Aneurysmal Subarachnoid Haemorrhage and Sex Difference: Analysis of Epidemiology, Outcomes and Risk Factors

doi:10.21203/rs.3.rs-3348125/v1

Background and Purpose

The differences in outcomes after aneurysmal subarachnoid haemorrhage (aSAH) between the different sexes remains controversial. This study aimed to study the differences in epidemiology, outcomes and risk factors between male and female aSAH patients.

Methods

We performed a multicentre retrospective study of aSAH patients from 2017 to 2020. We investigated epidemiology differences between the two sexes. Propensity score matching (PSM) was used to compare short-term outcomes in different sexes. Binary logarithmic regression was performed to investigate the odds ratio for dependent survival in different sexes.

Results

A total of 5407 consecutive aSAH patients were included in this study, and the female-to-male ratio was 1.8:1. The peak incidence of aSAH occurred in the 6^th and 7^th decade in males and females, respectively. Female patients had more ICA/PCoA aneurysms (53.2%), and male patients had more ACA/ACoA aneurysms (43.2%). The incidence of multiple aneurysms was higher in female patients (21.5% vs. 14.2%, P<0.001). There was no significant difference in outcomes before and after PSM at discharge. The dependent survival risk was only related to the clinical condition upon admission in females. In addition, age of more than 50 years (OR, 1.88; 95% CI, 1.17-3.02; P=0.01) and hypertension (OR, 1.81; 95% CI, 1.25-2.61; P=0.002) were also risk factors in male patients.

Conclusions

The number of female patients was higher than that of male patients. Most aneurysm locations were different between the two groups. There was no significant difference in discharge outcomes before and after PSM. The risk factors for dependent survival were different in female and male patients.

aneurysm

subarachnoid hemorrhage

female

male

outcome

epidemiology

Subarachnoid haemorrhage (SAH) accounts for approximately 5% of all strokes¹. Aneurysmal subarachnoid haemorrhage (aSAH), where blood results from the rupture of intracranial aneurysm (IA), has an outsized burden of mortality and morbidity in approximately 85% of cases^2,3. Sex differences are related to intracranial aneurysm prevalence. While sex differences have been well delineated in ischaemic stroke outcome, the relationship between sex difference and outcomes after aSAH remains controversial. Most sex-specific studies are also focused on predisposing factors, aneurysm characteristics and incidence^4,5. Sex-specific studies specifically focused on sex differences in outcomes were relatively fewer. It has long been recognized that risk factors for poor outcome in aSAH patients include age, hypertension, smoking, poor clinical condition at admission, and aneurysm location^6,7. However, the risk factors for dependent survival in patients of different sexes with aSAH remain relatively less described. Defining sex differences in aSAH outcomes and risk factors for dependent survival could be used to evaluate the prognosis of patients and develop individualized management strategies.

Consequently, this study aims to investigate the sex differences in patients with aneurysmal subarachnoid haemorrhage in terms of epidemiology and discharge outcomes and to analyse the risk factors for dependent survival in patients of different sexes.

Data Collection

Data from all patients with aneurysmal subarachnoid haemorrhage were collected from the Chinese Multi-Center Cerebral Aneurysm Database (CMAD) from January 1st, 2017, to December 31^st, 2020. The CMAD data were collected from medical records (Trial registration: ChiCTR, ChiCTR2200065083. Registered 10/27/2022, https://www.chictr.org.cn/bin/project/edit?pid = 178501)⁸. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of hospital, and patients have signed informed consent forms.

Inclusion criteria were as follows: 1) age ≥ 20 years, 2) spontaneous subarachnoid haemorrhage (SAH) diagnosed by head computed tomography (CT) or lumbar puncture, and 3) intracranial aneurysm confirmed by computed tomography angiography (CTA), digital subtraction angiography (DSA) or magnetic resonance angiography (MRA). The exclusion criteria were as follows: 1) missing clinical information, 2) a history of SAH, 3) a modified Rankin Scale (mRS) score ≥ 4 before the onset of aSAH due to a history of cerebral infarction (CI) or intracerebral haemorrhage (ICH), and 4) age ≥ 80 years.

