Stroke in women — from evidence to inequalities

Journal name:
Nature Reviews Neurology
Volume:
13,
Pages:
521–532
Year published:
DOI:
doi:10.1038/nrneurol.2017.95
Published online

Abstract

Stroke is the second largest cause of disability-adjusted life-years lost worldwide. The prevalence of stroke in women is predicted to rise rapidly, owing to the increasing average age of the global female population. Vascular risk factors differ between women and men in terms of prevalence, and evidence increasingly supports the clinical importance of sex differences in stroke. The influence of some risk factors for stroke — including diabetes mellitus and atrial fibrillation — are stronger in women, and hypertensive disorders of pregnancy also affect the risk of stroke decades after pregnancy. However, in an era of evidence-based medicine, women are notably under-represented in clinical trials — despite governmental actions highlighting the need to include both men and women in clinical trials — resulting in a reduced generalizability of study results to women. The aim of this Review is to highlight new insights into specificities of stroke in women, to plan future research priorities, and to influence public health policies to decrease the worldwide burden of stroke in women.

At a glance

Figures

  1. Hypertensive disorders of pregnancy.
    Figure 1: Hypertensive disorders of pregnancy.

    Risk factors for endothelial activation and possible resultant end organ damage in hypertensive disorders of pregnancy. HELLP, haemolysis, elevated liver enzymes, and low platelet count.

  2. Causes of stroke in pregnancy.
    Figure 2: Causes of stroke in pregnancy.

    Multiple potential systemic causes of stroke in pregnancy. PAI, plasminogen activator inhibitor.

  3. Hypertensive disorders of pregnancy are associated with a high risk of stroke.
    Figure 3: Hypertensive disorders of pregnancy are associated with a high risk of stroke.

    A 38 year-old woman was admitted for a first-ever generalized seizure with eclampsia at 27 weeks of gestation. The eclampsia was associated with a reversible posterior encephalopathy. a | An axial MRI fluid attenuation inversion recovery (FLAIR) sequence and apparent diffusion coefficient (ADC) cartography showing bilateral symmetrical posterior hyperintense lesions with increased ADC, suggesting vasogenic oedema (arrows). No vessel irregularity was present (image not shown). The patient underwent a caesarean section, and was treated with intravenous magnesium, enalapril, nicardipine and furosemide. On day 11, the patient presented with a left middle cerebral artery stroke. b | An axial MRI diffusion-weighted imaging sequence performed 2 h after symptom onset with a large left hemispheric ischaemic stroke. NIH Stroke Scale score was 7 and intravenous thrombolysis was not administered owing to the prior caesarean. Mechanical thrombectomy was performed but failed to achieve recanalization. c | A middle cerebral artery occlusion is visible on an axial view of the angiogram at the end of the endovascular procedure (arrow). A paradoxical embolism was excluded, owing to the absence of patent foramen ovale and the absence of deep vein thrombosis. d | Severe vasoconstriction syndrome was present at the time of stroke, as illustrated by this coronal plane CT angiogram, which shows a segmental and focal stenosis on the anterior circulation (arrow).

Key points

  • Hypertension and atrial fibrillation, key risk factors for stroke, are more frequent in women than in men
  • The effect of some risk factors for stroke — including diabetes mellitus and atrial fibrillation — are stronger in women than in men
  • Hypertensive disorders of pregnancy are important causes of stroke in pregnancy, and intracerebral haemorrhage is the leading cause of maternal death
  • Women are under-represented in clinical trials despite governmental actions highlighting the need for inclusive and nondiscriminatory trials that include both men and women
  • Women are more difficult to include in stroke trials than men because they tend to be older at stroke onset, have more comorbidities, and tend to live alone
  • Women living in societies with low access to education and to adequate healthcare have particularly little awareness of stroke

Introduction

In 2015, stroke became the second largest cause of disability-adjusted life-years lost worldwide, behind ischaemic heart disease1. With an anticipated increase in the average age of the female population worldwide, the prevalence of stroke in women is projected to rapidly increase, particularly among elderly women, leading to challenges for health care systems2. Stroke is not only a leading cause of disability, but is also a leading cause of death worldwide — particularly in women, among whom mortality due to stroke consistently exceeds that among men. The WHO reported an excess of total stroke-related deaths among women compared with men between 1990 and 2006, of which 60% occurred in those aged over 75 years3. These data highlighted that we have entered a period of rapidly increasing international inequality in stroke risk.

Women differ from men in a multitude of ways, including anatomy, vascular biology, immunity, neuroprotective factors, coagulation (for example, differences in levels of plasminogen activator inhibitor 1 or platelet counts4), hormonal profiles, vascular risk factors, lifestyle factors and societal roles. All of these factors can influence the risk of stroke and affect prognosis5. This Review, written on behalf of the Women Initiative for Stroke in Europe (WISE) group (Box 1), aims to highlight new insights into specificities of stroke in women, to plan future research priorities, and to influence public health policies to decrease the burden of stroke in women worldwide (Box 2).

Box 1: Members of the Women Initiative for Stroke in Europe (WISE) group

• Monica Acciarresi (University of Perugia, Perugia, Italy)

• Diana Aguiar de Sousa (Hospital Santa Maria, Lisbon, Portugal)

• Carine Ali (Université de Caen Normandie, Caen, France)

• Anne W. Alexandrov (University of Tennessee, Memphis, Tennessee, USA)

• Anita Arsovska (University Clinic of Neurology, Skopje, Macedonia)

• Ljiljana Beslac Bumbasirevic (University of Belgrade, Belgrade, Serbia)

• Marina Boban (University of Zagreb, Zagreb, Croatia)

• Rosa Maria Cabanas Veldes (Universitat Internacional de Catalunya Barcelona, Barcelona, Spain)

• Valeria Caso (University of Perugia, Perugia, Italy)

• Hanne Christensen (University of Copenhagen, Copenhagen, Denmark)

• Adriana B. Conforto (Sao Paolo University, Sao Paolo, Brazil)

• Charlotte Cordonnier (University of Lille, Lille, France)

