Purpose The aim of this statement is to summarize data on stroke risk factors that are unique to and more common in women than men and to expand on the data provided in prior stroke guidelines and cardiovascular prevention guidelines for women. This guideline focuses on the risk factors unique to women, such as reproductive factors, and those that are more common in women, including migraine with aura, obesity, metabolic syndrome, and atrial fibrillation. Methods Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Stroke Council s Scientific Statement Oversight Committee and the AHA s Manuscript Oversight Committee. The panel reviewed relevant articles on adults using computerized searches of the medical literature through May 15, 2013. The evidence is organized within the context of the AHA framework and is classified according to the joint AHA/American College of Cardiology and supplementary AHA Stroke Council methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive AHA internal peer review, Stroke Council Leadership review, and Scientific Statements Oversight Committee review before consideration and approval by the AHA Science Advisory and Coordinating Committee. Results We provide current evidence, research gaps, and recommendations on risk of stroke related to preeclampsia, oral contraceptives, menopause, and hormone replacement, as well as those risk factors more common in women, such as obesity/metabolic syndrome, atrial fibrillation, and migraine with aura. Conclusions To more accurately reflect the risk of stroke in women across the lifespan, as well as the clear gaps in current risk scores, we believe a female-specific stroke risk score is warranted. (Stroke. 2014;45:1545-1588.) Key Words: AHA Scientific Statements atrial fibrillation hormone replacement therapy menopause metabolic syndrome X preeclampsia/eclampsia sex differences stroke Guidelines for the Prevention of Stroke in Women A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Endorsed by the American Association of Neurological Surgeons and Congress of Neurological Surgeons Cheryl Bushnell, MD, MHS, FAHA, Chair; Louise D. McCullough, MD, PhD, FAHA, Vice-Chair; Issam A. Awad, MD, MSc; Monique V. Chireau, MD, MPH, FAHA; Wende N. Fedder, DNP, RN, FAHA; Karen L. Furie, MD, MPH, FAHA; Virginia J. Howard, PhD, MSPH, FAHA; Judith H. Lichtman, PhD, MPH; Lynda D. Lisabeth, PhD, MPH, FAHA; Ileana L. Pi a, MD, MPH, FAHA; Mathew J. Reeves, PhD, DVM, FAHA; Kathryn M. Rexrode, MD, MPH; Gustavo Saposnik, MD, MSc, FAHA; Vineeta Singh, MD, FAHA; Amytis Towfighi, MD; Viola Vaccarino, MD, PhD; Matthew R. Walters, MD, MBChB, MSc; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Council for High Blood Pressure Research TheAmerican HeartAssociation makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 13, 2013. A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The American Heart Association requests that this document be cited as follows: Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL, Howard VJ, Lichtman JH, Lisabeth LD, Pi a IL, Reeves MJ, Rexrode KM, Saposnik G, Singh V, Towfighi A, Vaccarino V, Walters MR; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Council for High Blood Pressure Research. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:1545 1588. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/01.str.0000442009.06663.48 AHA/ASA Guideline Stroke has a large negative impact on society, with women disproportionately affected. An estimated 6.8 million (2.8%) of people in the United States are living after having had a stroke, including 3.8 million women and Stroke is the fifth-leading cause of death for men, but the third leading cause for women.2 By 2030, there will be an estimated 72 million people >65 years old (19% of the population), and women will increasingly outnumber These demographics suggest an anticipated increase of the burden of stroke in women.4 Nearly half of stroke survivors have residual deficits, including weakness or cog- nitive dysfunction, 6 months after stroke,5 which translates into 200 000 more disabled women with stroke than men. Some of the impact is explained by the fact that women live longer, and thus the lifetime risk of stroke in those aged 55 to 75 years is higher in women (20%) than men Women are more likely to be living alone and wid- owed before stroke, are more often institutionalized after stroke, and have poorer recovery from stroke than men.7 13 Therefore, women are more adversely affected by stroke than men. How our society adapts to the anticipated increase in stroke prevalence in women is vitally important. Now more than ever, it is critical to identify women at higher risk for stroke and initiate the appropriate prevention strategies. Despite the importance of stroke in women, there has never been anAmerican HeartAssociation (AHA)/American Stroke Association guideline dedicated to stroke risk and preven- tion in women. This endeavor is important because women differ from men in a multitude of ways, including genetic differences in immunity,14,15 hormonal fac- reproductive factors including pregnancy and child- birth, and social factors,5,9 all of which can influence risk for stroke and impact stroke outcomes. This document provides a new stroke prevention guideline that covers topics specific to women in more detail than has been included in current primary and secondary stroke prevention guidelines19,20 and provides more emphasis on stroke-specific issues in women than are included in the current cardiovascular prevention guideline for women.21 Writing group members were nominated by the com- mittee chair on the basis of their previous work in relevant topic areas and were approved by the AHA Stroke Council s Scientific Statement Oversight Committee and the AHA s Manuscript Oversight Committee. Multiple disciplines are represented, including neurology, neuroscience research, internal medicine, obstetrics/gynecology, cardiology, phar- macology, nursing, epidemiology, and public policy. The panel reviewed relevant articles on adults using computer- ized searches of the medical literature through May 15, 2013. The evidence is organized within the context of the AHA framework and is classified according to the joint AHA/ American College of Cardiology and supplementary AHA Stroke Council methods of classifying the level of certainty and the class and level of evidence (Tables 1 and 2). The document underwent extensive AHA internal peer review, Stroke Council Leadership review, and Scientific Statements Oversight Committee review before consideration and approval by the AHA Science Advisory and Coordinating Committee. Each topic was assigned to a primary author and a secondary reviewer. In this guideline, we focus on the risk factors unique to women, such as reproductive fac- tors, and those that are more common in women, including migraine with aura, obesity, metabolic syndrome, and atrial fibrillation (AF). Topics that are not covered in detail include management of diabetes mellitus and cholesterol, because there are no recommendations for these risk factors that are specific to women. We therefore direct readers to the most recent primary and secondary prevention guidelines for spe- cific detailed recommendations.19,20 One of the writing group s goals was to review risk fac- tors that are unique to women or might affect women s risk of stroke differentially, as well as to determine whether there is a need for