Passive Smoking Is Not Associated with Risk of Intracranial Aneurysm Rupture in Nonsmoking Women

Accepted Manuscript Passive smoking is not associated with risk of intracranial aneurysm rupture in nonsmoking women Xin Feng, MS, Luyao Wang, MS, Erkang Guo, MS, Baorui Zhang, Zenghui Qian, MD, Xiaolong Wen, MS, Wenjuan Xu, MS, Youxiang Li, MD, Chuhan Jiang, MD, Zhongxue Wu, MD, Aihua Liu, MD PII:

S1878-8750(17)31220-2

DOI:

10.1016/j.wneu.2017.07.120

Reference:

WNEU 6182

To appear in:

World Neurosurgery

Received Date: 10 June 2017 Revised Date:

18 July 2017

Accepted Date: 20 July 2017

Please cite this article as: Feng X, Wang L, Guo E, Zhang B, Qian Z, Wen X, Xu W, Li Y, Jiang C, Wu Z, Liu A, Passive smoking is not associated with risk of intracranial aneurysm rupture in nonsmoking women, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.07.120. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Feng

ACCEPTED MANUSCRIPT

1

Passive smoking is not associated with risk of intracranial aneurysm rupture in

2

nonsmoking women

3

Xin Feng, MSa,b,*; Luyao Wang, MSa,b*; Erkang Guo, MSa,b; Baorui Zhanga,b; Zenghui Qian,

4

MDa,b; Xiaolong Wen, MSa,b; Wenjuan Xu, MSa,b; Youxiang Li, MDa,b; Chuhan Jiang, MDa,b;

5

Zhongxue Wu, MDa,b; Aihua Liu, MDa,b

6

a

7

Medical University, Beijing 100050, China

8

b

9

University, Beijing 100050, China

SC

Department of Interventional Neuroradiology, Beijing Neurosurgical Institute, Capital

M AN U

10

RI PT

1

Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical

*Xin Feng and Luyao Wang contributed equally to this work.

TE D

11

Correspondence to: Aihua Liu, MD

13

Address: No. 6, Tiantan Xili, Dongcheng District, Beijing 100050, China

14

Tel: 86-010-67098850; Fax: 86-010-67098064, E-mail: [email protected]

15

Running title: Rupture of intracranial aneurysm in women

16

Word count:

17

Table Count: 2

18

Keywords: female, intracranial aneurysm, passive smoking, risk factors, rupture

19

AC C

EP

12

Feng

21

BMI, body mass index

22

CI, confidence interval

23

HRT, hormone replacement therapy

24

IA, intracranial aneurysm

25

IAR, intracranial aneurysm rupture

26

OR, odds ratio

27

SAH, subarachnoid hemorrhage

AC C

EP

TE D

28

SC

Abbreviations and Acronyms:

M AN U

20

RI PT

ACCEPTED MANUSCRIPT

2

Feng

ACCEPTED MANUSCRIPT

3

Abstract

30

Background

31

Active smoking is a major risk factor for intracranial aneurysm (IA) rupture (IAR); however,

32

little is known about the effects of passive smoking on IAR. In China, female passive

33

smoking is widespread and severe. This study aimed to assess whether passive smoking is

34

associated with increased risk of IAR among nonsmoking women.

35

Methods

36

We enrolled and retrospectively analyzed 385 consecutive female patients with IAs (87

37

ruptured, 298 unruptured) who were admitted to our center between June 2015 and January

38

2017. Data on female active smoking, passive smoking, and other factors potentially

39

influencing IAR were precisely compared between ruptured and unruptured IAs.

40

Results

41

For all aneurysms, when adjusting for potential confounders, current smoking was

42

significantly associated with IAR (odds ratio [OR], 3.31; 95% confidence interval [CI], 1.08–

43

10.20; P = 0.037). Furthermore, bifurcation location (OR, 5.73; 95% CI, 3.27–10.03; P <

44

0.001) and educational level (OR, 1.90; 95% CI, 1.10–3.28; P = 0.022) significantly

45

increased the risk of IAR. However, for nonsmoking female patients, approximately one-fifth

46

of those with IAs were affected by passive smoking; however, passive smoking was not

47

significantly associated with IAR. The results also showed that bifurcation location (OR, 6.21;

48

95% CI, 3.46–11.15; P < 0.001) and the location of posterior circulation (OR, 3.23; 95% CI,

49

1.31–7.93; P = 0.011) significantly increased the risk of IAR.

AC C

EP

TE D

M AN U

SC

RI PT

29

Feng

ACCEPTED MANUSCRIPT 50

4

Conclusion Although active current smoking was strongly associated with aneurysm rupture in

52

female patients, passive smoking was not an independent risk factor for aneurysm rupture in

53

nonsmoking women.

