Conventional vascular and specific risk factors for intracerebral hemorrhage in females
Valentina Arnao1,2, Marta Fedele3, Riccardo Altavilla2, Valeria Caso2
1. PhD School of: Medicina Clinica e Scienze del Comportamento-Biomedical Department of Internal and Specialistic Medicine (DiBiMIS), University of Palermo, Palermo, Italy;
2. Stroke Unit and Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy;
3. Pronto Soccorso ed Emergenza Territoriale, AUSL Bologna, area nord, Bologna, Italy.
Received 3 May 2017; accepted 22 October 2017.
Summary. Intracerebral hemorrhage (ICH) is responsible for 10 to 15% of all strokes and associated with high mortality and disability. Conventional risk factors for ICH are advancing age, hypertension, cerebral amyloid angiopathy, tobacco and alcohol abuse, oral anticoagulation and reversible cerebral vasoconstriction syndrome (RCVS). Conventional vascular risk factors, as well as female specific risk factors, have not been thoroughly investigated for their possible sex specific roles in the risk of an ICH. This narrative review reports on studies to date that have investigated for sex specific roles in ICH risk. The limited body of research on females to date, however, does suggest that elderly age, pregnancy and RCVS are implicated in the reported higher risks of ICH. Large prospective studies are needed to investigate conventional and sex specific risk factors in ICH and their reciprocal interaction.
Key words: intracerebral hemorrhage, stroke.
Fattori di rischio convenzionali e specifici per emorragia cerebrale nelle donne
Riassunto. L’emorragia cerebrale (ICH) è responsabile del 10-15% di tutti gli ictus ed è associata ad elevata mortalità e disabilità. I fattori di rischio convenzionali per ICH sono età, ipertensione, angiopatia amiloide, abuso di tabacco e alcol, l’anticoagulazione orale e la sindrome cerebrale da vasocostrizione reversibile (RCVS). I fattori di rischio vascolari convenzionali, nonché i fattori di rischio specifici per il sesso, non sono stati ancora adeguatamente valutati nell’ambito degli aspetti di genere nell’ICH. Questa revisione narrativa riporta i dati osservati dagli studi fino ad oggi pubblicati, che hanno indagato lo specifico ruolo del sesso nel rischio di ICH. I dati sulla relazione tra sesso e ICH sono ad oggi limitati. Tuttavia questi suggeriscono che l’età, la gravidanza e la RCVS sono connessi con un maggior rischio nel sesso femminile per ICH. Sono comunque necessari, visto il limitato numero di studi significativi disponibili, grandi studi prospettici per indagare i fattori di rischio convenzionali e specifici per il sesso nell’ICH e la loro reciproca interazione.
Parole chiave: emorragia cerebrale, ictus.
Intracerebral hemorrhage (ICH) is a spontaneous extravasation of blood into the brain parenchyma, responsible for 10 to 15% of all strokes and associated with poor outcome, including mortality and disability. According to the location, ICH is classified into either ganglionic (putamen, caudate and thalamus), lobar, cerebellar or pontine. ICH location correlates with causes, outcomes and potential treatments (Figure 1). Conventional risk factors for ICH are advancing age, hypertension, cerebral amyloid angiopathy (CAA), tobacco and alcohol abuse and oral anticoagulation.
These conventional vascular risk factors, as well as female specific risk factors, have not been thoroughly investigated for their possible sex specific roles in the risk of an ICH event1-3 (Figure 2). This narrative review reports on studies to date that have investigated for sex specific roles in ICH risk.
In a meta-analysis, carried out in 2010, ICH incidence was not significantly lower for either females or males1, whereas the Dijon Stroke Registry, between 1987 and 2012, recorded crude ICH incidence rates per 100,000 of 8 and 12.9 for females and males, respectively. While for subarachnoid hemorrhage (SAH), these percentages were 3.9 and 3.5, respectively4.
