Cerebrovascular disease in women

Pregnancy

The peripartum period confers a high risk of stroke, with an estimated incidence of about 30 cases per 100,000 deliveries. ²³ HDP are the leading cause of both IS and ICH in pregnant and postpartum women.^24,25 Pregnant women with ICH have fewer traditional risk factors, comorbidities, and tend to have a better outcome than their non-pregnant counterparts. ²⁶

Pregnancy-related complications like gestational diabetes and HDP are associated with a higher risk for stroke and future cardiovascular disease (CVD), a risk that extends beyond childbearing age.^27,28 A 2012 study reported over 13-fold increased odds of an adverse cardiovascular event within 10 years of pregnancy in women with history of preeclampsia compared with women with uncomplicated pregnancies. The lifetime risk was reported to be 3.25-fold higher. ²⁹

Notably, despite no absolute contraindication to therapy, pregnant women with IS are less likely to receive thrombolysis with tissue plasminogen activator (tPA) therapy by almost 3.5%, per the ‘Get with the guidelines’ data. ³⁰

Oral contraceptives

In the US, four out of five sexually active women have taken hormonal contraception. ³⁷ Although the crude incidence of stroke associated with hormonal contraception is low at 21.4 per 100,000 person-years, multiple studies and meta-analysis have shown an almost 2.5-fold increased risk of IS in women who take oral contraceptives (OCs). ³⁸ This is more notable in older women, increasing to about 64.4 per 100,000 person-years in women aged 45–49 years. ³⁹ A meta-analysis of studies from 1980 to 2002 limited to low-dose combined OCs (second and third generation only) also showed 2.12-fold odds of having an IS. ⁴⁰ Studies on progestin-only hormonal contraception have not shown any significant increase in stroke risk. ⁴¹

Longitudinal data from a Danish study concluded that among the 10,000 women included in the study, and who were taking a 20 μg dose of desogestrel with ethinyl estradiol for 1 year, two women will have arterial thrombosis and 6.8 will have venous thrombosis. ³⁸ Another Swedish study which included 49,259 women followed for more than a decade, did not find any association between the use of OCs and incident stroke (ischemic and hemorrhagic), in the 285 cases of stroke that occurred during the study. ⁴²

Data on ICH and OC use are far less consistent, with some reports of a higher risk noted in developing countries. A study of Chinese women evaluated single-nucleotide polymorphisms (SNPs) and the association between OC use and stroke risk and found that women with rs10958409 GA/AA (located near SOX17, a transcription factor that modulates cardiovascular development and endothelial cell biology) or rs1333040 CT/TT genotypes (associated with risk of intracranial aneurysm) had an increased overall risk of stroke, with the rs1333040 SNP only increasing the risk for ICH. ⁴³

Age at menarche

In the Million Women Study from the United Kingdom, a U-shaped relationship between age at menarche and cerebrovascular disease was observed. Women who experienced menarche at age ⩽10 years and at ⩾17 years of age, were at higher risk of having a stroke compared with those who had menarche at age 13. ⁴⁶ Some studies have shown an association between early menarche and increased cardiovascular risk but not all. As many of the studies rely on self-reported data, and many other confounding factors (i.e. obesity) may influence stroke risk, ⁴⁷ the link between age of menarche and ‘exposure years’ to gonadal hormones remains unclear.

Menopause and postmenopausal hormonal therapy

Menopause is associated with a decrease in estrogen and an increase in the risk of cardiovascular and cerebrovascular disease, a risk that is clearly also linked to aging. According to a meta-analysis of over 300,000 women, early onset of menopause (<45 years), increases relative risk of coronary artery disease, stroke, and all-cause mortality. ⁴⁸