RI PT

51

54

SC

55

M AN U

56

57

58

62

63

64

65

66

67

EP

61

AC C

60

TE D

59

Feng

ACCEPTED MANUSCRIPT

5

Introduction

69

Intracranial aneurysm (IA) rupture (IAR) accounts for 85% of cases of spontaneous

70

arachnoid hemorrhage (SAH), which is associated with high morbidity and mortality.1 SAH

71

occurs with an incidence of 10 per 100,000 person-years and 50–70% more frequently in

72

women than in men.2 The female preponderance of SAH is due to the relatively higher

73

incidence of IAs in women. However, several epidemiologic studies have also suggested that

74

the female preponderance of IAR can be attributed to the effect of hormonal factors.3

75

Moreover, some studies have proven that hormone replacement therapy (HRT) is associated

76

with reduced risk of IAR.4-6

M AN U

SC

RI PT

68

In addition, smoking is a major factor for IAR in both women and men. Thousands of

78

studies have evaluated the impact of active smoking on IAR, and the toxic impact of active

79

smoking is generally recognized.7,8 In comparison, the effects of passive smoking on IAR are

80

not fully understood. China is home to more than 300 million smokers, and female passive

81

smoking is widespread and severe owing to the high proportion of men who smoke.

82

Moreover, the rates of exposure to secondhand smoke in Chinese women are among the

83

highest in the world.7,9 Inadequate evaluations of exposure may result in an underestimation

84

of the risks, if they do exist.10 Therefore, in this two-part study, we assessed the relationship

85

between active smoking and the risk of IAR among women, and then studied the relationship

86

between passive smoking and the risk of IAR among female nonsmokers.

87

Methods

88

Study design and ethics

AC C

EP

TE D

77

Feng

ACCEPTED MANUSCRIPT

6

The study population consisted of female patients with IAs evaluated and/or treated at the

90

Beijing Tiantan Hospital between June 2015 and January 2017. The exclusion criteria were (i)

91

fusiform, traumatic, multiple, or mycotic aneurysms; (ii) intracranial hemorrhage for

92

unknown reasons; and (iii) aneurysms associated with arteriovenous malformations,

93

arteriovenous fistulas, and moyamoya disease.

94

This study was approved by the Beijing Tiantan Hospital review committee. All participants

95

provided informed consent.

96

Data collection and definitions

97

All female patients with IAs between the study dates included. The clinical and radiological

98

data of female patients with IAs were precisely collected. Socio-demographic characteristics

99

including age, sex, and educational level, and clinical characteristics including body mass

100

index (BMI), medical comorbidities, alcohol use (current or previous intake >5 drinks per

101

day), family history of IA, postmenopausal status, and history of postmenopausal hormone

102

treatment were collected. The higher education level consisted of those who graduate from

103

high school (higher secondary education), university degree or those with >12 years spent in

104

formal education (beginning from first grade). Those who graduate from middle school

105

(lower secondary education) or those with <12 years of formal education were classified into

106

the lower education level.11 Postmenopausal status was defined as at least 1 year of

107

amenorrhea. Postmenopausal HRT was defined as previous or active hormone use (estrogen

108

only, or estrogen and progesterone).

109

AC C

EP

TE D

M AN U

SC

RI PT

89

We obtained information through a telephone survey and by using a structured

Feng

ACCEPTED MANUSCRIPT

7

questionnaire in a face-to-face interview conducted by trained interviewers. Information on

111

smoking and passive smoking was obtained from the medical history recorded by the treating

112

physicians during interviews of patients or family members. If the patient's information was

113

incomplete, we obtained information using a telephone survey. We collected the women

114

patients with ruptured aneurysms from interviews of patients or family members or telephone

115

survey. Women were classified as nonsmokers if they reported never smoking or smoking

116

<100 cigarettes during their lifetime.12 Women environmentally exposed to cigarette smoke

117

were defined as nonsmokers who declared staying at least 1 h/day in rooms where cigarettes

118

were smoked, or staying at least 30 min/day in the immediate vicinity of cigarette-smoking

119

people, or sharing a flat with one or more persons smoking cigarettes at home.13 We also

120

collected data about sources of smoke exposure. First, we asked whether their husband or

121

other family members ever smoked in the house. Second, the subject was asked whether

122

someone ever smoked within 3 m around her in the workplace.9

TE D

M AN U

SC

RI PT

110

The size and location of the aneurysm were also recorded. Bifurcation IAs were defined

124

as aneurysms at artery bifurcations in the circle of Willis, originating from more than one

125

parent vessel (internal carotid artery terminus, anterior communicating artery, internal