• Anna Czlonkowska (Institute of Psychiatry and Neurology, Warsaw, Poland)

• Julia Ferrari (Krankenhaus Barmherzige Brüder Wien, Vienna, Austria)

• Ana Catarina Fonseca (University of Lisbon, Lisbon, Portugal)

• Alison Halliday (University of Oxford, Oxford, UK)

• Mirjam R. Heldner (University of Oxford, Oxford, UK)

• Virginia J. Howard (University of Alabama at Birmingham, Alabama, USA)

• Petra Ijas (University of Helsinki, Helsinki, Finland)

• Dejana Jovanovic (Faculty of Medicine, University of Belgrade, Belgrade, Serbia)

• Christine Krarup Hansen (University of Copenhagen, Copenhagen, Denmark)

• Christine Kremer (Skåne University Hospital, Malmö; Lund University, Lund, Sweden)

• Svetlana Lorenzano (Sapienza University of Rome, Rome, Italy)

• Arijana Lovrencic-Huzjan (Sestre Milosrdnice University Clinical Hospital Center, Zagreb, Croatia)

• Asa Lundgren-Nilsson (University of Gothenburg, Gothenburg, Sweden)

• Satu Mustanoja (University of Helsinki, Helsinki, Finland)

• Nathalie Nasr (Toulouse University Hospital, Toulouse, France)

• Annika Nordanstig (University of Gothenburg, Gothenburg, Sweden)

• Paola Palazzo (University of Poitiers, Poitiers, France)

• Aleksandra Pavlovic (University of Belgrade, Belgrade, Serbia)

• Fabienne Perren (University Hospital and Medical Faculty of Geneva, Geneva, Switzerland)

• Hélène Pessah-Rasmussen (Skåne University Hospital, Malmö; Lund University, Lund, Sweden)

• Francesca Romana Pezzella (Azienda Ospedaliera San Camillo Forlanini, Rome, Italy)

• Kirsi Rantanen (University of Helsinki, Helsinki, Finland)

• Christina Kruuse (Copenhagen University Hospital Herlev Gentofte, Herlev, Denmark)

• Christine Roffe (Keele University, Stoke on Trent, UK)

• Simona Sacco (Università degli Studi dell'Aquila, L'Aquila, Italy)

• Denisa Salihovic (University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina)

• Else Charlotte Sandset (Oslo University Hospital, Oslo, Norway)

• Paola Santalucia (Ospedale Maggiore Policlinico, Milan, Italy)

• Iwona Sarzynska-Dlugosz (Institute of Psychiatry and Neurology, Warsaw, Poland)

• Nikola Sprigg (University of Nottingham, Nottingham, UK)

• Nadezda Sternic (Bel Medic, Belgrade, Serbia)

• Sumanjit Gill (University College London Institute of Neurology, London, UK)

• Katharina S. Sunnerhagen (University of Gothenburg, Gothenburg, Sweden)

• Ana Isabel Figueira Verdelho (Hospital de Santa Maria, Lisbon, Portugal)

• Marija Zarkov (University of Novi Sad, Novi Sad, Serbia)

• Marialuisa Zedde (IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy)

• Miroslava Zivkovic (University of Nis, Nis, Serbia)

Box 2: Areas for future work

• Data regarding stroke in women should be collected in all countries in order to develop specific actions tailored to each society structure and health care system.

• Major sex differences in presentation of stroke and the effect of risk factors suggest a possible benefit of personalized medicine — including investigation and treatment — for women with stroke.

• Early detection and treatment of hypertensive disorders of pregnancy (HDP) should be promoted. A clear understanding of the aetiology of HDP could lead to the development of preventive strategies.

• Future studies assessing the effects of hormone replacement therapy on the risk of stroke early after menopause should focus on robust clinical endpoints to personalize stroke treatment on the basis of women's individual risks of stroke.

• More evidence is urgently required regarding the effects of treatment interventions in elderly women with stroke, particularly in stroke that is related to atrial fibrillation, and how these interventions influence cardiovascular outcomes in women.

• Data are needed on the incidence of inherited thrombophilia and prevention of cerebral venous thrombosis in individuals who are at high risk of these conditions. Randomized controlled trials or high-quality registry data are needed to better assess therapeutic interventions.

• Large-scale cohort studies assessing the risk factors for and outcomes of intracerebral haemorrhage in women are required to confirm whether women have worse outcomes following intracerebral haemorrhage than do men, independent of age and premorbid functional status, and whether this association is related to a difference in care.

• Educational campaigns for stroke awareness in women should include stroke symptoms and time-dependent therapeutic options, and should be tailored to different societal models worldwide.

• Enrolment age limits for randomized controlled trials should be avoided, and enrolment should instead mirror the sex distribution of the disease being investigated.

• Barriers to access to care and rehabilitation for women should be identified and addressed to provide equal access for both sexes.

Epidemiology

In 2009, a review of 56 population-based studies conducted in high-income countries revealed a 42% decrease in worldwide stroke incidence rates from 163 per 100,000 person–years in 1970–1979 to 94 per 100,000 person–years in 2000–2008. A faster decline in incidence was observed in men than in women6. Data from the Framingham Heart Study also suggest that one in five women and one in six men who reach the age of 55 years free from stroke will develop a stroke event during their remaining lifetime7.

A meta-analysis of individual participant data from high-quality stroke incidence studies confirmed that women consistently have greater long-term mortality after stroke than do men, regardless of study location and time period. In women, advanced age, more-severe strokes, worse prestroke function, and the presence of atrial fibrillation contributed to a greater mortality after stroke compared with men8.