The hypothesized vasoprotective role of estrogen did not translate into direct clinical benefit in women who were treated with hormonal therapy (HT) after menopause. In fact, results from multiple randomized controlled trials (RCTs) of stroke prevention suggested an almost 30% increase in stroke risk with HT despite some protection against CVD noted in observational studies. ³ After 3 years of HT, the risk of stroke increases from 6 to 6–12 per 1000 treated women. After 7 years, it increases from 24 to 25–40 per 1000 women. ⁴⁹ However, the timing of initiation of HT has differed between observational studies and RCTs, with early initiation at the start of menopause in observational studies which showed benefit, and late enrollment of women in RCTs, up to a decade or more after menopause, showing increased risk. It has since been hypothesized that HT may have beneficial vasoprotective effects, decreasing stroke risk, only when started early after menopause. ⁵⁰ Estrogen has also been hypothesized to have a beneficial effect in slowing atherogenesis but an adverse role later in the disease course. ⁵¹

In the ELITE (Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol) trial, HT initiated within 6 years after menopause led to a significantly lower increase in carotid intima-media thickness (CIMT) after 5 years follow up than did initiation of HT 10 years or later after menopause, independent of progesterone treatment. ⁵² Most recently, the results of the Kronos Early Estrogen Prevention Study of women 42–58 years of age, within 36 months of their final menstrual period and randomized to receive different formulations of HT, did not show any effect of HT on progression of CIMT. No adverse cardiac events, venous thrombosis, or adverse increase in systolic BP were noted. ⁵³ At this point, it remains unclear if HT could be beneficial or harmful, and current guidelines recommend limiting their use for short periods during the menopausal transition, primarily for menopausal symptoms.

Hypertension

Hypertension is the most common modifiable risk factor for stroke in both men and women and has the highest population-attributable risk. ⁵⁴ Multiple analyses have shown that intensive BP control is the most beneficial for stroke risk reduction.^55,56 Studies have shown that postmenopausal women are more likely to have hypertension than men, and have a higher risk of first stroke with hypertension. About 75% of women >60 years of age become hypertensive. ³ Hypertensive women are more likely than men to be treated for their hypertension but less likely to achieve BP control. Differences in vascular physiology, arterial stiffness, and vascular compliance may possibly contribute to this discrepancy.^57,58 Adherence to therapy and sex differences in the effects of specific antihypertensive agents may also contribute but remain relatively unexplored.

Migraine with aura

Women are four times more likely to have migraines than men. ⁵⁹ Migraine with aura is associated with an up to 2.5-fold increase in IS, especially in those <55 years of age. ⁶⁰ Data from the Women’s Health Study showed that migraine with aura accounted for 4 additional IS cases per 10, 000 women per year, with higher risk with increasing migraine frequency, and if the aura did not include nausea and vomiting.^{61 –63} It is also associated with a higher risk of transient ischemic attack (TIA) and non-disabling stroke. ⁶⁴ In women with migraine with aura, the risk increases to ninefold in those using OCs and smoking cigarettes. This increased risk was not observed in women who did not smoke, suggesting a possibly synergistic effect of smoking and OC use in women who have migraine with aura.^65,66 Current consensus from headache and stroke experts does not preclude the use of OCs in women who suffer from migraine with aura, although caution is warranted. ³ Screening for all traditional stroke risk factors is recommended.

Metabolic syndrome, obesity, and lifestyle factors

Metabolic syndrome is a combination of cardiometabolic risk factors that includes insulin resistance, abdominal adiposity, dyslipidemia, and hypertension. Studies suggest that metabolic syndrome may account for a higher percentage of stroke events in women than men, 30% versus 4%. ⁶⁷ An analysis of data from the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2012 revealed that the prevalence of metabolic syndrome among women increased from 25.0% during 1988–1994 to 34.9% during 2007–2012. During the entire study period, the largest increase in the prevalence of metabolic syndrome was observed among non-Hispanic Black men (55%), then non-Hispanic White women (44%), and non-Hispanic Black women (41%), while the smallest increase was observed among Mexican American women (2%). Strikingly, the prevalence of metabolic syndrome increased from about 10% among those aged 18–29 years for all racial/ethnic groups to almost 70% among women aged 70 or older in 2007–2012. The component with the most significant increase during the study period was the prevalence of elevated waist circumference (>88 cm in women and >102 cm in men), from 23.6% in 1988–1994 to 42.6% in 2007–2012 in men, and from 38.2% to 60.9% in women. ⁶⁸