126

carotid–posterior communicating artery, middle cerebral artery bifurcation, and apex of the

127

basilar artery).14 If the aneurysm originated from only one parent vessel , the aneurysm was

128

defined as sidewall aneurysm.15 Irregular aneurysm shape was defined as the presence of

129

blebs, aneurysm wall protrusions, or multiple lobes.16

130

AC C

EP

123

Feng

ACCEPTED MANUSCRIPT

8

Statistical analysis

132

All data were analyzed with SPSS 22.0 (IBM Corp., Armonk, NY, USA). Differences in

133

characteristics were assessed by using either χ2 tests for categorical variables or t tests for

134

continuous variables. Continuous data were expressed as means ± standard deviations, and

135

categorical variables were calculated as frequencies (percentages). As predetermined,

136

variables with a P value of <0.20 in the univariate logistic regression analysis were evaluated

137

in the multivariate analysis. To identify the independent risk factors that had significant

138

correlations with aneurysm rupture in female patients, multivariate logistic regression

139

analyses were separately performed for all of the female patients with IAs and for

140

nonsmoking female patients. We estimated the odds ratios (ORs) and 95% confidence

141

intervals (CIs) for the association between factors and IAR, with P < 0.05 indicating

142

statistical significance.

143

Results

144

Factors related to IAR in all female patients

145

A total of 385 women with IAs (87 ruptured and 298 unruptured) were enrolled (age range,

146

24–75 years). The mean patient age was 55.1 ± 9.3 years in the unruptured group and 55.9 ±

147

9.3 years in the ruptured group. The demographics and main aneurysm characteristics in both

148

groups are summarized in Table 1. The following covariates met our previously determined

149

level of significance and were entered into the stepwise forward selection for the

150

unconditional logistic model: age (P = 0.055), smoking status (P = 0.025), alcohol use (P =

151

0.127), education level (P < 0.001), hypertension (P = 0.081), cerebral ischemic

AC C

EP

TE D

M AN U

SC

RI PT

131

Feng

ACCEPTED MANUSCRIPT

9

comorbidities (P = 0.098), postmenopausal HRT (P = 0.146), aneurysm size (P = 0.009),

153

bifurcation location (P < 0.001), and location of the anterior circulation artery (P = 0.096).

154

However, postmenopausal status was far from being significantly associated with IAR in the

155

female patients.

RI PT

152

When adjusting for age, alcohol use, education level, hypertension, cerebral ischemic

157

comorbidities, postmenopausal HRT, aneurysm size, and aneurysm location, the multivariate

158

analysis indicated that current smoking was significantly associated with IAR (OR, 3.31;

159

95% CI, 1.08–10.20; P = 0.037). Furthermore, bifurcation location (OR, 5.73; 95% CI, 3.27–

160

10.03; P < 0.001) and educational level (OR, 1.90; 95% CI, 1.10–3.28; P = 0.022)

161

significantly increased the risk of IAR (Table 1).

162

Factors related to IAR in all nonsmoking female patients

163

After excluding smokers (n = 28), 357 female patients who had never smoked were enrolled,

164

including 282 with unruptured IAs and 75 with ruptured IAs. Of the 282 patients with

165

unruptured IAs, 67 (23.8%) were exposed to passive smoke, including 48 with home

166

exposure, 13 with workplace exposure, and 6 with both home and workplace exposure. Of

167

the 75 patients with ruptured IAs, 19 (25.3%) were exposed to passive smoke, including 14

168

with home exposure, 4 with workplace exposure, and 1 with both home and workplace

169

exposure. However, the univariate analysis comparing the two groups indicated that passive

170

smoking was not significantly associated with IAR (Table 2).

AC C

EP

TE D

M AN U

SC

156

171

The following covariates met our previously determined level of significance and were

172

entered into the stepwise forward selection for the unconditional logistic model: age (P =

Feng

ACCEPTED MANUSCRIPT

10

173

0.191), diabetes mellitus (P = 0.143), alcohol use (P = 0.018), postmenopausal HRT (P =

174

0.129), aneurysm size (P = 0.019), location of the anterior circulation artery (P = 0.083), and

175

bifurcation location (P < 0.001). Table 2 shows the results of multivariate logistic regression analysis of risk factors for

177

IAR in nonsmoking female patients. When adjusting for age, alcohol use, diabetes mellitus,

178

aneurysm size, location of the anterior circulation artery, and bifurcation location, the

179

multivariate analysis indicated that bifurcation location significantly increased the risk of

180

IAR (OR, 6.21; 95% CI, 3.46–11.15; P < 0.001) and the location of the posterior circulation

181

artery (OR, 3.23; 95% CI, 1.31–7.93; P = 0.011) was associated with an increased risk of

182

IAR in nonsmoking female patients.