The quality and availability of data regarding stroke in women is highly heterogeneous between countries. Rigorous evaluation of the epidemiology of stroke among women is difficult in some regions of the world9. The data on the fatality of stroke provide evidence for considerable variation between countries, even with a focus on studies with strict inclusion criteria10. Ethnicity could contribute to this variation, but data on this topic are lacking, especially regarding the potential for sex differences to be influenced by ethnicity. Women from some countries might be excluded from epidemiological data because they are not admitted to hospital, or because ascertainment and diagnosis patterns might be different in men compared with women2. Moreover, data from the Global Burden of Disease 2013 study highlighted that inequality in stroke outcome exists throughout the world: higher mortality is observed in women than in men in many regions around the globe. This inequality is strongly associated with socioeconomic status: the majority of countries in which stroke mortality was higher in women than men were developing countries and/or countries that underwent negative historical events, such as natural disaster or war, within the past few years2. Consequently, data on incidence and fatality of stroke in women should be collected in all countries to enable development of specific actions to address this issue that are tailored to each society structure and health care system.

Specific risk factors in women

Evidence increasingly shows that risk factors for stroke differ between men and women: frequencies of vascular disease vary between the sexes and some risk factors are specific to women. Women are older at the time of stroke onset than are men, and rates of hypertension (60% versus 56%) and atrial fibrillation (24% versus 22%) are higher in women than in men. Conversely, rates of diabetes mellitus (16% versus 20%) and smoking (15% versus 16%) are lower in women than in men11. Differences in smoking rates are decreasing between sexes, but smoking still has a male preponderance12.

Some female-specific characteristics increase the risk of stroke, including gestational hypertension (relative risk (RR) 1.51; 95% CI 1.27–1.80), oophorectomy (RR 1.42; 95% CI 1.34–1.50), preterm delivery (RR 1.62; 95% CI 1.46–1.79), and still birth (RR 1.86; 95% CI 1.15–3.03), whereas hysterectomy might protect against stroke (RR 0.88; 95% CI 0.85–0.90)13. Furthermore, the effect of some individual risk factors seems to be stronger in women than in men. Atrial fibrillation is associated with double the risk of stroke in women compared with the risk in men (RR 1.99; 95% CI 1.46–2.71)14. In a study based on 12,701 patients with cardioembolic stroke, women with atrial fibrillation experienced more-severe strokes than men (median NIH Stroke Scale score 14 versus 8)15. The excess risk of stroke from diabetes mellitus is higher in women than in men: RR 2.28 (95% CI 1.93–2.69) versus 1.83 (95% CI 1.60–2.08)16. This result is in line with findings from a large-scale meta-analysis of patients with metabolic syndrome, in which the increased risk of stroke associated with metabolic syndrome was greater among women (RR 1.83; 95% CI: 1.31–2.56) than among men (RR 1.47; 95% CI 1.22–1.78)17. Data also suggest that abdominal obesity has a stronger effect on stroke risk among women than men18.

Other risk factors have the same effects in men and women. A systematic review and meta-analysis based on 1.2 million individuals concluded that the effects of systolic hypertension19 and increased total cholesterol20 were equal in men and women. Evidence with regard to why certain risk factors have a stronger effect on women than men is inconclusive. Suggested explanations include the under-treatment of women, and physiological differences between the sexes14, 21. The different burden of risk factors between the sexes needs to be thoroughly explored to personalize prevention and treatment. In this regard, screening programs or interventions for type 2 diabetes mellitus or atrial fibrillation in women could carry considerably more benefit than those in men.

Three periods of stroke risk in women

Risk of stroke differs throughout the life-course. In this section, we will examine the factors associated with an increased stroke risk in women at three stages of life: child-bearing age, postmenopause and over 80 years of age.

Child-bearing age

Oral contraceptives. Hormonal contraception is common, and its use is increasing: four of five sexually active women have taken the oral contraceptive pill in the USA22. Use of the oral contraceptive pill varies considerably between regions worldwide, from less than 10% of total contraceptive use in developing countries to more than 25% in Europe23. A 2015 meta-analysis showed that combined hormonal contraception increased the risk of stroke 2.47-fold (95% CI 2.04–2.99). Low-dose oestrogen was associated with a reduced stroke risk, whereas the type of progestin was not associated with stroke risk. No excess risk was observed in gestagen-only formulations24. A systematic review found a 1.7-fold (95% CI 1.5–1.9) increase in the risk of stroke as a result of combined oral contraceptives25. Despite the fact that the crude incidence of stroke associated with hormonal contraceptives is very low (the crude incidence rate of ischaemic stroke was 21.4 per 100,000 person–years)26, the observed increase in risk remains important, as other modifiable risk factors might exist in healthy women. However, study findings underline that hormonal contraception is a very rare cause of ischaemic stroke and should be considered as such in clinical care.

Pregnancy. The increased risk of stroke in pregnancy, particularly around the time of delivery, is well recognized. The reported incidence of stroke varies from 25–34 cases per 100,000 deliveries27. The rate of stroke is increased by ninefold at the time of delivery and threefold in the early postpartum period, with an increase in the risk of both ischaemic and haemorrhagic stroke.

Hypertensive disorders of pregnancy (HDP) (Fig. 1), a spectrum that includes gestational hypertension (blood pressure>140/90 mmHg), pre-eclampsia (hypertension with proteinuria) and eclampsia (seizures) are a leading cause of maternal and perinatal morbidity and mortality worldwide1. The exact aetiology is unclear. Although only 1% of patients with pre-eclampsia experience a stroke, pre-eclampsia is the most common cause of stroke in pregnancy28 (Fig. 2). In addition, the effects of HDP persist beyond pregnancy, resulting in increased vascular disease29 and mortality30 later in life. Women with HDP are usually unaware of the long-term cardiovascular risks of this condition31, and long-term follow-up of these individuals should be encouraged.

Figure 1: Hypertensive disorders of pregnancy.
Hypertensive disorders of pregnancy.

Risk factors for endothelial activation and possible resultant end organ damage in hypertensive disorders of pregnancy. HELLP, haemolysis, elevated liver enzymes, and low platelet count.

Figure 2: Causes of stroke in pregnancy.
Causes of stroke in pregnancy.

Multiple potential systemic causes of stroke in pregnancy. PAI, plasminogen activator inhibitor.