Studies have revealed an almost linear increase in stroke risk with increasing body mass index. Obesity affects stroke risk almost equally in both men and women, even after adjustment for factors such as age, physical activity, smoking, alcohol consumption, and comorbid conditions such as hypertension and diabetes mellitus.^{69 –72} However, abdominal obesity has a stronger correlation with insulin resistance, diabetes, and CVD, impacting women more, given its higher prevalence.^68,73 Studies in women have shown about a 2% relative increase in total stroke risk with each single-unit increase in waist circumference. ⁷⁴ The biological pathways by which abdominal adiposity contributes to increased stroke risk are not fully understood, but endothelial dysfunction, platelet and immune system activation, increased very-low-density lipoprotein production, and an overactive endocannabinoid system may all have roles to play. ⁷⁵

Atrial fibrillation

AF increases IS risk by 4–5-fold in both sexes, and is associated with higher morbidity and mortality. ⁵⁴ This risk increases with age, with an attributable risk of about 1.5% in those aged 50–59 years, to almost 25% among persons aged ⩾80 years.^54,76 About 60% of AF patients >75 years of age are women. ⁷⁷ Given current population dynamics and increasing prevalence of AF with age, there will be an increasing number of women with AF as the population ages. In Get With The Guidelines-Stroke, a third of hospital admissions for stroke were for stroke patients ⩾80 years of age, and AF was identified in ~5% more women than men. ⁷⁸

Stroke risk with AF can be stratified using the CHA2DS2-VASc score, and female sex is an independent predictor of stroke risk. ⁷⁹ Several large studies of non-valvular AF have confirmed a higher stroke risk in women ⩾75 years with AF compared with men, even in those taking warfarin.^80,81 However, more recently, warfarin use was associated with a greater stroke reduction in women by about 20%. ⁸²

Despite this, studies have shown that women are significantly less likely than men to use any oral anticoagulant at all levels of thromboembolic risk.^83,84 Higher rates of bleeding in women taking warfarin, provider bias, concerns about frailty and higher fall risk, and older age at the time of stroke may all be potential reasons for this discrepancy. No sex differences in safety or efficacy have been reported in the multiple RCTs of novel oral anticoagulants (NOACs) in AF and stroke prevention. ⁵⁰ However, women represented <40% of the secondary prevention subgroups in most of these trials, ⁸⁵ being as low as <20% in some. ⁸⁶ It is also important to be mindful of dose adjustments with some NOACs like apixaban in patients aged ⩾80 years, weight ⩽60 kg and serum creatinine ⩾1.5 mg/dl (two out of three), which may be more likely in women. In women with contraindications for anticoagulation, left atrial appendage closure with the use of a Watchman device is a viable option. Data are emerging on its safety in both sexes and there may be a greater improvement of mobility, self-care, and resumption of usual activities in female patients compared with men, presumably from discontinuation of anticoagulation. ⁸⁷ Low-dose edoxaban may be a safe option for stroke prevention in elderly women who otherwise may not have been candidates for oral anticoagulation. ⁸⁸

Age over 80 years

Elderly women represent an especially vulnerable cohort of the population with more severe strokes, poorer outcomes, higher rates of institutionalization and more limited access to healthcare. ⁵⁰ Analysis of multiple studies in stroke have shown that they are also less likely to have optimal BP control after stroke and to receive anticoagulation for AF to prevent subsequent strokes.^89,90

Social factors

In women, social factors such as education, gender roles, social support, integration into society, and education, have an influence on stroke risk and outcomes, as they directly influence access to preventative health care as well as acute treatment. In particular, perceived psychosocial stress associated with family relationships, living situation, finances, and stressful life events, was associated with an increased risk of stroke in both men and women, but with a greater increase in women. ⁵⁰