Key baseline characteristics of patients were recorded, which included sex, age, history of hypertension, history of diabetes mellitus (DM), history of CI and ICH, drinking and smoking status, World Federation of Neurosurgical Societies (WFNS) score, CT Fisher grade, Hunt-Hess (H-H) grade, location of aneurysm, number of aneurysms, treatment modality, length of stay (LOS), and time from onset to admission. Drinking included former drinking and current drinking, and smoking included former smoking and current smoking in this study. Conservative treatment was those who refused operative treatment. Patients were separated into 2 groups: male and female.

Outcome

The outcome measure was the mRS at discharge after onset, and the functional outcome of the patient was dichotomized as independent survival (mRS 0–2) or dependent survival (mRS 3–5). Mortality was also recorded.

Statistical Analysis

Statistical analysis was performed with SPSS (version 26.0, IBN). Descriptive statistics were used to calculate frequencies, means, and SDs. Continuous variables were expressed as the mean ± SD and analysed using an independent sample t test between groups. Categorical data were analysed with a χ2 test between groups. The nearest neighbour method with no replacement was used to control for age, history of hypertension, history of DM, history of CI and history of ICH, drinking, smoking, WFNS, CT Fisher grade, H-H grade, location of aneurysm, number of aneurysms, treatment modality and time from onset to admission in propensity score matching (PSM). PSM (1:1) was performed with a match tolerance of 0.02. After PSM, we compared the baseline characteristics and prognosis between male and female patients. Binary logistic regression analysis was used to explore the risk factors affecting the dependent survival (mRS 3–5) of male and female patients after aSAH. Associations are shown as odds ratios (ORs) and 95% confidence intervals (95% CIs). In this study, age was either analysed as a continuous or categorical variable.

Patient characteristics

A total of 5837 patients were diagnosed with aSAH in the CMAD from January 2017 to December 2020. Finally, 5407 patients were eligible for inclusion in the present study, and the flow chart is shown in Fig. 1.

A total of 3504 patients were female, 1903 patients were male, and the total female-to-male ratio was 1.8:1. The ratios of women to men ranged from 0.6 to 3.2 according to different decade ages. The peak incidence of aSAH occurred in the 6th decade in male patients and in the 7th decade in female patients. The details of the distribution of aSAH patients are shown in Fig. 2. Differences between the two groups were significant in terms of age, hypertension, DM, history of CI, smoking, drinking, number of IAs, location of IA, H-H grade, WFNS grade, and treatment modality (P < 0.05). Female patients had more ICA/PCoA aneurysms (53.2%), and male patients had more ACA/ACoA aneurysms (43.2%). The incidence of multiple aneurysms was higher in female patients than in male patients (21.5% vs. 14.2, P < 0.0001). After PSM, 1233 male patients were matched with 1233 female patients, and there were no significant differences in baseline information between the two groups (Table 1). After PSM, 1203 female patients and 1198 male patients were used to study dependent and independent survival. In female patients, differences between the two groups were significant in terms of age, hypertension, history of CI, CT Fisher grade, H-H grade, WFNS grade, treatment modality and LOS (P < 0.05). In male patients, differences between the two groups were significant in terms of age, hypertension, smoking status, CT Fisher grade, H-H grade, WFNS grade, treatment modality and LOS (P < 0.05). Detailed information is shown in Supplemental Table 1.

Outcomes

The outcome results were available for 5407 patients before PSM and for 2466 patients after PSM at discharge. The distribution of mRS scores was not significantly different between the two groups at discharge before and after PSM (Fig. 3). After PSM, no significant differences were found between males and females in independent survival (77.0% VS. 76.0%, P = 0.537) and mortality (2.8% VS. 2.4%, P = 0.530) at discharge. No significant difference was found between males and females in LOS (16.12 ± 12.52 VS. 15.86 ± 11.29) after PSM (Table 2).