a stroke risk score for women that incorporates female-specific factors such as reproductive and menopausal factors (Table 3). Recommendations that are unique to women are included, as well as gaps in knowledge where additional research is needed to inform risk identification and thus improve stroke prevention in women. To demonstrate the importance of enhancing stroke risk scores for women, we have reviewed existing stroke risk scores and assessed their relevance on the basis of our summary of the literature on specific risk factors. Evidence from this guideline will inform providers and researchers of the current understanding of stroke risk and prevention in women. More importantly, this guideline may empower women and their families to under- stand their own risk and how they can minimize the chances of having a stroke. Epidemiology of Ischemic and Hemorrhagic Stroke in Women Overview In the United States, more than half (53.5%) of the esti- mated 795 000 new or recurrent strokes occur among women annually, resulting in 55 000 more stroke events in women than men.1 Results from the Framingham cohort show that women have a higher lifetime risk of stroke than Although stroke incidence rates have declined, data suggest that the decline may be smaller for women than Data from epidemiological studies demonstrate that the majority (87%) of strokes are ischemic (IS), with the remainder hemorrhagic (10% intracerebral [ICH] and With an anticipated increase in the aging population, the prevalence of stroke survivors is projected to increase, particularly among elderly women.4 Because the United States lacks a national surveillance sys- tem for cardiovascular disease (CVD),25 and sex-specific or age- and sex-specific stroke incidence data have not been routinely reported in published studies, there are important gaps in our understanding of sex differences in incident and recurrent stroke events, temporal patterns of stroke events, and outcomes after stroke. Most of what is known about the epidemiology of stroke comes from mortality data. As noted previously, the higher stroke mortality for women is often attributed to the longer life expectancy of women. Of occurred in women.1 Bushnell et al Guidelines for Prevention of Stroke in Women 1547 Incidence Ischemic Stroke Within most age strata, women have a lower IS incidence than men, and as such, the overall age-adjusted incidence of IS is lower for women than men4,24,26 31 ; however, sex differences in IS incidence rates differ across the age strata. In the oldest age groups (generally >85 years of age), women tend to have or similar incidence of IS as men.4,26 Because women tend to be older when they have their stroke events, and women have a longer life expectancy than men, age- adjusted rates can be misleading and may underestimate the total burden of stroke in women. Differences by race/ethnicity have also been noted, with higher rates among blacks and than among whites for both women and men.1,28 31 Hemorrhagic Stroke (SAH and ICH) The majority of studies show that women have higher rates of SAH incidence than men26,32 43 ; however, sex differences are modified by age such that SAH rates are higher in men at younger ages but higher in women relative to men begin- ning at 55 years of age.44,45 Data reported from non-US populations have shown differing sex-related patterns across countries, with higher SAH incidence among men in Finland and eastern Europe, possibly because of regional differences in risk factor prevalence in men and women.46 The incidence Table 1. Applying Classification of Recommendation and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. of ICH has been reported to be lower in women than men in but not all42 studies. Differences by race/ethnicity have been noted, with higher ICH incidence rates in blacks and in Hispanics than whites for both women Increased Prevalence of SAH in Women: Risks Related to Cerebral Aneurysms There has been significant debate about the potential cause of the increased risk of SAH in women. Autopsy and angi- ographic studies have documented a higher prevalence of cerebral aneurysms in women,49 as well as a higher risk of These findings are in agreement with results of a recent study from the Nationwide Inpatient Sample, which claimed that more than twice as many women as men were discharged with both ruptured and unruptured cerebral aneu- There is also a difference in the distribution of aneu- rysm locations in women versus men, and this may convey a higher hemorrhagic risk, especially with greater prevalence of aneurysms at the posterior communicating artery.52 Other studies have suggested similar trigger factors for aneurysm rupture in men and women.53 There is also no convincing evi- dence of increased risk of aneurysmal SAH in pregnancy or and before age 50 years, aneurysmal SAH is more common in men.55 A population-based case-control study showed that the risk of SAH was lower in women with first pregnancy after 23 years of age and in those who had ever used hormone therapy (HT).56 The literature certainly confirmed a higher incidence of SAH and a higher prevalence of cerebral aneurysms in women, but not necessarily a higher risk for rupture of aneurysms with similar characteristics. Prevalence On the basis of self-report data from the US 2010 National Health Interview Survey, it is estimated that just more than half (51.8%, 3.223 million) of the 6.226 million adults (3%) in the United States who have been told they had a stroke were Data from the Behavioral Risk Factor Surveillance System for the time period 2006 to 2010 showed that the age- adjusted self-reported prevalence of stroke survivors did not change significantly for women (2.5% 2.6%), whereas it did for men, with prevalence declining from 2.8% in 2006 to 2.5% in 2009 and then increasing to 2.7% in 2010.58 Mortality In the United States, 60% of deaths related to stroke in Table 3. Stroke Risk Factors, Categorized by Those That Are Sex-Specific, Stronger or More Prevalent in Women, or Similar Between Women and Men Risk Factor Sex-Specific Risk Factors Risk Factors That Are Stronger or More Prevalent in Women Risk Factors With Similar Prevalence in Men and Women but Unknown Difference in Impact Pregnancy X Preeclampsia X Gestational diabetes X Oral contraceptive use X Postmenopausal hormone use X Changes in hormonal status X Migraine with aura X Atrial fibrillation X Diabetes mellitus X Hypertension X Physical inactivity X Age X Prior cardiovascular disease X Obesity X Diet X Smoking X Metabolic syndrome X Depression X Psychosocial stress X Table 2. Definition of Classes and Levels of Evidence Used in AHA/ASA Recommendations Class I Conditions for which there is evidence for and/ or general agreement that the procedure or treatment is useful and effective. Class II Conditions for which there is conflicting evi dence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa The weight of evidence or opinion is in favor of the procedure or treatment. Class IIb Usefulness/efficacy is less well established by evidence or opinion. Class III Conditions for which there is evidence and/ or general agreement that the procedure or treatment is not useful/effective and in some cases may be harmful. Therapeutic recommendations Level of Evidence A Data derived from multiple randomized clinical trials or meta-analyses Level of Evidence B Data derived from a single randomized trial or nonrandomized studies