Vascular aging

Age-related changes in vascular function generally include endothelial dysfunction and arterial stiffness, accompanied by increasing systolic BP and pulse pressure. ⁹¹ This progresses at a faster rate in women than men after the sixth decade of life. Postmenopausal women have stiffer arteries than their male counterparts, which is consistent with higher rates of hypertension in women than men after the age of 65. ⁹²

CIMT, coronary artery calcification, and carotid atherosclerotic plaques all increase in prevalence with advancing age.^93,94 Women are less likely than men to have severe, flow-limiting plaques. ⁹⁵ In women, the prevalence of typical obstructive coronary disease is low prior to menopause and then increases dramatically after age 50, affecting up to 79% of women age 75 or older. Women are more likely to have microvascular and/or endothelial dysfunction, and are overall more likely to suffer angina and acute coronary syndromes in the presence of non-obstructive coronary artery disease. ⁹²

Thrombolysis and mechanical thrombectomy

Prior studies have shown that women have a longer time from symptom onset to hospital arrival, more delays in thrombolytic treatment, and receive appropriate diagnostic evaluation and thrombolytic treatment for stroke less frequently than men.^101,102 In a study spanning over a decade (1997–2006), men were more likely than women to receive intravenous tPA, angioplasty/stents, carotid endarterectomy, or cardiac reperfusion. However, toward the end of the study period, sex differences in the use of intravenous (IV) tPA were no longer present. ¹⁰³ Reasons for these differences are unclear, although they might be due in part to sex-related differences in clinical presentation, timing of presentation, differences in patients’ knowledge of stroke and response to symptoms, and physician perception of patients. Many of these gaps in care are closing, possibly due to increased education efforts for both patients and providers.

Overall, evidence that thrombolytic therapy may have increased efficacy in women compared with men has largely been surmised from the absence of sex differences in 90-day functional outcomes after thrombolysis despite more severe strokes, older age, and higher prevalence of AF and hypertension in women, perhaps due to a greater tendency for recanalization of small cardioembolic clots.^{104 –106} A small study of 100 patients found higher rates of recanalization after tPA for anterior circulation strokes among women than men despite comparable age, BP, symptom-to-needle time, and stroke etiology. ¹⁰⁷ In addition, neurological improvement within 72 h of treatment occurred significantly more frequently in women. Data from the Safe Implementation of Treatments in Stroke- International Stroke Thrombolysis Register (SITS-ISTR) which included 45,079 patients (42.8% women), also suggested greater benefit of thrombolysis in women, and a higher mortality and rate of symptomatic ICH in men. ¹⁰⁸ On the other hand, an analysis of data from multiple European registries revealed that women had 1.15-fold odds of poor functional outcome after IV thrombolysis compared with men, independent of age. ¹⁰⁹ A more recent pooled analysis of thrombolysis outcomes from Asian stroke registries also found that women were more likely to have a cardioembolic stroke, more severe neurological deficits after stroke, and a worse functional outcome after thrombolysis, especially in in women aged >70 years. ¹¹⁰ The retrospective nature of these studies, potentially unaccounted confounders, lower tPA dose, as well as ethnic differences in the cohorts studied may be responsible for these conflicting results. Further investigation is needed for a more definitive conclusion of whether thrombolytic therapy has sex-specific effects, whether this holds for ‘newer’ thrombolytic agents like tenecteplase, and the potential mechanisms of these differences.

Endovascular thrombectomy (EVT) for acute stroke management is now standard of care in patients with large-vessel occlusions presenting in a variety of time windows with appropriate imaging characteristics. A recent analysis of data from three early EVT trials, Solitaire FR With the Intention for Thrombectomy (SWIFT), Solitaire FR Thrombectomy for Acute Revascularization (STAR), and Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) to assess sex differences in thrombectomy outcomes, found no difference in the rates of reperfusion, time to reperfusion, or adjusted rates of functional independence. However, after adjusting for age at presentation and stroke severity, females had more years of optimal life (disability-adjusted life-years) after EVT. ¹¹¹ Another analysis of data from seven RCTs on EVT within the Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration also concluded that sex did not influence outcomes after EVT. ¹¹² Older women have a higher likelihood of functional dependence and higher modified Rankin Scale (mRS) scores at baseline which may have precluded them from inclusion in some of these studies.^113,114