Intracranial haemorrhage is the leading cause of maternal death32, and the majority of these haemorrhages are due to HDP33. Management of pre-eclampsia and intracerebral haemorrhage (ICH) in pregnant women should focus on rapid, aggressive blood pressure control in combination with delivery of the baby as soon as possible34. Notably, on average, pregnant women with haemorrhagic stroke are younger, have fewer comorbidities and have a better outcome than non-pregnant women with haemorrhagic stroke35. Other neurological syndromes, such as reversible cerebral vasoconstriction syndrome — an important cause of pregnancy-associated stroke36 — and posterior reversible encephalopathy, can occur as a consequence of HDP37 (Fig. 3).

Figure 3: Hypertensive disorders of pregnancy are associated with a high risk of stroke.
Hypertensive disorders of pregnancy are associated with a high risk of stroke.

A 38 year-old woman was admitted for a first-ever generalized seizure with eclampsia at 27 weeks of gestation. The eclampsia was associated with a reversible posterior encephalopathy. a | An axial MRI fluid attenuation inversion recovery (FLAIR) sequence and apparent diffusion coefficient (ADC) cartography showing bilateral symmetrical posterior hyperintense lesions with increased ADC, suggesting vasogenic oedema (arrows). No vessel irregularity was present (image not shown). The patient underwent a caesarean section, and was treated with intravenous magnesium, enalapril, nicardipine and furosemide. On day 11, the patient presented with a left middle cerebral artery stroke. b | An axial MRI diffusion-weighted imaging sequence performed 2 h after symptom onset with a large left hemispheric ischaemic stroke. NIH Stroke Scale score was 7 and intravenous thrombolysis was not administered owing to the prior caesarean. Mechanical thrombectomy was performed but failed to achieve recanalization. c | A middle cerebral artery occlusion is visible on an axial view of the angiogram at the end of the endovascular procedure (arrow). A paradoxical embolism was excluded, owing to the absence of patent foramen ovale and the absence of deep vein thrombosis. d | Severe vasoconstriction syndrome was present at the time of stroke, as illustrated by this coronal plane CT angiogram, which shows a segmental and focal stenosis on the anterior circulation (arrow).

Unenhanced CT remains the standard first-line imaging technique for the investigation of suspected stroke in pregnancy in many medical centres worldwide, but early use of MRI can distinguish between stroke and other neurological conditions38. In the context of HDP and neurological symptoms, MRI can help to differentiate permanent lesions (resulting from cytotoxic oedema) from reversible lesions (resulting from vasogenic oedema). Moreover, MRI enables assessment of intracranial vessels and diagnosis of reversible cerebral vasoconstriction syndrome.

Until the past few years, uncertainty surrounded the use of thrombolysis in pregnancy, and reports of the use of thrombolysis and other reperfusion strategies had been limited to small case reviews. Although alteplase does not cross the placenta, some concerns surround the use of this drug in pregnancy, particularly regarding the potential for placental haemorrhage. In the large US Stroke Registry 'Get with the Guidelines', pregnant women with ischaemic stroke were less likely to receive thrombolysis with alteplase (4.4%) than were non-pregnant women (7.9%, P = 0.03) despite significantly greater stroke severity in pregnant women. In pregnant or post-partum patients who were treated with alteplase, no increase in systemic bleeding was detected, but a nonsignificant increase in the risk of symptomatic ICH was found39. Notably, most strokes related to pregnancy occurred during the post-partum period40. Use of intra-arterial therapy for ischaemic stroke in pregnancy has been reported in a number of case series, and could be preferable to thrombolysis when the risk of maternal haemorrhage is high41.

The presence of a patent foramen ovale in pregnancy is associated with an increased risk of stroke in individuals with prothrombotic risk factors, including activated protein C resistance and reduced blood levels of protein S. However, in contrast to the risk of stroke from other factors, the risk owing to a patent foramen ovale peaks during the first and second trimesters of pregnancy. Pregnant women with hypercoagulable states should be considered for antithrombotic therapy with low-molecular-weight heparin, but patent foramen ovale is not a barrier to normal healthy delivery42.

In conclusion, early detection of HDP should be promoted, and patients should undergo aggressive treatment of high blood pressure and management of conventional risk factors before, during, and after pregnancy. A clearer understanding of the aetiology of HDP could lead to development of preventive strategies for this condition. Prospective registries are necessary to evaluate treatment strategies (such as thrombolysis and endovascular reperfusion), as randomized controlled trials are probably unfeasible owing to the rarity of HDP.

Menopause

The burden of risk factors for vascular dysfunction increases in women after the menopause43 — presumably owing to the postmenopausal decrease in oestrogen, a hormone with vasoprotective properties. This assumption is consistent with the finding that early menopause increases the risk of stroke. According to a meta-analysis of 310,329 women from 32 observational studies, onset of the menopause before the age of 45 years increases the relative risks of overall coronary heart disease (RR 1.50, 95% CI 1.28–1.76), overall stroke (RR 1.11, 95% CI 1.03–1.20), cardiovascular mortality (RR 1.19, 95% CI 1.08–1.31) and all-cause mortality (RR 1.12, 95% CI 1.03–1.21)44.

Hormone replacement therapy (HRT) is thought to be vasoprotective, owing to the protective properties of oestrogen, although this hypothesis has not been confirmed. A pooled analysis of results from randomized controlled trials (RCTs) of stroke prevention from the past two decades has even suggested a 30% increase in the risk of stroke in women who receive HRT45, in contrast to the apparent protection of HRT against cardiovascular disease that has been found in large observational trials46. A higher risk of stroke is also associated with a longer duration of continuous use of HRT. After 3 years of HRT use, the risk of stroke increases from 6 to 12 per 1,000 treated women. After 7 years of HRT use, the risk of stroke increased to 25–40 per 1000 women47.

Results from observational and interventional studies of HRT have differed considerably. In the observational studies, HRT was generally initiated at the onset of menopause, whereas women in RCTs were often enrolled a decade or more after menopause. This discrepancy has led to the 'timing hypothesis', which proposes that HRT has different effects on the cardiovascular system at different ages and stages of cardiovascular health. Potential vasoprotective effects of oestrogen include beneficial effects on the vascular endothelium and on cardiovascular disease risk factors48. Oestrogen has been hypothesized to have a beneficial role in early atherogenesis and an adverse role later in the disease course49. This idea has led to studies investigating cardiovascular health in women early after menopause, with a focus on atherogenesis as an endpoint. However, no substantial effect of HRT on increase in carotid artery intima–media thickness (CIMT) was documented: initiation of HRT 6–36 months after last menses did not affect CIMT compared with placebo during a 48-month follow-up50.