183

Discussion

TE D

M AN U

SC

RI PT

176

In this study, we analyzed the smoking status between female patients with ruptured and

185

unruptured IAs, and compared the environmental exposure to cigarette smoke between

186

female nonsmokers with ruptured IAs and those with unruptured IAs. The results revealed

187

that active tobacco smoking was significantly associated with IAR among female patients.

188

However, in both our univariate and multivariate analyses, we failed to detect an effect of

189

passive smoking on the risk of IAR. These findings suggest that passive smoking status

190

should not be a risk factor for including patients in prophylactic treatment of IAs.

AC C

EP

184

191

Active smoking, passive smoking, and IAR

192

National antismoking laws cover 16% of the global population; however, significant

193

exposure of many individuals remains. The World Health Organization has estimated that

Feng

ACCEPTED MANUSCRIPT

11

around 6 million people die each year of active smoking, including 600,000 who die of

195

exposure to tobacco smoke.17 Active smoking has been well characterized as a major IAR

196

risk factor during the recent years. Cigarette smoking has also been proved to affect aneurysm

197

growth, and rupture is more likely to occur with faster aneurysm growth.18 However, the

198

interaction between the thousands of chemicals comprising tobacco smoke and IAs remains

199

incompletely understood. Several interdependent mechanisms were suggested to contribute to

200

aneurysm formation and rupture in active smokers, including increased wall shear stress,

201

atherosclerosis, endothelial dysfunction, and altered gene regulation.19,20 There is little

202

information about the effect of active smoking on IAR in female patients. In our study, active

203

smoking contributed to the IAR risk (OR, 3.31; 95% CI, 1.08–10.20; P = 0.037), independent

204

of age, BMI, education, drinking status, medical comorbidities, postmenopausal status, and

205

postmenopausal HRT. This result was consistent with those of a previous studies in patients

206

of both sexes.21,22

TE D

M AN U

SC

RI PT

194

Several studies revealed that both active and passive smokers may develop cerebrovascular

208

and cardiovascular diseases owing to continuous exposure to secondhand smoke.7,9,10,23

209

However, most studies investigating the association between smoke exposure and IAR

210

focused on active smoking, whereas the association between passive smoking and IAR risk is

211

rarely investigated. Adams et al.24 directly investigated the vascular endothelium in 25

212

healthy active smokers, 23 healthy passive smokers, and 23 healthy control subjects who had

213

never smoked and had no regular exposure to secondhand smoke. They used the minimally

214

invasive method of endothelial biopsy, and found that passive smoking reduces active

215

endothelial nitric oxide synthase and increases vascular endothelial inflammation to a similar

AC C

EP

207

Feng

ACCEPTED MANUSCRIPT

12

extent as active tobacco smoking, indicating the direct toxic effects of passive smoking on the

217

vasculature. In the present study, we conducted a retrospective analysis to investigate the

218

association between passive smoking and IAR in female nonsmokers. It should be noted that

219

we excluded male nonsmokers in evaluating the effects of smoking on IAR, because there is

220

an obvious sex difference with regard to rupture risk. In fact, passive smoking is widespread

221

in women. In our study, of 282 female nonsmokers with unruptured IAs, 67 (23.8%) were

222

exposed to passive smoke, and of 75 female nonsmokers with ruptured IAs, 19 (25.3%) were

223

exposed to passive smoke. The two main sources of passive smoke exposure are the home

224

(e.g., through a smoking spouse) and the workplace. Scientific evidence has proven that there

225

is no safe level of exposure to passive smoke.25 Although the results of our study indicated no

226

significant association between passive smoking and aneurysm rupture, it remains important

227

to provide counseling to all patients with IAs and their families and coworkers about the risks

228

of passive smoking.

TE D

M AN U

SC

RI PT

216

Postmenopausal status, postmenopausal HRT, and IAR

230

Previous studies examined the sex differences in IAR and found that IAR occurs more

231

frequently in women. Moreover, the prevalence of postmenopausal status is also high among

232

female patients with IAs, suggesting that reduced levels of estrogen in postmenopausal

233

women may increase the risk of aneurysm formation.26,27 In addition, clinical observations

234

suggested that postmenopausal women have a higher incidence of IAR than premenopausal

235

women,28whereas our study found that the prevalence was similar between female patients

236

with ruptured IAs and those with unruptured IAs (74.1% vs. 78.7%, P = 0.539). We

237

hypothesize that this result may be partly biased by the use of HRT in some postmenopausal

AC C

EP

229

Feng

ACCEPTED MANUSCRIPT

13

women, as HRT use is prevalent in this population.20 Qureshi et al.6 found that the risk of

239

SAH was 1.5-fold higher among postmenopausal women receiving HRT (both estrogen only,

240

and estrogen and progesterone). Tada et al., in their experimental IA mouse model, showed

241

that estrogen prevented aneurysm rupture in ovariectomized mice.28 However, the results of

242

our study revealed that the prevalence of postmenopausal HRT in the unruptured IA group

243

was higher than that in the ruptured IA group, whereas the difference between the two groups

244

was far from being significant after adjusting for potential confounders. Considering the

245

relatively low rate of hormone use and limited sample in this series, we could not conclude

246

that postmenopausal HRT was not associated with IAR.