Level of Evidence C Consensus opinion of experts, case studies, or standard of care Diagnostic recommendations Level of Evidence A Data derived from multiple prospective cohort studies using a reference standard applied by a masked evaluator Level of Evidence B Data derived from a single grade A study or 1 or more case-control studies, or studies using a reference standard applied by an unmasked evaluator Level of Evidence C Consensus opinion of experts AHA/ASA indicates American Heart Association/American Stroke Association. Bushnell et al Guidelines for Prevention of Stroke in Women 1549 Age-specific stroke mortality is higher for men than women for all age groups except 85 years, and this pattern is con- sistent across all racial/ethnic groups (Figures 1 and 2).1,2,59 In 2010, age-adjusted stroke mortality (based on International Classification of Diseases, 10th Revision, codes I60 I69) for women was 38.3 per 100000 compared with 39.3 per 100000 for men (relative risk [RR], 0.97).59 For most of the past century, age-adjusted stroke mortality rates declined dra- matically in the United States,60 and between 1996 and 2005, these declines were marginally greater for men ( 28.2%) than Stroke is a major cause of death world- wide, accounting for an estimated 10% of all deaths in 2002. Similar to the United States, women worldwide have lower stroke mortality than men except in the older age groups,62 65 and IS mortality has declined for both men and women, with some acceleration in the rate of decline in the 1990s for cer- tain age-sex groups.66 Ischemic Stroke An analysis of US death certificate data from 1995 to 1998 found that IS constitutes a larger percentage of stroke mor- tality overall in women than men (82% of stroke deaths in women versus 78% in men), with the greatest difference seen for older women.67 The overall age-adjusted IS death rate in women is slightly lower (74.3 per 100000 compared with 78.8 per 100000 for men; RR, 0.94; 95% confidence interval [CI], 0.93 0.95). Younger women have lower age-specific IS mor- tality than men, but there is a crossover at 65 years of age, at which point older women have higher age-specific IS mortal- ity than men.67 This study also reported that the age-adjusted death rate for IS was higher for white women than white men (RR, 1.21; 95% CI, 1.21 1.22), but for all other racial/ethnic groups, the age-adjusted death rate for IS was lower or similar for women and men.67 Hemorrhagic Stroke Women have higher age-adjusted SAH mortality than men Sex differences persisted across racial/ethnic groups and were highest among Asian Americans. In addition, the risk ratio of mortality in women versus men increased with In contrast to SAH, women have lower age-adjusted ICH mortality rates than men (13.3 per 100000 for women and 16.2 per 100000 for men; RR, 0.82; 95% CI, 0.81 0.83). Mortality was lower for women aged <65 years, but there was no sex difference in ICH mortality risk for adults 65 years of age.67 Total Stroke Case Fatality The findings of studies that have examined sex differences in short-term case-fatality rates (commonly defined as within 30 days of onset and inclusive of all strokes) have been quite vari- able and are complicated by a lack of age adjustment. Some studies have reported that women have higher case fatality whereas others have not.9,13,42,71 Although a recent systematic review found that short-term case fatality was higher in women than men in 26 of 31 studies (with a pooled rate of 24.7% versus 19.7%),26 these results were based on crude unadjusted data. Much of the higher case fatality in women is likely to be attributable to the fact that women tend to be older at the time of their stroke.4 Studies that have adjusted for age (as well as other characteristics) show that the sex difference in short-term mortality can actually reverse, with women having lower mortality after adjustment.72,73 A study of temporal trends (1950 2004) in the US Framingham Study found that age-adjusted 30-day fatality decreased sig- nificantly for men but not women.22 Non-US populations have also reported mixed results in terms of sex differences in stroke case fatality over time,69 which may be attributable to differ- ences in the time periods studied, underlying demographics, lack of age adjustment, and other factors. Case-fatality studies for IS have shown either no sex differences or higher rates in A study from the Netherlands that examined trends in IS 30-day case fatality for the period 1997 to 2005 showed that in all age-sex groups, the case fatality declined significantly; the largest decline for men was from 12.5% to 6.9% ( 0.42 change) in the 65- to 74-year-old age group, and the largest decline for women was from 6.4% to 3.5% ( 0.45) in the 35- to Data are limited to assess case fatality for hemorrhagic strokes. A study restricted to a younger popu- lation (20 44 years of age) reported lower 30-day case fatality after SAH in women than in men (9% versus 17%).41 Studies have shown differing patterns of ICH case fatality by sex. The Atherosclerosis Risk in Communities study (ARIC) reported a lower 30-day ICH case fatality for women than for men but the Northern Manhattan Stroke Study found slightly higher 1-month case fatality for women than men (40% versus 35%).41 Temporal trends in case fatality for hemorrhagic stroke are largely unreported. A Finnish study Figure 1. US stroke mortality rates for women, 2009. Am Indian indicates American Indian; Non-Hisp, non-Hispanic; and PI, Pacific Islander. found similar declines in 28-day case fatality for women and men over a 12-year period from 1991 to 2002.74 Sex Differences in Stroke Awareness (Delay, Warning Signs, Risk Factors) Delayed hospital arrival is the single most important reason for the failure to administer thrombolytic treatment within the eligible time window of 3 or 4.5 hours. Most studies have not found important sex differences in delayed hospital arrival,4,75 but a few found women have longer prehospital delay than Most studies that have explored knowledge and awareness of stroke symptoms in either stroke patients or at-risk populations have not compared results by sex; how- ever, several population-based studies have shown that knowl- edge and awareness of stroke warning signs and symptoms are somewhat higher in women than men.81 83 One study reported that although women were more likely than men to have heard of tissue-type plasminogen activator therapy for stroke, they were less likely to know that it must be administered within 3 Population-based surveys of women conducted by the AHA have identified an overall poor level of knowledge about CVD and stroke, particularly in minority women85,86 ; however, the studies excluded men and were therefore unable to report on sex differences. Epidemiology of Ischemic and Hemorrhagic Stroke in Women: Summary and Gaps Stroke epidemiology research predominantly describes IS events. Additional research is needed to understand sex differ- ences for hemorrhagic stroke events. Data are limited in terms of sex-, race-, and age-specific rates of stroke incidence, mortality, and case fatality. This represents an important gap, because disease patterns and outcomes have been shown to vary by these characteristics. Future studies should report data separately for men and women, stratify by age when examining sex differences in dis- ease rates, and clarify whether first-ever stroke events, recur- rent