The risk of ICH in females has been reported to increase exponentially with age and sharply increase after age 55, doubling for each successive decade5. Moreover, in a large cohort of ICH patients, males had a higher risk of ICH than females for all groups under 80 years of age, but this risk was significantly increased in females over 805. Likewise, the BasicMar hospital-based registry observed that females were on average older than males at ICH onset2. Furthermore, a systematic review reported that the age-adjusted male/female incidence ratio for ICH had two peaks: between 65-74 years and ≥85 years, with 1.74 and 1.75 of rate ratios, respectively6. Finally, a population-based incidence study has reported that at age below 65, males were at a significantly greater risk of having ICH than females (risk ratio 3.4, 95% CI 2.7-4.3) but ≥65 years, males and females had similar risks (risk ratio 0.8, 95% CI 0.5-1.2)7.
Numerous studies investigating for sex differences have failed to detect any differences regarding lobar location7. Regarding deep hematomas, a 43% occurrence rate was reported for females in the Northern Manhattan Study7. A similar result has also been reported by Roquer et al., in the BasicMar hospital-based registry for ICH patients2.
Cerebral amyloid angiopathy
CAA is characterized by cerebrovascular amyloid deposition, which is known to significantly increase the risks of both ICH and dementia. Age is the most powerful risk factor for CAA-related ICH8. To this regard, a recent Japanese pathology based study has reported a corrected female-to-male ratio (F/M) of 2.2, with significant female predominance, particularly in the 65-74-year age group (F/M = 3.7). Moreover, non-significant female predominance has also been reported for a small patient series investigating for the presence of CAA9.
The BasicMar hospital-based registry, including more than 500 primary ICH patients, reported hypertension to be the most common risk factor (77.0%), without sex differences (p = 0.471)2. Likewise, an Italian prospective multicenter observational study, including 470 consecutive primary ICH patients, reported no sex differences in hypertension rates10.
Alcohol and tobacco abuse
A meta-analysis including 19 cohort studies and 16 case-control studies, with a total of 259,257 patients, reported heavy alcohol consumption (>60 g of ethanol/day) to be significantly associated with increased relative risk (RR) of both ischemic (RR 1.7) and hemorrhagic strokes (RR 2.2) for both males and females11,12. According to a previous meta-analysis, females were reported to have a protective effect from moderate drinking, defined as up to 36 g of pure alcohol. In the same study, heavy alcohol consumption, defined as 96 g, was seen to significantly increase the risk of ICH in females12. Cigarette smoking has been reported in 28% of ICH patients both males and females over a 3-year follow-up13.
Cigarette smokers, defined as smoking at least one cigarette, cigar, or pipe per day for the previous year, of both sexes, had a 3-fold greater risk of SAH, compared with non-smokers, whereas it was reported that female smokers had a 20% risk of aneurysmal SAH14.
Anticoagulant and antithrombotic treatment
Intracerebral bleeding is the most serious complication associated with oral anticoagulant and antithrombotic drugs, as they increase the risk of hematoma enlargement, therein more than often severely compromising functional outcome15. According to results from several large multicenter studies, about 20% of all patients prior to ICH had been prescribed anticoagulant treatment, and up to 30% were prescribed platelet inhibitors16-18.
A large, multicenter observational study including 4,093 patients over 80 years of age receiving treatment with vitamin K antagonists (VKA), reported no significant sex differences in ICH rates19. The age-standardized relative risk (RR) of hemorrhagic stroke during oral anticoagulant treatment has been reported to be 10.9 (95% CI 6.7-17.6) for males and 9.3 (95% CI 5.7-15.0) for females20.
Regarding the prescription of the new oral anticoagulants (NOACs), female sex has not been reported to be a risk factor for ICH in randomized clinical trials (Table 1). According to the Danish National Patient Registry on major bleeding complications and NOAC use in patients with nonvalvular atrial fibrillation, apixaban had a lower adjusted major bleeding risk compared with rivaroxaban, dabigatran, and warfarin in women compared to men21.
Female specific risk factors
Pre-eclampsia and eclampsia are known to induce hypertensive disorders, which in turn can lead to ischemic stroke or ICH onset in up to 36% of patients, with an estimated incidence from 0.4 to 38.9 per 100,000 pregnancies22. It is well-recognized (or similar) that stroke is the main cause of maternal death (almost 12%)23-25.