247

Limitations and strengths

248

This study has several strengths. First, to our knowledge, this cohort study is the first to

249

investigate the association between secondhand smoke and IAR. Second, we included only

250

nonsmoking women, which allowed us to distinguish the effects of active smoking. The

251

present study also has several limitations. First, this is a retrospective study from a single

252

center, Beijing Tiantan hospital is one of the largest cerebrovascular intervention centers in

253

China, patients who come from all over the country, especially those who have complex

254

intracranial aneurysms which difficulty in treatment in the local hospital, went to our hospital,

255

suggesting that the collection of data was potentially biased. Besides, secondhand smoke

256

exposure data and postmenopausal HRT were collected by using self-reported measures, with

257

no biomarker data (e.g., nicotine or polycyclic aromatic hydrocarbon levels) obtained.

258

Therefore, recall and reporting biases may have affected the accuracy of our results, for

259

example, with respect to exposure level misclassifications. Finally, some studies have

AC C

EP

TE D

M AN U

SC

RI PT

238

Feng

ACCEPTED MANUSCRIPT

14

reported an increased risk of rupture in patients with multiple aneurysms 29,30However，it has

261

been still unclear if the results of study confounding by patient-specifc characteristics by

262

studying patients with aneurysmal SAH and multiple intracranial aneurysms, and patients

263

with multiple aneurysms may be subject to the cumulative risk of all individual

264

aneurysms,31so the patients with multiple intracranial aneurysms were excluded in our study.

265

Conclusion

SC

RI PT

260

Although active current smoking was strongly associated with aneurysm rupture in

267

female patients, passive smoking was not an independent risk factor for aneurysm rupture in

268

nonsmoking women.

269

Funding:

270

This research was supported by the Natural Science Foundation of Beijing, China

271

(No.7142032),

272

(2014-3-2044).

273

Conflicts of Interest:

274

None

275

References

276

1. Nieuwkamp DJ, Setz LE, Algra A, et al. Changes in case fatality of aneurysmal

277

subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis.

278

Lancet Neurol. 2009;8:635–642.

279

2. Eden SV, Meurer WJ, Sánchez BN, et al. Gender and ethnic differences in subarachnoid

TE D

Specific Research

Projects

for Capital

Health

Development

AC C

EP

and

M AN U

266

Feng

ACCEPTED MANUSCRIPT

15

hemorrhage. Neurology. 2008;71:731–735.

281

3. De Rooij NK, Linn FHH, van der Plas JA, et al. Incidence of subarachnoid haemorrhage. J

282

Neurol Neurosurg Psychiatry. 2015;78:1365–1372.

283

4. Shiue I, Arima H, Anderson CS. Life events and risk of subarachnoid hemorrhage: the

284

Australasian cooperative research on subarachnoid hemorrhage study (ACROSS). Stroke.

285

2010;41:1304-1306.

286

5. Mhurchu CN, Anderson C, Jamrozik K, et al. Hormonal factors and risk of aneurysmal

287

subarachnoid hemorrhage: an international population-based, case-control study. Stroke.

288

2001;32:606–612.

289

6. Qureshi AI, Malik AA, Saeed O, et al. Hormone replacement therapy and the risk of

290

subarachnoid hemorrhage in postmenopausal women. Stroke. 2016;124:45–50.

291

7. Schwartländer B, Pratt A. Tobacco in China: taming the smoking dragon. Lancet.

292

2015;385:2123-2124.

293

8. Brown RD Jr, Broderick JP. Unruptured intracranial aneurysms: epidemiology, natural

294

history, management options, and familial screening. Lancet Neurol. 2014;13:393–404.

295

9. Li N, Li Z, Chen S, et al. Effects of passive smoking on hypertension in rural Chinese

296

nonsmoking women. J Hypertens. 2015;33:2210–2214.

297

10. Jha P, Ramasundarahettige C, Landsman V, et al. 21st-century hazards of smoking and

298

benefits of cessation in the United States. N Engl J Med. 2013;368:341–350.