events, or both are being reported. In addition to reporting by sex and age, for each stroke subtype, the incidence, mortal- ity, and case fatality should be reported by race/ethnicity. In general, stroke event rates are lower in women than men, but sex comparisons based on age-adjusted rates mask important differences by age. There is a higher lifetime risk of stroke in women than men and a greater number of stroke deaths in women than men. Vascular Differences in Stroke Risk: Sex and Hypertension Hypertension is the most common modifiable risk factor for stroke in both men and women and has the highest population- There are a number of important sex dif- ferences in the prevalence, treatment, and pathophysiology of hypertension that should be highlighted to improve awareness and treatment of this risk factor in women. Sex Differences in Stroke Risk With Hypertension Among stroke patients, some studies,9,13,71,72,88,89 but not all,90,91 have shown that women are more likely to have hypertension than men. Similarly, women may have a higher risk of first stroke with hypertension. For example, the INTERSTROKE study showed that women had a higher risk of stroke with self- reported blood pressures (BPs) of 160/90 mmHg (odds ratio 3.22 4.68), although the CIs overlapped.92 In addition, older women (mean age 63 years) with prehypertension had a 93% increased risk of stroke compared with normotensive women in the Women s Health Initiative (WHI) cohort, which implies that early and sustained treatment of hypertension is critical.93 Efficacy of Hypertension Treatment and Reduction of Stroke in Women The effects of pharmacological intervention to lower BP and thereby reduce the risk of stroke on cardiovascular outcomes and surrogate cardiovascular end points have been studied and women have been well represented in large clinical trials of antihypertensive therapy; however, no trials have specifically examined a differential effect of phar- macological BP treatment in men and women on stroke events. Similarly, post hoc analyses and meta-analyses of clinical trial data have not reported sex differences in response to treat- ment or stroke events. In a recent meta-analysis of 31 large, randomized BP trials, treatment of hypertension in women aged >55 years (90% of whom were white) was associated with a 38% risk reduction in fatal and nonfatal cerebrovascu- lar events (95% CI, 27% 47%). A reduction of 25% in fatal and nonfatal cardiovascular events (95% CI, 17% 33%) was Figure 2. Female-male US stroke mortality ratio, 2009. Am Indian indicates American Indian; Non-Hisp, non-Hispanic; and PI, Pacific Islander. Bushnell et al Guidelines for Prevention of Stroke in Women 1551 also reported, together with a 17% reduction in cardiovascu- lar mortality (95% CI, 3% 29%).108 Therefore, women benefit significantly from these interventions, as do men, and the type of medication used to lower the BP may be less relevant than the achievement of target BP goals. Analyses of women of different racial/ethnic and age groups have suggested particular benefit of BP reduction in younger and black women. In 1 large systematic review of prospective studies, BP treatment in those aged 30 to 54 years (of whom 79% were white) yielded a reduction in risk of fatal and nonfa- tal cerebrovascular events of 41% (95% CI, 8% 63%), as well as a 27% reduction in fatal and nonfatal cardiovascular events In this same study, when black women were considered as a separate group, BP treatment reduced the risk of fatal and nonfatal cerebrovascular events by 53% Sex, BP, Antihypertensive Treatment, and Achieving BP Goals Numerous studies have shown that females have lower BP levels over much of their life span than their age-matched but this changes with age. For example, the prevalence of hypertension in adults <45 years of age is lower in women than men, but hypertension becomes increas- ingly prevalent and is higher in postmenopausal women than men after the age of 55 years, which suggests an important role of sex hormones in the regulation of BP.1 The lifetime risk of developing hypertension in the United States is 29% for women and 31% for men1 ; however, 75% of women >60 years of age become hypertensive.2 Age-adjusted hypertension prevalence, both diagnosed and undiagnosed, from 1999 to 2002 was 78% for older women and only 64% for older men.111 Sex differences in the pattern of prescribed antihyperten- sive medications have been seen across several large studies. For example, in the Framingham Heart Study, 38% of women but only 23% of men were prescribed thiazide diuretics,112 and similar rates were seen in the National Health and Nutrition Examination Survey (NHANES) cohorts, with higher diuretic (31.6% versus 22.3%) and angiotensin receptor blocker Currently, there is no compelling evidence that there are differences in the response to BP medications between the ; however, in large-scale reviews that examined the efficacy of -blockers, angiotensin-converting enzyme inhibi- tors, angiotensin receptor blockers, and diuretics,114 there is no mention that sex-specific efficacy end points were evaluated or even considered. The possibility of differences in efficacy of BP medications therefore exists. Some studies have suggested that antihypertensive medica- tion use is significantly higher among women than men (61.4% versus 56.8%). Among treated hypertensive people, the pro- portion taking 3 antihypertensive drugs was lower among women than men, especially among older people (60 69 years of treated women achieved BP control versus 51.1% of treated Notably, hypertensive women are significantly more likely to be treated than men but less likely to have achieved BP control. This may be because of unknown physiological mechanisms (ie, arterial stiffness, overactivation of the renin- angiotensin system) or poorer compliance in women. The recent PARITE study, which examined 3440 patients, found that in French office-based cardiology practices, the antihy- pertensive regimen is adjusted as often in female as in male patients. Hypertension was uncontrolled in 76% of both men and women, and 69% were at high global cardiovascular risk Unfortunately, control of hypertension is poor in high-risk elderly women. Data from the Framingham Heart Study showed an age-related decrease in BP control rates that was more pronounced in women than men.112 Among participants >80 years of age with hypertension, only 23% of women (ver- sus 38% of men) had BP <140/90 mmHg.112 In analyses from the NHANES III and IV cohorts, the age- adjusted prevalence of uncontrolled BP was 50.8 2.1% in men and 55.9 1.5% in women, which was not significantly different; women had a higher prevalence of other concomi- tant cardiovascular risk factors,110 which likely contributed to poorer BP control in elderly women. These included cen- tral obesity, elevated total cholesterol, and low high-density lipoprotein cholesterol levels.110 Among adults with hyper- tension in NHANES from 1999 to 2004, women were at higher risk of cardiovascular events than men, such that 53% of women but only 41% of men had >3 of the 6 risk factors studied (P<0.001). Sex differences in hypertension and BP regulation are com- plex, because ovarian hormones influence BP considerably. Therefore, studies that examine vascular function and BP must take hormonal status into account.111,116 Sex differences in sympathetic activity, vascular reactivity, water regulation (arginine vasopressin signaling), and autonomic control have been well documented,116 but most of these studies were per- formed in young women. Efforts to assess the effects of hor- monal effects on the vasculature have examined specific points in the menstrual cycle or suppressed ovarian function using gonadotropin- releasing hormone agonists or antagonists. In addition to hormone-dependent effects, these investigations have demonstrated hormone-independent sex differences in the Hormone-independent approaches to BP regu- lation may be more relevant to older, postmenopausal women and may provide important information that will inform future clinical trials of different BP reduction strategies. Several nonpharmacological recommendations for BP man- agement are relevant to both men and women. A recent meta- analysis showed that even a modest reduction in salt intake for 4 weeks led to significant and important decreases in BP in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. This was accompanied by a small physiological increase in plasma renin activity, aldosterone, and noradrenaline. Therefore, reductions in salt intake from 9 to 12 g/d to 3 g/d have been recommended.117 Side effects of antihypertensive therapy tend to be encoun- tered with a higher degree of frequency in women than men. Diuretic-induced disturbances of electrolyte concentration are seen more frequently in women,118,119 as is angiotensin- converting enzyme inhibitor induced cough and calcium channel blocker (CCB) related dependent edema.120 Hypertension in Women of Childbearing Age Prepregnancy hypertension increases the risk for preeclamp- sia/eclampsia and stroke during pregnancy. The choice of BP-lowering medications before pregnancy should be made based on a woman s intentions for future pregnancy, because some categories of medications are associated with various risks if continued during pregnancy (Table 4).120a,121* -Blockers, -blockers, CCBs, hydralazine, and thiazide diuretics have been used in pregnancy; all transfer across the placenta. There are no data from large, well-controlled, random- ized controlled trials directly comparing specific antihyperten- sive agents in pregnancy. Methyldopa has been extensively used in pregnancy and appears to be safe,122 127 including for neonates in a long-term pediatric study.128 A Cochrane review of the use of -blockers in pregnancy noted that these drugs decreased the risk of progression to severe hypertension but may have increased risk for fetal growth restriction (n=1346; RR, 1.36; 95% CI, although this may have been confounded in part by the inclusion of trials that used atenolol, which is not recom- mended in pregnancy because of its known association with fetal Pindolol and metoprolol appear safe for use in pregnancy.131 CCBs appear to be safe in pregnancy, with the most commonly used CCB being nifedipine.132,133 Cochrane review indicated that there was a small increase in the risk for preeclampsia with the use of CCBs versus no ther- Diuretics, predominantly thiazide-type, have been indicated to be safe in and women taking thiazides before pregnancy do not need to discontinue them; however, a 2007 Cochrane review examined the use of diuretics to prevent preeclampsia.135 For thiazides, the reviewers noted that several studies were of uncertain quality and that there was insufficient evidence for any differences between treatment and control groups (4 trials, 1391 Angiotensin-converting enzyme inhibitors, angio- tensin receptor blockers, and direct renin inhibitors are contraindicated at all stages of pregnancy because of teratoge- nicity and adverse fetal outcomes.136 139 Sex and Hypertension in Relation to Prevention of Stroke: Summary and Gaps There is insufficient evidence to warrant a different approach to BP treatment in women from that used for men; as such, the existing guidelines for measurement, identification, and man- agement of BP in adults should be followed. Existing guide- lines for nonpharmacological intervention (predominantly dietary modification) to lower BP and to reduce stroke risk in adults should be followed.19,140 It is unclear whether the age- related decline in BP control among women is related to inad- equate intensity of treatment, inappropriate drug choices, lack of compliance, true treatment resistance, biological factors, or other factors. Further research to resolve these questions is needed. In addition, hormone-dependent and -independent approaches to BP treatment require further study. Sex and Hypertension in Relation to Prevention of Stroke: Recommendations The recommendations for BP treatment to prevent stroke are currently the same for women as for men and can be found in the AHA/American Stroke Association Guidelines for the Primary Prevention of Stroke, 19 the European Society of Hypertension/ European Society of Cardiology guidelines,141 and the Seventh ReportoftheJointNationalCommitteeonPrevention,Detection, Evaluation, and Treatment of High Blood Pressure. 142 Sex-Specific Risk Factors Pregnancy and Stroke Pregnancy is a condition unique to women. Although stroke is uncommon in pregnancy (34 strokes per 100000 deliver- the risk for stroke is higher in pregnant than in non- pregnant young women (21 per 100000144 ), with the highest stroke risk occurring in the third trimester and post partum. The physiological changes of pregnancy, specifically venous stasis, edema, and hypercoagulability caused by activated Table 4. Summary of Antihypertensive Drugs Used During Pregnancy Category Maternal Side Effects Teratogenicity or Fetal-Neonatal Adverse Effects Class/Level of Evidence (see Table 2) Centrally acting 2-adrenergic agonist (eg, methyldopa) Sedation, elevated LFTs, depression No IIa/C Diuretics (thiazide) Hypokalemia No III/B -Blockers (atenolol) Headache Associated with fetal growth restriction III/B -Blockers (pindolol, metoprolol) Headache Possible fetal growth restriction, neonatal bradycardia IIa/B Calcium channel blockers (eg, nifedipine) Headache; possible interaction with magnesium sulfate; may interfere with labor No I/A Combined - blockers (labetalol) May provoke asthma exacerbation Possible neonatal bradycardia IIa/B Hydralazine Reflex tachycardia, delayed hypotension Neonatal thrombocytopenia, fetal bradycardia III/B ACE inhibitors, angiotensin receptor blockers, renin inhibitors Skeletal and cardiovascular abnormalities, renal dysgenesis, pulmonary hypoplasia III/C ACE indicates angiotensin-converting enzyme; and LFTs, liver function tests. Modified from Umans et al120a with permission from Elsevier, Copyright 2009. *American College of Obstetricians and Gynecologists Bulletin withdrawn in lieu of a newer version. Access date was May 15, 2013. Bushnell et al Guidelines for Prevention of Stroke in Women 1553 protein C resistance, lower levels of protein S, and increased fibrinogen, combine to make pregnancy and the postpartum period a time of increased risk for stroke. Pregnancy-related hypertension is the leading cause of both hemorrhagic stroke and IS in pregnant and postpartum women.145 147 Hypertensive Disorders of Pregnancy Preeclampsia/eclampsia and pregnancy-induced hypertension are the 2 most important hypertensive disorders of pregnancy. Preeclampsia is defined as progressively worsening high BP in pregnancy that occurs in the setting of proteinuria ( 300 mg of protein in a 24- hour urine specimen).148 Preeclampsia may be of early onset (before 37 weeks