Risk factors for dependent outcomes in male patients at discharge

Binary logistic regression analysis was used to investigate the risk factors affecting the dependent survival of male aSAH patients at discharge. The risk factors associated with dependent survival were age (≥ 50 years OR, 1.88; 95% CI, 1.17–3.02; P = 0.01), hypertension (OR, 1.81; 95% CI, 1.25–2.61; P = 0.002), CT Fisher grade 3 (OR, 1.71; 95% CI, 1.10–2.67; P = 0.017), H-H grade (grade III OR, 4.76; 95% CI, 1.93–11.73, P = 0.001; grade IV OR, 14.95; 95% CI, 5.24–42.70, P < 0.001; grade Ⅴ OR, 77.70; 95% CI, 12.34-489.37, P < 0.001), and WFNS V (OR, 3.92; 95% CI, 1.56–9.85; P = 0.004). Patients who underwent clipping had a 42% lower OR (OR, 0.58; 95% CI, 0.35–0.97, P = 0.037) than those who underwent conservative treatment. Patients who underwent coiling had a 75% lower OR (OR, 0.25; 95% CI, 0.15–0.40, P < 0.001) than those who underwent conservative treatment. Smoking reduced the OR of dependent survival (OR, 0.45; 95% CI, 0.22–0.92, P = 0.029). The details are shown in Fig. 4 and Supplemental Table 2.

Risk factors for dependent outcomes in female patients at discharge

In female patients, the risk factors associated with dependent survival were CT Fisher grade (grade 3 OR, 1.91; 95% CI, 1.25–2.93, P = 0.003; grade 4 OR, 2.01; 95% CI, 1.31–3.09; P = 0.002), H-H grade (grade IV OR, 3.14; 95% CI, 1.22–8.11, P = 0.018; grade V OR, 12.33; 95% CI, 2.88–52.72; P = 0.001), and WFNS (IV OR, 4.51; 95% CI 2.48–8.21; V OR, 5.74; 95% CI, 2.51–13.13; P < 0.05). Patients who underwent clipping had a 46% lower OR (OR, 0.54; 95% CI, 0.34–0.86, P = 0.009) than those who underwent conservative treatment. Patients who underwent coiling had a 76% lower OR (OR, 0.24; 95% CI, 0.15-0.0.38, P < 0.001) than those who underwent conservative treatment. The details are shown in Fig. 5 and Supplemental Table 3.

It has been reported that women are more susceptible to poor outcomes, such as in-hospital mortality, depression and disability, than men after ischaemic stroke. However, the relationship between sex differences and outcomes after aSAH remains controversial³. Consequently, the present study aims to investigate the sex differences in aSAH patients in terms of discharge outcomes and epidemiology and to analyse the risk factors for dependent survival in patients of different sexes. In turn, this study will provide valuable information for clinical practice and aid clinical doctors in making suitable decisions for such patients. As we have seen, this is the largest consecutive, multicentre, observational study reporting the role of sex in short-term outcomes and risk factors for dependent survival following aSAH.

In this study, 5407 patients were included, and the ratio of females to males was 1.8:1. We found female to male ratios ranging from 0.6:1 to 3.2:1 according to age. This was similar to some established studies that showed that the male to female ratios ranged from 1:1.2 to 1:3.1^9–11. This female preponderance was also shown in studies that compared unruptured and ruptured aneurysms, which demonstrated a sex difference in aSAH prevalence^7,12. In this study, the number of female patients began to exceed that of male patients in the 5th decade, and the peak incidence of aSAH occurred in the 7th decade in female patients and in the 6th decade in male patients. Decreased levels of the sex hormone oestrogen after menopause have been suspected to contribute to this phenomenon because menopause in females usually occurs in the late 5th and early 6th decades. Oestrogen can promote normal endothelial function and decrease the loss of collagen and elastin in the vascular wall, weakening vascular wall integrity¹³.