In the ELITE (Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol) trial, HRT initiated within 6 years after menopause led to a significantly smaller increase in CIMT after 5 years follow-up than did initiation of HRT 10 years or later after menopause, independent of progesterone treatment51. These data suggest that early initiation of HRT could be associated with a lower risk of stroke than later initiation.

A nested case–control study undertaken in France also examined the risk of transdermal HRT in women aged 51–62 years. No association was found between ischaemic stroke and use of progesterone (OR 0.78, 95% CI 0.49–1.26), pregnanes (OR 1.00, 95% CI 0.60–1.67), or nortestosterones (OR 1.26, 95% CI 0.62–2.58), whereas norpregnanes increased the risk of ischaemic stroke (OR 2.25, 95% CI 1.05–4.81)52. These results are consistent with a previous case-nested control study that found no increased risk of stroke with transdermal HRT53. Future studies assessing the effects of HRT early after menopause should focus on robust clinical endpoints that enable personalization of treatment on the basis of individual risk.

Age over 80 years

Elderly women represent a large proportion of the total population with stroke, and have more-severe strokes54, poorer outcome55, 56, 57 and more-limited access to care58 than other demographics. Secondary prevention is far from optimal in this high-risk group: compared with other groups, elderly women have a decreased likelihood of having adequate blood pressure control after stroke59, being treated with antithrombotic drugs, and receiving anticoagulation treatment when found to have atrial fibrillation57. Management of atrial fibrillation is crucial if we are to decrease the burden of stroke among elderly women, but data on this issue remain insufficient and conflicting60, 61. One study found that women had an increased risk of stroke and a reduced quality of life compared with men despite similar anticoagulation use62. The paucity of data that RCTs have generated about elderly women might contribute to these difficulties; consequently, more research into stroke in elderly women is urgently required. Future studies should focus on how treatment and interventions affect quality of life and cardiovascular outcomes of atrial fibrillation in women.

Psychosocial factors and depression

An increased risk of stroke has inconsistently been reported in individuals exposed to various psychosocial stressors. Psychosocial factors can include processes that are psychological (such as depression), behavioural (such as gender roles), vocational (such as work strain), and interpersonal (such as social support at work). These factors can also encompass social disruption (such as the depopulation of rural areas), social status (such as economic, education or heritage factors) and integration (for example, a lack of inclusion of women into society). A meta-analysis of 10,130 incidences of stroke found that people with perceived psychosocial stress — including self-reported sensations of tension, irritability, nervousness, anxiety or sleeplessness associated with poor health, family relationships, living arrangements, finance, work and stressful life events — had an increased risk of stroke (HR 1.33, 95% CI 1.17–1.50), with a larger increase in risk in women than in men63. The Chicago Health and Aging Project assessed psychosocial distress as a composite measure of depressive symptoms, perceived stress, neuroticism, and life dissatisfaction, and reported that a high distress score in elderly individuals was associated with an increased risk of death from stroke, after adjustment for age, race and sex. In this population, women reported higher distress scores than did men64.

Depression is a documented risk factor for stroke, and research has indicated a 'dose-dependent' association between higher stroke risk and higher severity of depression65. An analysis based on a nationwide sample in Sweden reported that depression was predictive of stroke (OR 1.22, 95% CI 1.08–1.38), and that the effect of depression on stroke was higher in men than in women (the difference in OR between men and women was 1.30; 95% CI 1.01–1.68)66. Depression could be associated with an increased risk of stroke through a variety of mechanisms. Depression has known neuroendocrine effects (such as dysregulation of the hypothalamic–pituitary–adrenocortical axis)67, and immunological or inflammatory effects68. Moreover, depression can be associated with poor health behaviours that might increase stroke risk: in a cohort of >80,000 nurses in the USA, women with depression were more likely to be single, had a higher BMI, were more likely to smoke cigarettes, and were less likely to be physically active44. Whatever the mechanisms are, the idea that women with depression could have an increased risk of stroke deserves more recognition. Further research is necessary to determine whether the risk associated with depression can be reduced by specific interventions. The role of negative historical events (such as war or tsunami) on the risk of stroke and the mechanisms of these effects among women also requires further investigation.

According to the Demand–Control Model of job stress, high-strain jobs are defined as those characterized by high psychological strain and low control. In a meta-analysis of prospective cohort studies, a questionnaire was used to assess the characteristics of jobs using the Demand–Control Model, and showed that women with high-strain jobs had a higher risk of stroke than did women with low-strain jobs (RR 1.33, 95% CI 1.04–1.69); this difference was not observed in men69, 70. However, the data are scarce and conflicting, and the influence of cultural habits (for example, the extent of additional daily responsibilities held by women at home) has not been explored71.

Socioeconomic status has also been associated with stroke risk. In a Danish nationwide study, the lowest-income group had double the risk of stroke compared with the highest-income group72. No sex differences were reported in this study, despite the fact that the women more often had low income, only basic education and were older than the men studied73. Moreover, low education, consistently low income and consistent financial strain predicted increasing CIMT in a cohort of women, even after adjustment for standard cardiovascular risk factors74.

Living alone increases the risk of dying from stroke in men but not women who are younger than 70 years of age (HR 3.47, 95% CI 2.13–5.65)75. Men also seem to be more vulnerable than women to unemployment as a stressor76. With regards to ambient stressors, pollution has been reported to affect the risk of stroke in women, but not in men, and has a greater effect on women with obesity77.

