 0.95 [95% CI, 0.84–1.07]; I2=8.9%; 4 studies; 10 666 patients; Figure S2).
Summary forest plot for nonfocal symptoms in patients with any type of stroke.
Cases: total number of women; controls: total number of men. GCS indicates Glasgow Coma Scale; LOC, level of consciousness; and OR, odds ratio.
The overall pooled estimate of all focal symptoms was not associated with sex (OR, 1.03 [95% CI, 0.97–1.09]; summary incidence: 40% for men versus 41% [95% CI, 39%–42%] for women), but there was considerable heterogeneity (I2=78.8%). However, dysarthria (OR, 1.14 [95% CI, 1.04–1.24]; summary incidence: 37% for men versus 40% [95% CI, 38%–42%] for women; I2=48.6%; 11 studies; 20 385 patients) and vertigo with or without nausea/vomiting (OR, 1.23 [95% CI, 1.13–1.34]; summary incidence: 19% for men versus 22% [95% CI, 21%–24%] for women; I2=44.0%; 8 studies; 9759 patients) occurred significantly more frequently in women. In contrast, the focal symptoms paresis/hemiparesis (OR, 0.73 [95% CI, 0.54–0.97]; summary incidence: 73% for men versus 66% [95% CI, 59%–72%] for women; I2=72.6%; 7 studies; 63 605 patients), diplopia (OR, 0.69 [95% CI, 0.53–0.90]; summary incidence: 5% for men versus 4% [95% CI, 3%–5%] for women; I2=81.8%; 3 studies; 1384 patients), and other focal visual disturbances (OR, 0.83 [95% CI, 0.70–0.99]; summary incidence: 16% for men versus 14% [95% CI, 12%–16%] for women; I2=62.8%; 16 studies; 27 796 patients) occurred significantly less frequently in women compared with men (Figure 3; Figure S3).
Summary forest plot for focal symptoms in patients with any type of stroke.
Cases: total number of women; controls: total number of men. OR indicates odds ratio.
Ischemic Stroke (Non-TIA)
For a subgroup analysis for sex differences in ischemic stroke, we included 18 studies with ischemic stroke only[5,7,19,22,23,27,29,30,32,40,41,49,52,54,56,62,65,68] and 3 studies that provided separate analyses for ischemic and hemorrhagic stroke.[17,39,44] In total, 53 226 ischemic stroke patients were included.
Most of the effect estimates (including headache with or without migraine) failed to reach significance. However, the association between female sex and change in level of consciousness/mental status change (GCS score ≤8: OR, 1.50 [95% CI, 1.20–1.88]; I2=34.1%; n=4 studies and GCS score ≤14: OR, 1.38 [95% CI, 1.27–1.50]; I2=29.3%; n=4 studies) remained statistically significant. The results of the subgroup analysis are provided in Figure S4 (nonfocal symptoms) and Figure S5 (focal symptoms). Heterogeneity of the overall pooled analysis in the ischemic stroke subgroup decreased from 93.6% to 85.0% for nonfocal and from 87.9% to 79.0% for focal symptoms.
Transient Ischemic Attack
In patients with TIA, we were only able to conduct a subgroup meta-analysis for headache. Headache was reported by all the studies that reported exclusively on a TIA population.[3,31,38,50] The OR of headache occurrence in women compared with men was 1.42 ([95% CI, 1.27–1.58] I2=0.0%; 4 studies; 8004 patients; Figure S6).
Subgroup Analysis for ICH or SAH
Due to the limited number of studies available on ICH, subgroup analysis for ICH was only possible for the symptom headache. Headache occurrence by ICH was reported by 5 studies[17,20,44,48,53] with 1096 patients in total. SAH was reported to be excluded in 2 studies[17,20] and included in another study. It was not clear whether the remaining 2 studies[48,53] analyzed SAH as a separate entity and not in combination with ICH.
The subgroup analysis showed no statistical differences in headache occurrence by women and men (OR, 1.27 [95% CI, 0.80–2.02]; I2=67.6%; n=5 studies; Figure S7). No studies were available that reported exclusively on SAH.
Stroke. 2022;53(2):345-354. © 2022 American Heart Association, Inc.