Decreased levels of sex hormonal influences on vascular wall remodelling were also the reasons for these sex differences in aneurysm multiplicity. Juvela et al.⁶ reported that female patients had an increased tendency to have multiple aneurysms after adjusting for smoking status. A study including 1277 aSAH patients also showed that female sex was a risk factor for presenting with 2 or more aneurysms¹⁴. In the present study, we also found that the incidence of multiple aneurysms was significantly higher in female patients (21.5%) than in male patients (14.2%).

This study also showed that female patients had more ICA/PCoA aneurysms, and male patients had more ACA/ACoA aneurysm. Haemodynamics and Circle of Willis anatomy may play a role in sex differences in aneurysm location. ACoA aneurysm is associated with Type A anatomy of Circle of Willis, which is more common in males, and ICA aneurysm is related to Type P anatomy, which is more commonly seen in females¹⁵. And the parent artery diameter and branches are smaller in females than in males, and the maximum wall shear stress of ICA bifurcation in women is 50% higher than that in men, which also increases the risk of aneurysm formation¹⁶.

Most studies have reported that there is no significant correlation between outcomes after aSAH and sex^9,17–20. In this study, there were also no significant differences in terms of dependent survival or mortality between female and male patients at discharge before and after PSM. However, a large cohort international trialist repository included 8051 aSAH patients and demonstrated that female sex was correlated with poor functional outcome³¹. Some studies have reported that females have worse quality of life and higher recurrence rates after aSAH^14,19. Vasospasm may play a role in the outcomes of different sexes. Rosenłrn et al.²¹ reported that females have a higher vasospasm rate than males. Some studies found that female sex was a risk factor for vasospasm after aSAH²². Catecholamines can stimulate the sympathetic nervous system, which plays a role in vasospasm. Higher noradrenaline was found in female patients by Lambert et al.²³ Because of the limitations of this retrospective study, we could not investigate the association between poor outcome and vasospasm. This information shows that the relationship between sex differences and outcomes after aSAH remains controversial, and more evidence within this topic is needed in future studies.

To clarify which factors might affect the discharge outcome of male or female patients, the present study also analysed the risk factors for dependent survival in female and male patients. We found that dependent survival was only related to the clinical condition on admission, such as CT Fisher grade, H-H grade and WFNS, in female aSAH patients. In addition to clinical conditions on admission, age older than 50 years and hypertension were also risk factors for dependent survival in male patients. Operative treatment would reduce the odds ratios of dependent survival in both female and male patients. Interestingly, smoking could reduce the risk of dependent survival in males. Dasenbrock et al.²⁴ also reported that smoking was related to decreased odds of poor outcome (OR 0.53, 95% CI 0.41–0.69, P < 0.05) and in-hospital mortality (OR 0.69, 95% CI 0.50–0.96, P < 0.05). Some studies found that transdermal nicotine replacement after aSAH was related to good clinical outcomes among smokers and a decreased risk of death 3 months after onset but a similar incidence of delayed cerebral ischaemia compared with smokers who did not receive nicotine^25,26. This may be associated with the neuroprotective effects of nicotine. Because of the nicotinic acetylcholine receptors on intracranial vessels, nicotine might have neurogenic vasodilatory and anti-inflammatory effects²⁶. In contrast, more studies have shown that smoking is associated with poor outcomes and vasospasm^27,28. Because of the limitations of retrospective studies, smoking included former smoking and current smoking and was not stratified by smoking status in this study. We will perform prospective studies to clarify the role of smoking on the outcomes of aSAH patients.

Limitations

The results of the present study are subject to the limitations of a multicentre retrospective study based on clinical medical records. For example, we could not obtain detailed information on smoke exposure and aneurysm diameter.