Cerebral venous thrombosis

Cerebral venous thrombosis (CVT) has a female preponderance of 75%78, with a 68% preponderance of female patients reported for isolated cortical vein thrombosis79. The sex distribution of CVT has shifted over time towards a larger proportion of affected women80, possibly owing to increased use of hormonal contraception by women. The 65% of women with stroke who have sex-specific risk factors (such as use of hormonal contraception, pregnancy, post-partum risk factors and use of HRT) have a much better prognosis after CVT than other women and men78, although differences in recanalization rates have not been observed81. Women more often have headache at the onset of CVT, and less often a head or neck infection82. Hormonal contraception remains the most frequent single risk factor for CVT, and doubles the risk of any venous thromboembolism (that is, CVT, deep vein thrombosis or pulmonary embolism)83. The risk of CVT increases in pregnancy, with most cases occurring during the post-partum period, and risk factors include caesarean section, dehydration and dural puncture after anaesthesia. CVT in early pregnancy is often due to inherited thrombophilias. Treatment with low-molecular-weight heparin is recommended as the safest option during pregnancy and the puerperium84. In women with previous CVT, the absolute risk of pregnancy-related CVT is one in 217 pregnancies, and the risk of noncerebral venous thromboembolism (VTE) is one in 37 pregnancies84. The risk of CVT is acceptably low in the case of subsequent pregnancy in women who previously had CVT when these individuals have access to good care; however, the risk of other VTE is high, and prophylaxis should be considered. Data are needed on the incidence of inherited thrombophilia and prevention of CVT in high-risk patients. RCTs or high-quality registry data are needed to better assess interventions. Similarly to many other rare conditions, guidelines are key for standardizing the management of CVT in women worldwide.

Haemorrhagic strokes

Data regarding sex differences in spontaneous ICH are limited. Available data are based mostly on single-centre hospital registries, and differences across the populations — such as age, ethnicity and location — might contribute to the inconsistent results. Independent of age and stroke severity, women with ICH are treated less aggressively than men. Do-not-resuscitate orders are more common for women85, and women are less likely than men to be admitted to intensive care units86.

Although data are inconsistent, women seem to have a worse prognosis than men overall. Studies have found that women have an increased risk of dependency87, and an increased risk of the combined end-point of death or dependency86. However, a meta-analysis from 2010 that was based on 4,658 patients with ICH recruited before the year 2000 found no difference in mortality between men and women88. Mortality ranged from 16–52% in women and 19–48% in men. Similar results have also been seen in subsequent studies86. Nevertheless, other studies have reported an overall lower89, 90 or higher risk of death in women than in men91.

ICH outcome in women versus men is influenced by age92, prestroke functional status and stroke severity87. Evidence increasingly suggests that sex-specific effects of genetic polymorphisms could play a part in sex differences in both the risk and outcome of ICH93.

Haematoma location might also differ between the sexes. In a prospective hospital registry of 515 patients with ICH in Spain, lobar haematoma location was more common in women (age-adjusted OR 1.75, 95% CI 1.18–2.58)86. No sex differences in cerebral amyloid angiopathy or hypertension were detected at baseline, suggesting explanations other than aetiology86. Despite the association with outcome, no sex differences in haematoma volume or expansion have been identified; however, women might have a smaller volume of perihaematomal oedema than men94.

No efficient acute treatment currently exists for ICH95. Trials have been neutral, male-dominated, and most have not reported subgroup analysis according to sex. The most promising treatment has been acute and intensive lowering of blood pressure96. A small trial suggested an association between a faster rate of blood pressure decline and mortality in men, but not in women97; however, large-scale clinical trials have not shown differential effects of blood-pressure-lowering treatment in subgroups according to sex96, 98. Large-scale cohort studies are required to identify specific risk factors for ICH in women. Data are also needed to confirm whether women have a worse outcome following ICH than men — independent of age and premorbid functional status — and whether this difference is related to difference in care.

Long-term consequences

Research has indicated that intravenous thrombolysis has less effect on functional outcome after stroke in women than in men, even after adjustment for age99. Consequently, women are more likely to be discharged with more-severe neurological deficits than men. In a Dutch study of young patients with ischaemic stroke (aged 18–50 years), women had a twofold to threefold higher risk of a poor functional outcome than men during 13 years of follow up100. Other studies have shown no such difference101, and extrapolation of results is difficult because confounding factors, such as access to acute care or rehabilitation, should also be taken into account.

Return to work after stroke is an important factor for overall life satisfaction in men and women of working age102. Nevertheless, in Sweden, men are more likely to be unhappy than women if they cannot return to work103, and data from Australia104 and Denmark105 suggest that women are less likely to return to work than men. Stroke severity is not the only factor that predicts the return to work after stroke: work characteristics (such as its physicality or time demands) and national healthcare policies (such as the duration of official sick-leave permitted), which differ drastically across countries, are also important.

Suicide after stroke might reflect the effect of the stroke on the life situation of the individual. A study from Sweden indicated that young men were more likely to attempt suicide after a stroke than were women106, in contrast to an earlier Danish study in which women had a higher risk of suicide107. However, in both studies, people younger than 50 years of age were more at risk than were older individuals.

Although no evidence currently supports sex disparities in cognition after stroke, women are at an increased risk of neurodegenerative dementia after stroke108; one proposed explanation of this disparity is that stroke onset occurs at an older age in women than in men. The occurrence of stroke has a substantial effect on the absolute risk of dementia in the general population; therefore, the prevention of stroke could reduce the rate of dementia109. However, the older age at stroke onset and the higher prevalence of mood symptoms after stroke in women than men could affect cognitive performance directly110. Studies have reported a lower quality of life in women than in men after stroke on the basis of self-reported generic health factors, such as mobility, self-care, pain, discomfort, anxiety and depression. Despite the fact that rates of fatigue after stroke seem higher in women than in men, this trend disappears when age is adjusted for in a population-based setting111, 112, 113. Further research is required to understand the so-called invisible handicaps after stroke — such as cognitive impairment, lack of initiative and extreme fatigue — particularly regarding the possible sex disparities that are not explained by age.

Stroke symptoms and risks

Prompt recognition of stroke symptoms is crucial for timely treatment. Women have a longer delay to treatment114, arrive later to hospitals, and less frequently receive acute stroke treatment and diagnostic investigation than men115, 116. Reasons for these delays are unclear, although they might be due in part to sex-related differences in clinical presentation and differences in patients' knowledge of stroke and response to symptoms56.