gestation) or late onset (after 37 weeks). Eclampsia is preeclampsia that progresses to seizures. Preeclampsia is a multisystem disorder, and abnor- malities such as HELLP (hemolysis, elevated liver enzymes, or low platelets), disseminated intravascular coagulation, acute renal failure, myocardial infarction (MI), pulmonary edema, and stroke may occur. Preeclampsia is hypothesized to be caused by as-yet-unnamed placental factors that enter the maternal circulation, provoking the signs, symptoms, and laboratory findings associated with this disorder.149 Pregnancy-induced (sometimes called gestational) hyper- tension is defined as an elevation in BP, usually near term, that occurs without the other signs and symptoms of preeclampsia. Although gestational hypertension may or may not progress to preeclampsia, it can result in markedly elevated BPs. By defi- nition, gestational hypertension usually resolves by 12 weeks Recognized risk factors for pregnancy-induced hyperten- sion include obesity, age (>40 years), chronic hypertension, personal or family history of preeclampsia or gestational hypertension, nulliparity, multiple pregnancy, preexisting vas- cular disease, collagen vascular disease, diabetes mellitus, and By far the most important predisposing factor is chronic hypertension, because superimposed preeclampsia develops in 25% of pregnant women with this condition. Regardless of its origin, high BP during pregnancy is associ- ated with risk to both mother and baby, and BP-related com- plications remain a leading cause of maternal morbidity and mortality, as well as preterm birth, fetal growth restriction, and Women with high BP during pregnancy who have given birth continue to be at risk for preeclampsia and stroke. Although less common than preeclampsia during pregnancy, postpartum preeclampsia is more insidious and potentially more dangerous, because women may be unaware of its development and are no longer being seen regularly, as they were for prenatal care. Postpartum preeclampsia is associated with a high risk for stroke and may be the underlying cause of severe postpartum headaches.152 Transient elevations in BP are common post partum because of volume redistribution, iatro- genic administration of fluid, alterations in vascular tone, and use of nonsteroidal anti-inflammatory drugs,153 155 but persis- tently elevated BP should be categorized and treated accord- ing to the adult guidelines.140 A 2010 Cochrane review noted that the RR of hyperten- sion in pregnancy was decreased with calcium supplementa- A reduction in preeclampsia/eclampsia was also noted (RR, 0.45; 95% CI, 0.31 0.65). Low-dose aspirin can also lower the risk for preeclampsia, on the basis of a meta-analysis of 46 tri- als and 32891 women (RR, 0.83; 95% CI, 0.77 0.89; number needed to treat, 72).157 Recent research suggests that vita- min D3 deficiency may be associated with increased risk for but there are insufficient data to support a recommendation. Treatment of Elevated BP During Pregnancy, Including Preeclampsia The central autoregulatory plateau in pregnancy is estimated at 120 mmHg, and women with moderate to severe high BP in pregnancy, especially those with preeclampsia, are at risk for loss of central cerebral vascular autoregulation. The association between high BP and stroke risk in women with preeclampsia is not linear, such that stroke can occur at moderately elevated BPs, which suggests that current thresholds for treatment may not be sufficiently stringent.159 Pharmacological treatment to lower BP during pregnancy should be chosen after consideration of tolerability, preex- isting therapy, and risk of teratogenicity, because all agents cross the placenta. (Table 4). High BP during pregnancy may be defined as mild (dia- stolic BP 90 99 mmHg or systolic BP 140 149 mmHg), moderate (diastolic BP 100 109 mmHg or systolic BP 150 159 mmHg), or severe (diastolic BP 110 mmHg or systolic BP 160 mmHg). The goal of BP management in pregnancy is to maintain systolic BP between 130 and 155 mmHg and diastolic BP between 80 and 105 mmHg, with lower target ranges in the context of comorbidity; however, the treatment rationale for women with mild to moderate high BP in preg- nancy is not as clear-cut as for severe high BP in pregnancy because maternal and fetal risk-benefit ratios have not been For example, a meta-analysis that examined the association between reduction in maternal BP and fetal growth found that a 10-mmHg decrement in maternal mean arterial pressure was associated with a 176-g decrease in neo- natal birth weight, regardless of the antihypertensive agent In addition, Abalos et al132 performed a meta-analysis of randomized controlled trials of treatment versus no treat- ment of mild to moderate high BP in pregnancy. Although the risk for development of severe hypertension in pregnancy was reduced by 50% in the treatment group (19 trials, 2409 women; RR, 0.50; 95% CI, 0.41 0.61; number needed to treat, 10), there was no statistically significant difference in risk for preeclampsia (22 trials, 3081 women; RR, 0.73; CI 0.50 1.08) and no evidence for benefit or harm to the fetus. Severe hypertension in pregnancy is categorized with the same criteria as for stage 2 hypertension in nonpregnant adults according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (BP 160/110 mmHg) and is associated with high risk for stroke and eclampsia.131,161 The American College of Obstetricians and Gynecologists recommends treatment of severe hypertension and suggests labetalol as first-line therapy,121 and it recommends avoidance of atenolol, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. In addition to pharmacological control of hypertension, the use of magnesium sulfate for seizure prophylaxis is well established and has been demonstrated in randomized trials to decrease risk of stroke in women with severe high BP in pregnancy and eclampsia. A Cochrane review showed a >50% reduction in eclampsia with the use of magnesium sulfate ver- 0.58; number needed to treat for additional benefit, 100), with a nonsignificant decrease in maternal death (RR, 0.54; 95% Although modest decrements in BP can be observed with magnesium sulfate alone, the latter has not been shown to effectively decrease BP in moderate to severe high BP in pregnancy, and there is no evidence to support its use as monotherapy.125 Pregnancy Complications and the Long-term Risk of Stroke An expanding body of research has shown that complica- tions of pregnancy (preeclampsia, gestational diabetes, and pregnancy-induced hypertension) are associated with higher risk for future CVD and stroke beyond the childbearing years than among women without these disorders163 (Tables 5 and 6). For example, women with a history of preeclampsia have a markedly increased risk for developing renal disease and a 2- to 10-fold increase in risk for development of chronic hypertension, a major risk factor for stroke. In addition, 50% of women with gestational diabetes will develop type 2 diabe- tes mellitus, a major risk factor for stroke, within 5 to 10 years of their pregnancy (although only 1 study has suggested an increased risk for CVD after a pregnancy complicated by ges- tational diabetes; CVD was defined as a composite outcome of admission to hospital for acute MI, coronary bypass, coronary angioplasty, stroke, or carotid endarterectomy [CEA]).180 182 A 2012 study of long-term risk for CVD reported that 18.2% of women