In this study, the female to male ratios ranged from 0.6:1 to 3.2:1 according to age, and the peak incidence of aSAH occurred in the 6th decade in male patients and the 7th decade in female patients. Female patients had more ICA/PCoA aneurysms, and male patients had more ACA/ACoA aneurysms. The incidence of multiple aneurysms was higher in female patients. There was no significant difference in discharge outcomes before and after PSM. The dependent survival was only related to the clinical condition upon admission of female aSAH patients. In addition to clinical conditions upon admission, age more than 50 years and hypertension were also risk factors for dependent survival in male patients.

Acknowledgment

This work was supported by the Tianjin Medical University General Hospital Clinical Research Program (Grant No. 22ZYYLCCG07) and the Natural Science Foundation of Tianjin, China (Grant No. 20JCZDJC00300).

Declaration of conflicting interests

None.

Funding

the Tianjin Medical University General Hospital Clinical Research Program (Grant No. 22ZYYLCCG07).

the Natural Science Foundation of Tianjin, China (Grant No. 20JCZDJC00300).

Ethical Approval

This study protocol was examined and approved by the Medical Ethics Committee of Tianjin Medical University General Hospital. (No. IRB2022-YX-175-01)

This manuscript format complies with all instructions to authors.

all authors approved the final manuscript, and the authorship requirements have been met.

Manuscript writing: Chao Peng, Yan Zhao and Fan Li.

Data collecting: Chao Peng, Yan Zhao, Fan Li, Tie-zhu Guo; Xiang-dong Wang; and Bang-yue Wang.

Data analysis: Chao Peng, Yan Zhao, Fan Li, Heng-rui Zhang; Yi-fan Yang; Qing-guo Liu and Xin-liang Ren

The study conception and design: Xin-yu Yang

Manuscript editing: Xin-yu Yang, Qing-guo Liu and Xin-liang Ren

Funding acquisition: Xin-yu Yang

Supervision: Xin-yu Yang

This manuscript has not been published elsewhere and is not under consideration by another journal.

Reporting checklist was used.

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Table1. The baseline characteristics of patients with aneurysmal subarachnoid hemorrhage before and after Propensity Score Matching.

Before Propensity Score Matching

After Propensity Score Matching

Variable

Male (%)

Female (%)

P-value

Male (%)

Female (%)

P-value

No. of Patients

1903

3504

1233

Age (Mean±SD)

56.45±10.80

60.61±10.12

<0.001

57.56±10.69

57.80±11.07

0.579

Hypertension

1064(55.9)

2125(60.6)

0.001

696 (56.45)

705 (57.18)

0.745

Diabetes mellitus

89(4.7)

262(7.5)

<0.001

64 (5.19)

66 (5.35)

0.928

History of CI

146(7.7)

216(6.2)

0.034

91 (7.38)

76 (6.16)

0.262

History of ICH

31(1.6)

85(2.4)

0.053

18 (1.46)

17 (1.38)

1

Smoke

717(37.7)

120(3.4)

<0.001

110 (8.92)

113 (9.16)

0.888

Drink

540(28.4)

72(2.1)

<0.001

68 (5.52)

65 (5.27)

0.858

Time from Onset to Hospital (Mean±SD)

32.75±98.30

33.57±108.90

0.784

30.99±67.21

32.24±82.17

0.682

Number of IA

<0.001

0.621

Single

1633(85.5)

2751(78.5)

1041 (84.43)

1031 (83.62)

Multiple

270(14.2)

753(21.5)

192 (15.57)

202 (16.38)

Location of IA

<0.001

0.928

ICA/PCoA

553(29.1)

1863(53.2)

393 (31.87)

399 (32.36)

MCA

373(19.6)

539(15.4)

234 (18.98)

229 (18.57)

ACA/ACoA

822(43.2)

804(22.9)

495 (40.15)

486 (39.42)