Outcomes

The overall impact of cerebrovascular disease is higher in women than in men. Women are institutionalized more often after stroke and have poorer recovery from stroke. Women consistently have greater long-term mortality after stroke than men, regardless of study location and time period, and controlling for pre-stroke function and stroke severity.^2,115,116

A pooled analysis of five international RCTs investigating differences in pre- and post-stroke treatments and outcomes, including the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage trials (INTERACT-1 and INTERACT-2), the Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED), the Head Position in Acute Stroke Trial (HeadPoST), and the Scandinavian Candesartan Acute Stroke Trial (SCAST), showed that women had higher odds of surviving than men after stroke (ischemic and hemorrhagic combined). This study also found that women lived with greater disability after IS, although there were no differences in disability after ICH or when both stroke types were combined. Women had poorer health-related quality of life after IS. ¹¹⁷

Another analysis pooled data from 11 international population-based studies in stroke, in 4852 survivors of stroke at 1 year (10 studies) and 2226 survivors at 5 years (7 studies), and confirmed the prior finding that women experience a lower quality of life after stroke than men. Among stroke survivors, women had more severe strokes, were older at stroke onset, and had a greater likelihood of dependency before their stroke than men. ¹¹⁸ In another study of 1370 patients who had a stroke, with a median age 65 years, women had significantly lower quality of life at 3 and 12 months after stroke, even after adjusting for important sociodemographic variables, stroke severity, and disability. ¹¹⁹ The cause of these differences needs further investigation; however, they may be in part due to advanced age, more severe strokes, higher pre-stroke dependency, and increased post-stroke depression in women. ¹²⁰

Subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is a major cause of morbidity and mortality worldwide in both sexes. Mortality rates for ruptured cerebral aneurysms continue to average near 50%, with 20% of survivors incurring severe disability. ¹⁴¹ Patients who survive the initial insult of aneurysm rupture are at risk for delayed cerebral ischemia (DCI), involving clinical deterioration, cerebral infarction and contributing to poor outcome. In women, the internal carotid artery is the most frequent site for ruptured aneurysm; however, aneurysms in the posterior communicating artery are more prevalent, overall. ¹⁴²

The incidence of intracranial aneurysms is disproportionally higher in women, and evidence also suggests that radiographic vasospasm and DCI after aSAH occur more frequently in women. ¹⁴³ Some studies have found this risk to be stratified by age, with older women >55 years having a higher risk of clinical deterioration compared with age-matched men. ⁹ A large study using pooled data from 10 studies with 6713 patients reported a greater risk of DCI in women, but no difference in the risk of cerebral infarction or outcomes. ¹⁴⁴ A more recent study of 994 patients identified female sex as an independent predictor of symptomatic vasospasm and reported that women appeared to be at greatest risk for DCI and unfavorable outcome at age 55–74 years. ¹⁴⁵ Mortality rates of female SAH patients are higher in some studies, and women also have multiple aneurysms more frequently than men.^9,146

According to prospective cohort studies, smoking is the most important lifestyle risk factor for aSAH. A recent study found a multiplicative and additive effect modification between sex and cigarette smoking, with women seemingly much more vulnerable to its deleterious effects, which may account for some of the sex differences seen in aSAH. ¹⁴⁷ Outcomes after aneurysm repair surgery have been similar in men and women. ⁹

It has been hypothesized that postmenopausal women have a higher rate of aSAH due to the loss of estrogen, which plays a role in vascular modeling and inflammation. ¹⁴⁸ Premenopausal women, especially those without a history of smoking or hypertension, are at a reduced risk for aSAH compared with age-matched postmenopausal women. A study of Japanese women after their first occurrence of aSAH found that an earlier age at menarche and nulliparity were associated with an increased risk of aSAH. ¹⁴⁹ In addition, HT was associated with a reduced risk for SAH in some studies, but not all. In preclinical studies, estrogens have been shown to attenuate cerebral vasospasm by inducing nitric oxide expression. However, groups with the highest estrogen levels also had a higher rate of radiographic vasospasm, suggesting a more complex interaction.^12,150 Change in estrogen levels may be more important than the absolute levels.