299

11. Fan Q, Verhoeven V J, Wojciechowski R, et al. Meta-analysis of gene-environment-wide

AC C

EP

TE D

M AN U

SC

RI PT

280

Feng

ACCEPTED MANUSCRIPT

16

association scans accounting for education level identifies additional loci for refractive error.

301

Nature Communications, 2016; 7:11008.

302

12. Sulsky SI, Fuller WG, Landingham CV, et al. Evaluating the association between menthol

303

cigarette use and the likelihood of being a former versus current smoker. Regul Toxicol

304

Pharmacol. 2014;70:231–241.

305

13. Gać P, Jaźwiec P, Mazur G, et al. Exposure to cigarette smoke and the carotid arteries

306

calcification index in patients with essential hypertension. Cardiovasc Toxicol. 2016.

307

14. Feng X, Wang L, Guo E, et al. Progressive occlusion and recanalization after

308

endovascular treatment for 287 unruptured small aneurysms (<5 mm): a single-center 6-year

309

experience. World Neurosurg. 2017;103:576-583

310

15. Backes D, Vergouwen M D, Velthuis B K, et al. Difference in aneurysm characteristics

311

between ruptured and unruptured aneurysms in patients with multiple intracranial aneurysms.

312

Stroke; 2014; 45(5):1299.

313

16. Kotowski M, Naggara O, Darsaut TE, et al. Safety and occlusion rates of surgical

314

treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of

315

unruptured

316

2014;45:1299–1303.

317

17. Durante AS, Massa B, Pucci B, et al. Effect of passive smoking on auditory temporal

318

resolution in children. Int J Pediatr Otorhinolaryngol. 2017;97:18–23.

319

18. Juvela S, Poussa K, Porras M. Factors affecting formation and growth of intracranial

AC C

EP

TE D

M AN U

SC

RI PT

300

aneurysms

in

patients

with

multiple

intracranial

aneurysms.

Stroke.

Feng

ACCEPTED MANUSCRIPT

17

aneurysms: a long-term follow-up study. Stroke. 2001;32:485–491.

321

19. Davis MC, Broadwater DR, Amburgy JW, et al. The clinical significance and reliability

322

of self-reported smoking status in patients with intracranial aneurysms: a review. Clin Neurol

323

Neurosurg. 2015;137:44–49.

324

20. Backes D, Rinkel GJE, Greving JP, et al. ELAPSS score for prediction of risk of growth

325

of unruptured intracranial aneurysms. Neurology. 2017;88:1600-1606.

326

21. Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the PHASES score for

327

prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective

328

cohort studies. Lancet Neurol. 2014;13:59-66.

329

22. Ho AL, Lin N, Frerichs KU, et al. Smoking and intracranial aneurysm morphology.

330

Neurosurgery. 2015;77:59-66.

331

23. Simsek E, Karaman Y, Gonullu M, et al. The effect of passive exposure to tobacco smoke

332

on perioperative respiratory complications and the duration of recovery. Braz J Anesthesiol.

333

2016;66:492–498.

334

24. Adams T, Wan E, Wei Y, et al. Secondhand smoking is associated with vascular

335

inflammation. Chest. 2015;148:112–119.

336

25. Bizoń A, Milnerowicz H. The effect of passive and active exposure to tobacco smoke on

337

lipid profile parameters and the activity of certain membrane enzymes in the blood of women

338

in the first trimester of pregnancy. Environ Toxicol Pharmacol. 2017;53:74-80.

339

26. Hamdan A, Barnes J, Mitchell P. Subarachnoid hemorrhage and the female sex: analysis

AC C

EP

TE D

M AN U

SC

RI PT

320

Feng

ACCEPTED MANUSCRIPT

18

of risk factors, aneurysm characteristics, and outcomes. J Neurosurg. 2014;121:1367–1373.

341

27. Andreasen TH, Bartek J Jr, Andresen M, et al. Modifiable risk factors for aneurysmal

342

subarachnoid hemorrhage. Stroke. 2013;44:3607-3612.

343

28. Tada Y, Wada K, Shimada K, et al. Estrogen protects against intracranial aneurysm

344

rupture in ovariectomized mice. Hypertension. 2014;63:1339–1344.

345

29. Sonobe M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial aneurysm

346

verification study: SUAVe study, Japan. Stroke 2010; 41: 1969-1977.

347

30. Thompson BG, Brown RD, Jr., Amin-Hanjani S, Broderick JP, Cockroft KM, Connolly,

348

ES, Jr., et al. Guidelines for the Management of Patients With Unruptured Intracranial

349

Aneurysms: A Guideline for Healthcare Professionals From the American Heart

350

Association/American Stroke Association. Stroke 2015;46:2368-2400.