Several studies have sought to evaluate knowledge of stroke symptoms and risk factors among the general population, but few have focused on sex differences. Women have been reported to possess a better knowledge of major stroke symptoms and stroke risk factors than men117. Moreover, in contrast to men, women have been shown to learn from health behaviour and stroke campaigns independently of their educational background, possibly owing to a greater average interest in health topics among women than among men117.

Despite a better awareness of stroke, women are less likely to call an ambulance for themselves and are more likely to have an unknown time of stroke onset than are men118. These differences remain after adjustment for age, residence or socioeconomic level — factors known to be associated with a more appropriate response to stroke119. This gap between knowledge and health behaviour is possibly due to societal factors. Specifically, women with stroke in low-income countries tend not to be admitted to hospitals9. Absence of universal health care systems — as well as a lack of stroke units, stroke care pathways and stroke guidelines — makes treatment more difficult to deliver in women than in men. Moreover, limited access to education and adequate health care in some societies leads to inequality of care between the sexes, independently of the knowledge of stroke symptoms9.

Improved control of risk factors for stroke, better treatment, and implementation of specific stroke guidelines for women are needed to reduce stroke incidence in women. These initiatives will be complemented by stroke awareness programs, such as the “I am woman” campaign by the World Stroke Organization, which focused on the burden of stroke among women, including the responsibility of being the primary caregiver for a family member recovering from a stroke45, 120. Specific campaigns regarding stroke in women are needed that include instructions on stroke symptoms and information on time-dependent therapeutic options. These campaigns need to be tailored to different societal models worldwide.

Inclusion in clinical trials

To date, most RCTs and meta-analyses on the use of antithrombotic agents in cerebrovascular disease have neither performed subanalyses on sex-related differences nor adequately represented women in their samples. One exception is the Women's Health Study, which showed that aspirin was effective in the primary prevention of ischaemic stroke among women, without a substantial increase in ICH121. On the other hand, the Men's Health Study reported that aspirin was effective among men in the primary prevention of myocardial infarction, but with a slight increase in the risk of ICH122.

Healthcare authorities sought to rectify the low representation of women in clinical trials with the introduction of the NIH Revitalization Act in 1993, which urged the inclusion of women in RCTs123. In 2005, the European Society of Cardiology and the European Medicines Agency recommended that there should be a meaningful representation of women in clinical trials124. In 2016, the Motion for a European Parliament Resolution on promoting sex equality in mental health and clinical research (2016/2096 (INI)) underlined the fact that clinical trials of pharmaceutical products on both men and women are necessary, and that these should be inclusive, nondiscriminatory and performed under conditions of equality and inclusion125. Unfortunately, the male:female ratio in stroke trials still does not reflect the real-world demographics of stroke.

Trials from the past few years that focused on novel oral anticoagulants (NOACs) illustrate the current situation. NOACs were evaluated in seven RCTs, in which less than 40% of the people enrolled were women126. To correspond with epidemiological data, more than 50% of the patients in these RCTs should have been women: firstly, because female sex is recognized as a risk factor in the CHA2DS2-VASc score for systemic embolism127, and secondly because cardioembolic strokes have a higher fatality rate at 1 month poststroke in women than in men128. These seven RCTs did not report any sex differences concerning the safety and efficacy of the NOACs. However, the overall mean age of the included patients was 71.5 years, almost 4 years lower than the average age of women admitted for cardioembolic strokes129.

Women might be more difficult to include in RCTs than men because they tend to be older at stroke onset, have more comorbidities, and are more likely to have pre-existing functional impairment. Moreover, they are more likely to live alone than are men. These factors might affect the availability of a representative who can give consent for treatment if they lack the capacity to give consent themselves. Social aspects also need to be considered: women tend to be the caregivers in families, and in many societies, decisions regarding women's health still depend on men. To foster the inclusion of women in clinical trials, age exclusions should be considered only in light of safety considerations and not as an arbitrary age cut-off. Indeed, trials often do not need to have an age restriction: instead, designs should include comorbidities or other health conditions to mirror the sex distribution of the disease investigated. Consequently, trials must be adequately powered or use stratified randomization by sex to enable the investigation of sex differences in treatment efficacy.

Access to care

Across the globe, access to stroke care seems to be more difficult for women than men. Key treatments such as intravenous thrombolysis are less likely to be offered to elderly women than to members of other demographics. Despite the fact that evidence indicates that older women benefit from thrombolysis as much as older men130, women are more likely to be excluded from thrombolysis treatment (38%) than men (19%) if they are over 80 years of age131.

Data from a range of clinical settings and from several countries around the world suggest that secondary prevention of stroke also varies between men and women. In a community setting in South America, men were more likely to receive adequate cardiovascular prevention than were women132. This finding was also reported in a primary care setting in northern Sweden, where women were less likely to receive statins than were men133. Whether secondary prevention of stroke in patients with atrial fibrillation differs between men and women remains unclear, and results vary geographically. In Germany134, women were less likely to receive adequate antithrombotic treatment than were men, whereas in Sweden135, sex had no effect on secondary treatment, but other socioeconomic factors, such as level of education or income, did have an effect.

Data regarding access to rehabilitation after stroke are lacking, and a huge variability in access is observed across different countries and healthcare systems. For example, a comparison between specialized rehabilitation in Latvia and Sweden showed that Latvian men were more likely to be admitted to rehabilitation than were Latvian women, whereas in Sweden, equal access to rehabilitation was observed136. This finding is in contrast to the UN Convention on the Rights of Persons with Disabilities, which highlights the vulnerability ofwomen to disabilities137. Besides access to rehabilitation, women tend to be discharged from specialized rehabilitation units despite having a remaining need for support138. In developing countries, access to rehabilitation is even more difficult: for example, only one stroke unit exists in sub-Saharan Africa139. In summary, barriers for access to care and rehabilitation for women should be identified, and equal access provided.