with a history of preeclampsia versus 1.7% of women with uncomplicated pregnancies had a CVD event in 10 years (OR, 8.43; 95% CI, 3.48 23.2) and lifetime risk (OR, 3.25; 95% CI, 1.76 6.11) for CVD for women who formerly had preeclampsia were significantly increased compared with women with uncomplicated pregnancies.183 A 2008 system- atic review and meta-analysis by McDonald et al181 noted that women with a history of preeclampsia/eclampsia had twice the risk of cerebrovascular disease (not further defined) as women without these disorders (RR, 2.03; 95% CI, 1.54 2.67). Another meta-analysis by Bellamy et al180 cohort studies and reported a cumulative OR of 1.81 for any stroke (OR, 1.81; 95% CI, 1.37 2.33) in women with a history of preeclampsia, whereas Brown et al184 noted an OR of 1.76 for cerebrovascular disease (95% CI, 1.43 2.21) for women with a history of pregnancies with preeclampsia. In one study, the mean age at stroke onset was 50 years in women with these disorders, which suggests an accelerated time course to severe CVD or cerebrovascular disease, as well as loss or attenuation of women s premenopausal cardiovascular advan- Early- onset preeclampsia (before 32 weeks gestation) in particular has been noted to increase risk for stroke 5-fold compared with later-onset preeclampsia.186 Early-onset pre- eclampsia is also associated with an increase in white mat- ter lesions independent of hypertension in women years after pregnancies complicated by preeclampsia or eclampsia, which suggests a vulnerability to future events.187 The basis of the association between preeclampsia and future stroke is not entirely known but is hypothesized to be possibly related to genetic factors; shared risk factors (hyper- tension, dyslipidemia, endothelial dysfunction) between pre- eclampsia/eclampsia or other pregnancy complications and stroke; unmasking of underlying metabolic or vascular dis- ease; or the induction during pregnancy of cardiovascular or cerebrovascular abnormalities that persist long-term.188 To assess the contribution by preeclampsia/eclampsia to future risk for CVD and stroke and the possible impact that lifestyle interventions may have on this risk, Berks et al189 performed a series of literature-based calculations on risk estimates. First, using a meta-analysis cumulative OR for stroke as the start- ing point, they found that preeclampsia increased the odds of stroke by 1.55-fold after correction for cardiovascular risk factors (interquartile range 1.76 1.98). This result suggests Table 5. Adverse Pregnancy Outcomes and Future Hypertension Study Date and First Author Total No. of Subjects Study Design Pregnancy Outcome Mean Follow-up, y RR or OR of Hypertension 815 Prospective cohort Preeclampsia and eclampsia 359 Prospective and retrospective cohort 60 Retrospective cohort Preeclampsia and eclampsia CI indicates confidence interval; OR, odds ratio; and RR, risk ratio. Adapted from Garovic et al149 with kind permission from Springer Science+Business Media. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. Bushnell et al Guidelines for Prevention of Stroke in Women 1555 that CVD risk factors antecedent to pregnancy did not fully explain the risk for CVD after preeclampsia. They hypoth- esized that preeclampsia/eclampsia is a risk factor rather than a marker for stroke and CVD. The authors then calculated the effect of literature-based cumulative benefits of lifestyle inter- ventions (dietary habits, exercise, and smoking cessation) on this risk for stroke with preeclampsia. They found the OR for the effect of lifestyle interventions on the risk for CVD after a preeclamptic pregnancy to be 0.91 (interquartile range, 0.87 0.96), which suggests that these interventions could reduce the risk of stroke in this population. Although one limitation of this research was the extrapolation of lifestyle interven- tions performed in older populations to a younger population of women 1 to 30 years after preeclampsia, prospective stud- ies are warranted on the basis of the implication that lifestyle interventions in these women might be effective.189 Preeclampsia and Pregnancy Outcomes: Summary and Gaps Hypertensive disorders of pregnancy and other complications (preterm birth, small size for gestational age, and first- trimester bleeding) are associated with increased risk of stroke during pregnancy, immediately after delivery, and years after deliv- ery. This risk has been quantified in large retrospective studies, mostly in northern European populations. Prospective studies on the pathophysiology underlying the association between hypertensive disorders of pregnancy and stroke, especially in diverse populations, are needed, because it is not known whether prepregnancy risk factors or pregnancy-associated factors predispose these women to subsequent risk of stroke. Research also suggests that clinicians are not aware of the asso- ciation between adverse pregnancy outcomes and CVD and stroke, which suggests a need for better clinician and patient Although a limited number of studies have exam- ined cardiovascular and stroke risk factors and documented increased risk for events long-term in women with these dis- orders, there are no prospective randomized controlled trials assessing interventions to reduce stroke risk in this population with clear risk factors (preeclampsia, gestational diabetes). There is a need for high-quality studies of women with a his- tory of adverse pregnancy outcomes to define their trajectory for the development of cerebrovascular disease and then to develop screening, risk stratification, and preventive strategies. Insufficient evidence exists to inform any recommendation for screening, prevention, or treatment in women with a history of pregnancy complications or adverse pregnancy outcomes. Preeclampsia and Pregnancy Outcomes: Recommendations Prevention of Preeclampsia 1. Women with chronic primary or secondary hyper- tension or previous pregnancy-related hypertension should take low-dose aspirin from the 12th week of gestation until delivery (Class I; Level of Evidence A). 2. Calcium supplementation (of 1 g/d, orally) should be considered for women with low dietary intake of calcium (<600 mg/d) to prevent preeclampsia (Class I; Level of Evidence A). Treatment of Hypertension in Pregnancy and Post Partum 1. Severe hypertension in pregnancy should be treated with safe and effective antihypertensive medications, Table 6. Adverse Pregnancy Outcomes and Risk for Stroke Study Date and Author Total No. of Subjects Study Design Pregnancy Outcome Cerebrovascular Outcome Follow-up, y HR or OR for Outcome (95% CI) Mannist et al, cohort study Gestational hypertension Ischemic cerebrovascular disease Bonamy et al, cohort study Preterm birth; SGA Cerebrovascular events (infarction, hemorrhage, subarachnoid hemorrhage, TIA, other stroke) Preterm birth 2.41 (1.4 4.17); SGA birth 1.68 (1.46 2.06); preterm and SGA birth Irgens et al, 2001175 cohort study Preeclampsia Stroke mortality Term preeclampsia 0.98 (0.5 1.91); preterm preeclampsia* 5.08 Wilson et al, 2003170 cohort study Ray et al, 2005176 cohort study Maternal placental syndrome Funai et al, 2005177 cohort study Kestenbaum et al, study Preeclampsia Cerebrovascular disease 2.53 (1.70 3.77) Lykke et al, 2009179 cohort Gestational hypertension, mild preeclampsia, severe preeclampsia Stroke 12.9 14.6 Gestational hypertension 1.58 CI indicates confidence interval; HR, hazard ratio; OR, odds ratio; SGA, small for gestational age; and TIA, transient ischemic attack. *Defined as preeclampsia between 16 and 36 weeks. such as methyldopa, labetalol, and nifedipine, with consideration of maternal and fetal side effects (Class I; Level of Evidence A). 