351

31. Backes, D., Vergouwen, M. D., Velthuis, B. K., Ic, V. D. S., Bor, A. S., & Algra, A., et al.

352

Difference in aneurysm characteristics between ruptured and unruptured aneurysms in

353

patients with multiple intracranial aneurysms. Stroke;2014: 45(5), 1299.

355

356

357

358

SC

M AN U

TE D

EP

AC C

354

RI PT

340

Feng

ACCEPTED MANUSCRIPT

19

359

360

RI PT

361

362

Figure legends and Tables

364

Figure 1. Study flowchart

365 366 367 368

Table 1. Summary of statistic data for all women with ruptured and unruptured intracranial aneurysms Table2. Summary of statistic data of nonsmoking women with ruptured and unruptured intracranial aneurysms

M AN U

SC

363

369

373

374

EP

372

AC C

371

TE D

370

ACCEPTED MANUSCRIPT Table 1. Summary of statistic data for all women with ruptured and unruptured intracranial aneurysms Multivariate Analysis

P=0.479

UIA, n (%)

RIA, n (%)

Number

298

87

Age (years)

55.1 ± 9.3

55.9 ± 9.3

< 65

40 (13.4)

19 (21.8)

≥ 65

258 (86.6)

68 (78.2)

P=0.055

< 25

169 (56.7)

49 (56.3)

P=0.949

≥ 25

129 (43.3)

38 (43.7)

M AN U

BMI category

Smoking

0.78 (0.38–1.57)

SC

Characteristics

OR (95% CI)

RI PT

Univariate Analysis

P=0.025 *

282 (94.6)

75 (86.2)

Former smoker

4 (1.3)

4 (4.6)

P=0.146

3.16(0.67–14.8)

Current smoker

12 (4.0)

8 (9.2)

P=0.037 *

3.31(1.08–10.2)

Yes

55 (18.5)

10 (11.5)

P=0.127

P=0.053

0.43 (0.18–1.01)

No

243 (81.5)

77 (88.5)

49 (56.3)

P < 0.001 *

P=0.022 *

1.90 (1.10–3.28)

P=0.081

P=0.686

1.12 (0.64–1.96)

AC C

Educational level

EP

Alcohol use

TE D

Never smoker

Junior high school or less

167 (56.0)

High school or more 131(44.0)

38

43.7

Hypertension Yes

14 (48.0)

51 (58.6)

No

15 (52.0)

36 (41.4)

Hyperlipidemia

ACCEPTED MANUSCRIPT Yes

30 (10.1)

6 (6.9)

No

268 (89.9)

81 (93.1)

Yes

34 (11.4)

6 (6.9)

No

264 (88.6)

81 (93.1)

Yes

16 (5.4)

9 (10.3)

No

282 (94.6)

78 (89.7)

Yes

14 (4.7)

7 (8.0)

No

28 (95.3)

80 (92.0)

Yes

232 (77.9)

65 (74.7)

No

66 (22.1)

P=0.372

Diabetes mellitus

Cerebral ischemic comorbidities

No

SC P=0.226

P=0.539

22 (25.3)

EP 13 (4.4)

AC C

Yes

1.40 (0.51–3.89)

TE D

Postmenopausal status

Postmenopausal hormone replacement therapy

P=0.516

M AN U

Cardiac comorbidities

P=0.098

RI PT

P=0.225

1 (1.1)

285 (95.6)

86 (98.9)

Yes

29 (9.7)

6 (6.9)

No

269 (90.3)

81 (93.1)

65 (21.8)

53 (60.9)

P=0.146

P=0.110

0.17 (0.02–1.50)

P < 0.001 *

5.73(3.27–10.0)

History of ovariectomy

P=0.418

Bifurcation location Yes

P < 0.001 *

ACCEPTED MANUSCRIPT No

233 (78.2)

34 (39.1)

Yes

165 (55.4)

4 (51.7)

No

13 (44.6)

42 (48.3)

<7

173 (58.1)

64 (73.6)

≥7

125 (41.9)

23 (26.4)

AC

277 (93.0)

76 (87.4)

PC

21 (7.0)

11 (12.6)

Irregular shape

Size, mm

0.23 (0.10–0.56)

SC

P=0.001 *

M AN U

Location

P=0.009 *

RI PT

P=0.548

P=0.096

P=0.007

3.46 (1.40–8.52)

AC C

EP

TE D

UIA: unruptured intracranial aneurysm; RIA: ruptured intracranial aneurysm; CI: confidence interval; OR: odds ratio; BMI: body mass index; AC: anterior circulation artery PC: posterior circulation artery

ACCEPTED MANUSCRIPT

Table 2. Summary of statistic data of nonsmoking women with ruptured and unruptured intracranial aneurysms RIA, n (%)

n

282

75

Age (years)