Pre-eclampsia-eclampsia has been reported to be associated with 24.7-fold increased risk of hemorrhagic stroke up to 12 months post-partum26. A Swedish population-based study observed that the highest risk of stroke for pregnant females was in the peripartum period (2 days prior to and 1 day after delivery; RR for cerebral infarction 33.8, 95% CI 10.5-84.0; RR for ICH 95.0, 95% CI 42.1-194.8), although excess risk also persisted during the puerperium period (2 days to 6 weeks postpartum) and the age and race-adjusted attributable risks of either cerebral infarction or ICH during or within 6 weeks after pregnancy was 8.1 per 100,000 pregnancies23. A US inpatient sample from 2000 to 2001, reported an ICH rate of 8.5/100,000 pregnancies26. In this study, an RR 2.5-fold higher risk of ICH during pregnancy increased to 28.3-fold during the first 6 weeks postpartum27.
Hormone replacement therapy (HRT)
Study results investigating estrogen therapy in post-menopausal females and stroke risk have been conflicting. The WEST trial (Women’s Estrogen for Stroke Trial) carried out in females with cerebrovascular disease, reported that estrogen use increased the risk of stroke (RR for fatal stroke 2.9; 95% CI 0.9-9.0%)28. The Women’s Health Initiative (WHI), a randomized trial of 16,608 postmenopausal females (95% with no history of cardiovascular disease), reported that estrogen plus progestin was not associated with an increased risk of ICH. The same study, including females following hysterectomy, reported that conjugate equine estrogen was not associated with a risk of ICH29,30. In a meta-analysis including WHI, WEST and the Estrogen/progestin Replacement Study, oral estrogen therapy with or without progestin was not associated with an increased ICH risk31. In a recent sub-analysis of the study WHI, the rate of SAH was higher among women on HRT, compared to controls (0.14% vs 0.11%, p <0.0001). An unadjusted analysis from the same study revealed that females on HRT were 60% more likely to suffer an SAH32.
Oral contraceptives (OCs) and parity
The World Health Organization has reported an overall slightly increased risk of ICH with OCs33, whereas a large prospective study on middle-aged Swedish females reported no such risk34. However, this latter study did conclude that the risk of ICH was significantly elevated among those starting and /or using OCs after age 30, those ceasing OCs for medical reasons, and those who were nulliparous33.
In the observational arm of the WHI, including 93,676 women 50-79 years of age, the risk of SAH continued to be higher among women reporting active use of OCs (RR 1.5, 95% CI 1.0-2.2) after adjusting for age, systolic blood pressure, cigarette smoking, alcohol consumption, body mass index, race/ethnicity, diabetes, and cardiovascular disease32.
Regarding parity, a Finnish cohort study reported a 4-fold higher risk of mortality following ICH among females with ≥10 live births compared to those with 2 to 4 live births34. This finding was later replicated in a Korean study (Acute Brain Bleeding Analysis, ABBA)35 and a population-based study, carried out in Chinese women, observed that the risk of stroke increased as the number of live births increased36. Pregnancy and delivery are considered risk factors for hemorrhagic stroke. Repeated pregnancies and deliveries may induce hypertension, physical and psychological stress that could damage the cardiovascular system in women with high parity37. During pregnancy, hemodynamic changes and oxidative stress may impair vascular resistance, and during delivery, vascular tension may also bring to vessel weakening or aneurysms, which may induce hemorrhagic stroke38.
Reversible cerebral vasoconstriction syndrome
Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headaches and reversible constriction of cerebral arteries, and has been reported to be associated with increased risks of both ischemic and hemorrhagic strokes. In a single-center retrospective study including 162 patients with RCVS, of which 126 were female, 21 ICH and 62 SAH have been observed. Comparing patients with isolated SAH to those with normal brain imaging, in this last group, a lower percentage of women has been observed and female sex predict ICH (p=0.043)39.