Posterior circulation

155(8.1)

298(8.5)

111 (9.00)

119 (9.65)

CT Fisher grade

0.380

200 (20.45)

336 (34.36)

84 (8.59)

2

1239(65.1)

2343(66.9)

814 (66.02)

808 (65.53)

3

300(15.8)

538(15.4)

203 (16.46)

204 (16.55)

4

364(19.1)

623(17.8)

216 (17.52)

221 (17.92)

Hunt-Hess grade

0.027

0.982

Ⅰ

198(10.4)

296(8.4)

126 (10.22)

121 (9.81)

Ⅱ

1085(57.0)

1962(56.0)

685 (55.56)

689 (55.88)

Ⅲ

319(16.8)

668(19.1)

220 (17.84)

214 (17.36)

Ⅳ

232(12.2)

467(13.3)

162 (13.14)

170 (13.79)

Ⅴ

69(3.6)

111(3.2)

40 (3.24)

39 (3.16)

WFNS grade

0.011

0.668

Ⅰ

1048(55.1)

1809(51.6)

648 (52.55)

631 (51.18)

Ⅱ

292(15.3)

569(16.2)

196 (15.90)

195 (15.82)

Ⅲ

96(5.0)

179(5.1)

70 (5.68)

60 (4.87)

Ⅳ

277(14.6)

629(18.0)

196 (15.90)

219 (17.76)

Ⅴ

190(10.0)

318(9.1)

123 (9.98)

128 (10.38)

Treatment modality

0.024

0.972

Clipping

673(35.4)

1111(31.7)

445 (36.09)

440 (35.69)

Coiling

969(50.9)

1888(53.9)

613 (49.72)

615 (49.88)

Conservative treatment

261(13.7)

505(14.4)

175 (14.19)

178 (14.44)

Abbreviations: No.=number; CI=cerebral infraction; ICH=intracranial hemorrhage; IA=intracranial aneurysm; ICA=internal carotid artery; PCoA=posterior communicating artery; MCA=middle cerebral artery; ACA=anterior cerebral artery; ACoA=anterior communicating artery; WFNS= World Federation of Neurosurgical Societies score.

Table2. The outcome in different sex before and after PSM at discharge.
Outcome	Before Propensity Score Matching			After Propensity Score Matching
Outcome	Male (%)	Female (%)	P-value	Male (%)	Female (%)	P-value
Function outcome			0.198			0.537
Independent Survival (mRS 0-2)	1442 (78.0)	2714 (79.5)		923 (77.0)	914 (76.0)
Dependent Survival (mRS 3-5)	406 (22.0)	698 (20.5)		275(23.0)	289(24.0)
Mortality			0.568			0.530
Survival	1848 (97.1)	3412 (97.4)		1198 (97.2)	1203 (97.6)
Death	55 (2.9)	92 (2.6)		35 (2.8)	30 (2.4)
Length of Stay (mean±SD)	16.34±12.62	16.00±11.91	0.328	16.12±12.52	15.86±11.29	0.596

SupplementTable1.Thebaselinecharacteristics.docx
Supplement Table1.The baseline characteristics of dependent and independent survival in different sex at discharge after Propensity Score Matching.
SupplementTable2.docx
Supplement Table2.The binary logistic regression analysis of dependent survival of male at discharge.
SupplementTable3.docx
Supplement Table3.The binary logistic regression analysis of dependent survival of female at discharge.
STROBEchecklistv4combined.docx

Aneurysmal Subarachnoid Haemorrhage and Sex Difference: Analysis of Epidemiology, Outcomes and Risk Factors

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Data Collection

Outcome

Statistical Analysis

Results

Patient characteristics

Outcomes

Risk factors for dependent outcomes in male patients at discharge

Risk factors for dependent outcomes in female patients at discharge

Discussion

Limitations

Conclusions

Declarations

References

Tables

Supplementary Files

Status:

Journal Publication

Version 1