Conclusions

Stroke is the leading cause of death and disability in women, who have worse outcomes after stroke than do men. Risk factors differ between men and women and across age groups, and specific stroke subtypes, such as cardioembolic strokes, are more common in women than in men.

Personalized medicine is needed to improve prevention and treatment of stroke in women. Little is known about the treatment and prognosis of stroke subtypes that are specific to women. Stroke is very prevalent in older women; however, women, especially older women, are under-represented in clinical trials, resulting in a paucity of evidence in this group. Further research is needed to establish why outcomes are worse in women than in men, and to identify effective interventions to reduce the unequal burden of stroke in women. In many countries, the position of women in society might influence their access to care, which could contribute to the poor outcome of women undergoing a stroke worldwide.

Publisher's note

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Author information

Affiliations

  1. University of Lille, INSERM U1171, Degenerative & vascular cognitive disorders, Centre Hospitalier Universitaire, Department of Neurology, F-59000 Lille, France.

    • Charlotte Cordonnier
  2. Division of Clinical Neurosciences, University of Nottingham, Hucknall Road, NG5 1PB, UK.

    • Nikola Sprigg
  3. Department of Neurology, Oslo University Hospital, Oslo, Norway and the George Institute of Public Health, Sydney, Australia.

    • Else Charlotte Sandset
  4. Neurology Clinic, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotica 6, Belgrade 11000, Serbia.

    • Aleksandra Pavlovic
  5. Rehabilitation Medicine, Sect for Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Blå Stråket 7, University of Gothenburg, Gothenburg, 41345, Sweden.

    • Katharina S. Sunnerhagen
  6. Stroke Unit, Santa Maria della Misericordia Hospital, University of Perugia, Via E. Dottori, 06156 Perugia, Italy.

    • Valeria Caso
  7. Department of Neurology, Bispebjerg og Frederiksberg Hospital, Bispebjerg Bakke 23, University of Copenhagen, 2400 NV, Denmark.

    • Hanne Christensen

Consortia

  1. the Women Initiative for Stroke in Europe (WISE) group

Contributions

All authors helped research data for this Review and made substantial contribution to the discussion of the content. C.C., N.S., E.S., A.P., K.S., V.C. and H.C. wrote the article. C.C., N.S., E.S. and H.C. reviewed and/or edited the manuscript before submission.

Competing interests statement

The authors declare no competing interests.

Corresponding author

Correspondence to:

Author details

  • Charlotte Cordonnier

    Charlotte Cordonnier gained her MD in neurology in 2003, her PhD in neuroscience in 2007, and was appointed as Professor of Neurology in 2012 at Lille University, France. Currently, she is the Head of the Department of Neurology & Stroke Center at Lille University Hospital, France. She has published over 150 papers. Her main topic of research is stroke, with a speciality in haemorrhagic stroke. Since 2016, she has been the Vice-President of the European Stroke Organisation. She is also a member of the Institut Universitaire de France.

  • Nikola Sprigg

    Nikola Sprigg undertook her medical training in Sheffield, Leicester and Nottingham, UK. She is currently Associate Professor of Stroke Medicine at Nottingham University, and an Honorary Consultant Physician in Stroke Medicine for Nottingham University Hospitals Trust. Her current interests include developing treatments to improve recovery after stroke, treatment of haemorrhagic stroke, quality of life after stroke, management of blood pressure after stroke, venous thrombosis prophylaxis after stroke and antiplatelet treatment for the secondary prevention of stroke. She is a Fellow of the Royal College of Physicians and a member of the Board of Directors of the European Stroke Organisation.

  • Else Charlotte Sandset

    Else Charlotte Sandset is a neurologist and postdoctoral fellow at the Department of Neurology, Oslo University Hospital, Norway. She received her undergraduate medical degree from the Royal College of Surgeons, Republic of Ireland, in 2006, and her PhD from the University of Oslo, Norway, in 2012. Her main area of interest is acute stroke, with special emphasis on haemodynamic variables, such as blood pressure. She is Chair of the Young Stroke Physician Committee of the European Stroke Organisation.

  • Aleksandra Pavlovic

    Aleksandra Pavlovic is a consultant neurologist at the Neurology Clinic of the Clinical Center of Serbia in Belgrade and an Assistant in Neurology at the Faculty of Medicine, University of Belgrade, Serbia. She received her PhD in neurology in 1999, completing her doctoral thesis on cerebral small vessel disease. Her research interest focuses mainly on small vessel disease, vascular cognitive impairment, dementia, neurosonology and behavioural neurology. She has published over 50 peer-reviewed papers and co-authored four books on these topics. She is Chair of the European Stroke Organisation research group Women Initiative for Stroke in Europe (WISE).

  • Katharina S. Sunnerhagen

    Katharina S. Sunnerhagen is professor and chair in Rehabilitation Medicine at the University of Gothenburg, Sweden, and senior consultant at Sahlgrenska University Hospital, Sweden. She has been active in stroke care and research since the early 1990s and has been involved in longitudinal studies as well as intervention studies, covering muscle function, spasticity, cognition, life situation and use of new technology. She has authored more than 180 papers. She is a member of the Board of Directors of the European Stroke Organisation. She is also European Society of Physical and Rehabiliation Medicine Senior Fellow.

  • Valeria Caso

    Valeria Caso is a stroke neurologist and associate professor in neurology at the University of Perugia Stroke Unit, Italy. She is currently president of the European Stroke Organisation. She is actively involved in international research projects on cervical artery dissections, heart and brain, intracerebral haemorrhage, and acute stroke treatment. She has a strong interest in the treatment and prevention of stroke in women, and has been involved in guidelines for the management of stroke in women.

  • Hanne Christensen

    Hanne Christensen is professor of neurology with a special focus on stroke at Copenhagen University, Denmark, and senior stroke consultant at Bispebjerg Hospital, Copenhagen, Denmark. She has been involved in stroke care and research for almost 20 years and her current interests focus mainly on acute stroke care, including intracerebral haemorrhage. She is Chairperson of the Danish Stroke Society and Chair of the Council of Fellows, European Stroke Organisation.

  • the Women Initiative for Stroke in Europe (WISE) group

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