Race is considered an important risk factor, but only if we take into account the dynamic relationship between race and age in ICH. According to the population-based study REGARDS, ICH risk in American and African participants has been observed to be approximately 5-times greater than in whites at age 45, but only one-third as great at age 8540. So, in white subjects only, risk for ICH has been shown to more than double per decade of age. Moreover, male sex was associated with a nearly 3-times higher risk of ICH37.
Conventional vascular risk factors, as well as sex specific risk factors, have not been thoroughly investigated for their possible sex specific roles in ICH. The limited body of research on females to date, however, does suggest that older age, pregnancy and RCVS are implicated in the reported higher risks of ICH. Being so, large prospective studies are needed to investigate these conventional and sex specific risk factors for their possible roles in ICH, in order to develop prevention and treatment strategies.
1. Van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9: 167-76.
2. Roquer J, Rodríguez-Campello A, Jiménez-Conde J, et al. Sex-related differences in primary intracerebral hemorrhage. Neurology 2016; 8: 257-62
3. Gokhale S, Caplan LR, James ML. Sex differences in incidence, pathophysiology, and outcome of primary intracerebral hemorrhage. Stroke 2015; 46: 886-92.
4. Giroud M, Delpont B, Daubail B, Blanc C, Durier J, Giroud M, Béjot Y. Temporal trends in sex differences with regard to stroke incidence: The Dijon Stroke Registry (1987-2012). Stroke 2017; 48: 846-9.
5. Hsieh JT, Ang BT, Ng YP, Allen JC, King NK. Comparison of gender differences in intracerebral hemorrhage in a multi-ethnic Asian population. PLoS One 2016; 11: e0152945.
6. Appelros P, Stegmayr B, Terént A. Sex differences in stroke epidemiology: a systematic review. Stroke 2009; 40: 1082-90.
7. Labovitz DL, Halim A, Boden-Albala B, Hauser WA, Sacco R. The incidence of deep and lobar intracerebral hemorrhage in whites, blacks, and Hispanics. Neurology 2005; 65: 518-22.
8. Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke 1987; 18: 311-24.
9. Hirohata M, Yoshita M, Ishida C et al. Clinical features of non-hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathy. Eur J Neurol 2010; 17: 823-9.
10. D’Amore C, Paciaroni M, Silvestrelli G, et al. Severity of acute intracerebral haemorrhage, elderly age and atrial fibrillation: independent predictors of poor outcome at three months. Eur J Intern Med 2013; 24: 310-3.
11. Zhang Y, Tuomilehto J, Jousilahti P, Wang, Y, Antikainen R, Hu G. Lifestyle factors on the risks of ischemic and hemorrhagic stroke. Arch Intern Med 2011; 171: 1811-8.
12. Patra J, Taylor B, Irving H, et al. Alcohol consumption and the risk of morbidity and mortality for different stroke types-a systematic review and meta-analysis. BMC Public Health 2010; 18: 258.
13. Smajlović D, Salihović D, C Ibrahimagić O, Sinanović O, Vidović M. Analysis of risk factors, localization and 30-day prognosis of intracerebral hemorrhage. Bosn J Basic Med Sci 2008; 8: 121-5.
14. Anderson CS, Feigin V, Bennett D, Lin RB, Hankey G, Jamrozik K; Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS) Group. Active and passive smoking and the risk of subarachnoid hemorrhage: an international population-based case-control study. Stroke 2004; 35: 633-7 .
15. Lauer A, Pfeilschifter W, Schaffer CB, Lo EH, Foerch C. Intracerebral haemorrhage associated with antithrombotic treatment: translational insights from experimental studies. Lancet Neurol 2013; 12: 394-405.
16. Pezzini A, Grassi M, Paciaroni M, et al. Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) Investigators. Antithrombotic medications and the etiology of intracerebral hemorrhage: MUCH-Italy. Neurology 2014; 82: 529-35.
17. Stead LG, Jain A, Bellolio MF, et al. Effect of anticoagulant and antiplatelet therapy in patients with spontaneous intra-cerebral hemorrhage: does medication use predict worse outcome? Clin Neurol Neurosurg 2010; 112: 275-81.