54.90 ± 9.39

55.28 ± 9.20

≥ 65

36 (12.8)

14 (18.7)

< 65

246 (87.2)

61 (81.3)

No passive smoking

219 (77.7)

< 20

9 (3.2)

≥ 20

54 (19.1)

P=0.533

0.78 (0.37–1.69)

56 (74.7)

P=0.658

4 (5.3)

15 (20.0)

P=0.926

TE D

Exposed Environment 219 (77.7)

56 (74.7)

Home

48 (16.0)

14 (18.7)

Workplace

13 (4.6)

4 (5.3)

EP

No

6 (1.8)

AC C

workplace

OR (95% CI)

M AN U

Duration of passive Smoking (years)

Home and

P=0.191

Multivariate Analysis

SC

Characteristics

Univariate Analysis

RI PT

UIA, n (%)

1 (1.3)

Alcohol use Yes No

50 (17.7)

5 (6.7)

232 (82.3)

70 (93.3)

160 (56.7)

41 (54.7)

122 (43.3)

34 (45.3)

P=0.018*

BMI category < 25 ≥ 25

P=0.748

P=0.079

0.41 (0.15–1.11)

ACCEPTED MANUSCRIPT Educational level Junior high school or lower or

155 (55.0)

36 (48.0)

127 (45.0)

39 (52.0)

Yes

135 (47.9)

42 (56.0)

No

147 (52.1)

33 (44.0)

Yes

29 (10.3)

6 (8.0)

No

253 (89.0)

P=0.282

High school or higher Hypertension

Diabetes mellitus

No

251 (89.0)

71 (94.7)

16 (5.7)

6 (8.0)

EP

No

4 (5.3)

TE D

31 (11.0)

Yes

266 (94.3)

SC

69 (92.0)

Yes

Cerebral ischemic comorbidities

P=0.554

M AN U

Hyperlipidemia

P=0.211

P=0.143

P=0.457

69 (92.0)

AC C

Heart comorbidities Yes

14 (5.0)

6 (8.0)

268 (95.0)

69 (92.0)

Yes

215 (76.2)

18 (24.0)

No

67 (23.8)

57 (76.0)

No

P=0.310

Menopause status

Postmenopausal hormone replacement

RI PT

unknown

P=0.965

P=0.088

0.37 (0.12–1.16)

ACCEPTED MANUSCRIPT therapy Yes

13 (4.6)

1 (1.3)

No

269 (95.4)

74 (98.7)

Yes

28 (9.9)

5 (6.7)

No

254 (90.1)

70 (93.3)

Yes

61 (21.6)

46 (61.3)

No

221 (78.4)

29 (38.7)

P=0.194

P=0.129

0.19 (0.02-1.63)

P=0.386

Bifurcation

Yes

154 (54.6)

No

12 (45.4)

Maximum aneurysm 7.0 ± 5.4 height (mm), mean ± SD

≥7

4.0 ± 2.2

0.47 (0.25–0.88)

SC

P=0.002 *

ratio, 1.1 ± 0.5

1.1 ± 0.5

P=0.505

8.1 ± 5.8

5.9 ± 3.3

165 (58.5)

55 (73.3)

117 (41.5)

20 (26.7)

262 (92.9)

65 (86.7)

Location AC

P=0.019

P < 0.001 *

4.9 ± 3.3

EP

<7

6.21(3.46–11.1)

34 (45.3

P < 0.001 *

AC C

Size ratio

P < 0.001 *

P=0.873

5.0 ± 2.9

Maximum aneurysm 7.2 ± 5.5 width (mm), mean ± SD Width/height mean ± SD

4 (54.7)

TE D

Aneurysm neck (mm), 5.2 ± 3.2 mean ± SD

P < 0.001 *

M AN U

Irregular shape

RI PT

History of ovariectomy

P=0.019 *

ACCEPTED MANUSCRIPT PC

20 (7.1)

10 (13.3)

P=0.083

P=0.011

3.23 (1.31–7.93)

*P < 0.05

AC C

EP

TE D

M AN U

SC

RI PT

UIA: unruptured intracranial aneurysm; RIA: ruptured intracranial aneurysm; SD: standard deviation; CI: confidence interval; OR: odds ratio; BMI: body mass index; AC: anterior circulation artery PC: posterior circulation artery

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Highlights

1. This cohort study is the first to investigate the association between secondhand

RI PT

smoke and intracranial aneurysm rupture. 2. We concluded that active current smoking was strongly associated with aneurysm

AC C

EP

TE D

M AN U

aneurysm rupture in nonsmoking women.

SC

rupture in female patients, but, passive smoking was not an independent risk factor for