The reported frequency of aSAH in pregnant women ranges from 8 to 31/100,000 deliveries, and it is estimated to cause up to 1 in 10 of all maternal deaths. It may also be higher in pregnant African American women. Repeated childbirths are associated with an increased risk of aSAH, possibly through pregnancy-induced hypertension and vascular tension during delivery, which weakens vessels and may lead to aneurysm formation. ¹⁵¹

Reversible cerebral vasoconstriction syndrome

RCVS is characterized by recurrent severe headaches and reversible narrowing of multiple medium-sized cerebral arteries.^152,153 IS, ICH, and convexity SAH are the major complications. RCVS has a striking female preponderance, seen almost four times more commonly in women than in men in most reported case series.^154,155 Common triggers include vasoactive prescription and illicit drugs, but pregnancy is a well-known risk factor. This postpartum angiopathy usually occurs within 2 weeks post-delivery.^152,154,156 OCs and HT may also increase risk. Furthermore, women are shown to have a more severe clinical syndrome than men, with more severe focal deficits, higher frequency of clinical and radiological worsening, more widespread vasoconstriction, and a longer hospitalization. ¹⁵⁴ Female hormones have been postulated to play a role in triggering this disease; however, there are no discernible differences in the clinical course and outcomes between various female subgroups regardless of pregnancy, menopause, or hysterectomy status. ¹⁵⁴ The combined case fatality is reported to be less than 1%. ¹⁵² Long-term outcomes are usually favorable; however, some patients may have residual deficits from stroke.^152,155,157

Sex hormones and IS

Pre-clinical studies have also consistently demonstrated that stroke severity varies with sex and age. ¹⁵⁸ Young female animals have smaller infarcts after an induced stroke compared with males, but this effect is lost in ovariectomized females. ¹⁵⁹ As female rodents age, stroke damage increases and surpasses that of males in mid-life (at approximately 12 months) coincident with reproductive senescence. ¹⁶⁰ Aged female animals have a more detrimental immune response in the brain compared with age-matched males at early timepoints after stroke (i.e. 24 h); however, at later timepoints, male mice had higher mortality, profound peripheral changes in gut permeability and ongoing inflammation compared with females, despite equivalent infarct size. ¹⁶¹ Future research in this area is needed, as the majority of studies have examined only young male mice, or only relatively short endpoints.

Sex chromosomes

The influence of sex chromosomes on stroke outcomes is being increasingly recognized. Using a four-core genotype (FCG) mouse model, it has been demonstrated that the sex chromosome complement contributes to the pathology of pain, addiction behavior, and inflammation.^162,163 In these mice, Sry, the testes determining gene, is deleted from the Y chromosome and inserted on an autosome, giving an XY male (XYM) genotype. This is crossed with a wild-type female giving rise to FCG mice with different gonadal and chromosomal complements. Among young gonadally intact FCG mice subjected to middle-cerebral artery occlusion, animals that had ovaries had smaller strokes. ¹⁶³ A subsequent study of gonadectomized mice, in which both ovaries and testes were removed, discovered that all mice, regardless of chromosome compliment (XX or XY) had equivalent infarct damage, implying that ischemic sensitivity is mediated primarily by the effects of circulating gonadal hormones in young animals. Interestingly, in aged FCG mice (18–20 months of age), after gonadal senescence, mice with two X chromosomes had larger strokes than those that were XY. These results suggest that there is a detrimental effect of the second X chromosome that is only evident after reproductive senescence and imply a complex interaction between aging, ischemia, and genetics. ¹⁶⁴ Ongoing studies are examining candidate genes on the X chromosome that may be responsible for these effects.