18. Flaherty ML. Anticoagulant-associated intracerebral hemorrhage. Semin Neurol 2010; 30: 565-72.
19. Poli D, Antonucci E, Testa S, et al. Gender differences of bleeding and stroke risk in very old atrial fibrillation patients on VKA treatment: results of the EPICA study on the behalf of FCSA (Italian Federation of Anticoagulation Clinics). Thromb Res 2013; 131: 12-6.
20. Själander A, Engström G, Berntorp E, Svensson P. Risk of haemorrhagic stroke in patients with oral anticoagulation compared with the general population. J Intern Med 2003; 254: 434-8.
21. Lamberts M, Staerk L, Olesen JB, et al. Major bleeding complications and persistence with oral anticoagulation in non-valvular atrial fibrillation: contemporary findings in real-life Danish patients. J Am Heart Assoc 2017; 6: e004517.
22. Crovetto F, Somigliana E, Peguero A, Figueras F. Stroke during pregnancy and pre-eclampsia. Curr Opin Obstet Gynecol 2013; 25: 425-32.
23. Kittner SJ, Stern BJ, Feeser BR, et al. Pregnancy and the risk of stroke. N Engl J Med 1996; 335: 768-74.
24. James AH, Bushnell CD, Jamison MG, Myers ER. Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 2005; 106: 509-16.
25. Salonen Ros H, Lichtenstein P, Bellocco R, Petersson G, Cnattingius S. Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 2001; 12: 456-60.
26. Tang CH, Wu CS, Lee TH, et al. Preeclampsia-eclampsia and the risk of stroke among peripartum in Taiwan. Stroke 2009; 40: 1162-8.
27. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics-2011: a report from the American Heart Association. Circulation 2011; 123: e18-e209.
28. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345: 1243-9.
29. Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al; WHI Investigators. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation 2006; 113: 2425-34.
30. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al; WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003; 289: 2673-84.
31. Bath PM, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ 2005; 330: 342.
32. Qureshi AI, Malik AA, Saeed O, Defillo A, Sherr GT, Suri MF. Hormone replacement therapy and the risk of subarachnoid hemorrhage in postmenopausal women. J Neurosurg 2016; 124: 45-50.
33. Chan WS, Ray J, Wai EK, et al. Risk of stroke in women exposed to low-dose oral contraceptives: a critical evaluation of the evidence. Arch Intern Med 2004; 164: 741-7.
34. Yang L, Kuper H, Sandin S, et al. Reproductive history, oral contraceptive use, and the risk of ischemic and hemorrhagic stoke in a cohort study of middle-aged Swedish women. Stroke 2009; 40: 1050-8.
35. Jung, S.Y, Bae H, Park B.J, Yoon B.W. Parity and risk of hemorrhagic strokes. Neurology, 2010; 74: 1424-9.
36. Zhang Y, Shen L, Wu J, et al. Parity and risk of stroke among Chinese women: cross-sectional evidence from the Dongfeng-Tongji Cohort Study. Sci Rep 2015; 5: 16992.
37. Grundy E, Tomassini C. Fertility history and health in later life: a record linkage study in England and Wales. Soc Sci Med 2005; 61: 217-28.
38. Castelao JE, Gago-Dominguez M. Risk factors for cardiovascular disease in women: relationship to lipid peroxidation and oxidative stress. Med Hypotheses 2008; 71: 39-44.
39. Topcuoglu M, Singhal A. Hemorrhagic reversible cerebral vasoconstriction syndrome: features and mechanisms. Stroke 2016; 47: 1742-7.
40. Howard G, Cushman M, Howard VJ, et al. Risk factors for intracerebral hemorrhage: the REasons for geographic and racial differences in stroke (REGARDS) study. Stroke 2013; 44: 1282-7.
Conflict of interest statement: V.C.: advisory boards and speaker fees from Boehringer Ingelheim, Pfizer/BMS, Bayer, Daiichi Sankyo, Ever-NeuroPharma. The other Authors declare no potential conflits of interest or any financial or personal relationships with other people or organizations that could inappropriately bias conduct and findings of this study.
Stroke Unit and Division of Cardiovascular Internal Medicine
Santa Maria della Misericordia Hospital