2. Consideration may be given to treatment of moder- ate hypertension in pregnancy with safe and effective antihypertensive medications, given the evidence for possibly increased stroke risk at currently defined systolic and diastolic BP cutoffs, as well as evidence for decreased risk for the development of severe hypertension with treatment (although maternal- fetal risk-benefit ratios have not been established) (Class IIa; Level of Evidence B). 3. Atenolol, angiotensin receptor blockers, and direct renin inhibitors are contraindicated in pregnancy and should not be used (Class III; Level of Evidence C). 4. After giving birth, women with chronic hypertension should be continued on their antihypertensive regi- men, with dosage adjustments to reflect the decrease in volume of distribution and glomerular filtration rate that occurs after delivery. They should also be monitored carefully for the development of postpar- tum preeclampsia (Class IIa; Level of Evidence C). Prevention of Stroke in Women With a History of Preeclampsia 1. Because of the increased risk of future hypertension and stroke 1 to 30 years after delivery in women with a history of preeclampsia (Level of Evidence B), it is reasonable to (1) consider evaluating all women start- ing 6 months to 1 year post partum, as well as those who are past childbearing age, for a history of pre- eclampsia/eclampsia and document their history of preeclampsia/eclampsia as a risk factor, and (2) eval- uate and treat for cardiovascular risk factors includ- ing hypertension, obesity, smoking, and dyslipidemia (Class IIa; Level of Evidence C). Cerebral Venous Thrombosis Cerebral venous thrombosis (CVT) is a stroke type that is caused by thrombus formation in 1 of the venous sinuses and manifests primarily as headache. CVT makes up 0.5% to 1% of all strokes but is the stroke type that shows the most prominent differential sex prevalence.191,192 In adulthood, the majority of affected individuals are women, who represent >70% of cases in most studies193 200 (Table 7). The overall adult incidence of and is higher in women (1.86 per 100000; 95% CI, 1.44 2.36) This sex difference is even more notable in women aged 31 to 50 years, in whom the incidence may be as high as 2.78 per 100000 person-years (95% CI, 1.98 3.82). Women tend to be younger (median age 34 years) than men (median age 42 years) at the time of diagnosis.193,198 Guidelines for the evaluation and treatment of CVT were published recently.200 Therefore, only interim studies with an emphasis on sex- specific factors are presented in this guideline. Risk Factors The female predominance of CVT has been attributed to hormonal factors (primarily oral contraceptive [OC] use and pregnancy), because the incidence is sex-independent in chil- dren and in the elderly.201,202 A link between thrombophilia and CVT has been relatively well established for several inherited conditions, including antithrombin III, protein C, and protein S deficiency and factor V Leiden.200 Many exogenous provok- ing factors for venous thrombosis have been described, such as cancer, infection, and hematologic and autoimmune condi- However, 2 major risk factors are female specific: OC use and pregnancy. The use of OCs is associated with an increased risk of CVT,200 a risk that is increased significantly in women with an underlying hereditary prothrombotic fac- tor, such as factor V Leiden or prothrombin gene mutation.203 Pregnancy and OC use are considered transient risk factors and do not necessarily indicate a higher risk for recurrence. Most pregnancy-related CVT occurs in the third trimester or Treatment and Recurrence The standard therapy for acute CVT is anticoagulation with intravenous unfractionated heparin or subcutaneous low- molecular-weight heparin (LMWH) followed by oral antico- There are no large studies of the use of newer anticoagulants that are currently only approved for use in patients with nonvalvular AF or deep venous thrombosis205 ; therefore, warfarin is usually recommended. Management and imaging recommendations are provided in detail in prior and are summarized below. There are no second- ary prevention trials of duration of anticoagulation in adults with CVT; therefore, guidelines are based solely on observa- tional data. Recurrence rates range from 2% to 5% in most studies, although many of these studies did not provide long- term follow-up of patients, and the level of anticoagulation at the time of recurrence was often not reported. In the International Study on CerebralVein and Dural Sinus Thrombosis (ISCVT), recurrence of CVT was seen in 2.2% of patients, and other recurrent thrombotic events were seen in 4.3%, with a mean (Table 7). A recent large, ret- rospective, multinational study performed follow-up of 706 patients for a median of 40 months and tracked prespecified risk factors and conditions such as infections, trauma, OC use, pregnancy, puerperium, HT, recent neurosurgical proce- dures, and the presence of myeloproliferative neoplasms.199 Significantly more women than men had at least 1 risk factor Table 7. CVT and Recurrence Rates in Published Studies Recurrence Rate, % Study Subjects Enrolled, n % Female CVT Other Thrombosis Length of Follow-up Martinelli et al197 Coutinho et al193 94 72 NA NA NA Dentali et al199 CVT indicates cerebral venous thrombosis; ISCVT, International Study on Cerebral Vein and Dural Sinus Thrombosis; NA, not available; and VENOPORT, Cerebral Venous Thrombosis Portuguese Collaborative Study Group. Bushnell et al Guidelines for Prevention of Stroke in Women 1557 (61.0% versus 45.7%; P<0.05). Recurrence rates were again low (4.4% for recurrent CVT and 6.5% with a recurrent venous thromboembolism [VTE] in a different site), which led to an overall incidence of recurrence of 23.6 events per 1000 patient-years (95% CI, 17.8 28.7). Most events occurred after anticoagulation discontinuation. Somewhat surprisingly, the recurrence rate was similar in patients with unprovoked CVT and in patients with CVT secondary to known risk fac- years [95% CI, 15.9 32.6] ver- previous VTE was the only significant predictor of recurrence with multivariate analysis (hazard ratio [HR], 2.70; 95% CI, Many of the recurrent VTEs occurred in women when the first CVT occurred during pregnancy/ puerperium or was secondary to OC or HT use; however, nei- ther female sex (HR, 1.37; 95% CI, 0.83 2.25), pregnancy/ puerperium (HR, 1.05; 95% CI, 0.48 2.28), or use of OC/HT (HR, 0.72; 95% CI, 0.45 1.14) was an independent risk factor for VTE recurrence.199 This was in contrast to the results from a study by Martinelli et al,197 which found that male sex was a risk factor for recurrence (HR, 9.66; 95% CI, 2.86 32.7). The higher risk in men could potentially be attributable to more correctable or transient risk factors in women (use of OCs, pregnancy, etc) or may simply reflect the fact that this study enrolled fewer patients (n=145) and may have been under- powered for sex-specific analysis.197 Recurrence tends to occur within the first year of the index CVT. Patients with severe thrombophilia (antithrombin, pro- tein C, or protein S deficiency; antiphospholipid antibodies; or combined abnormalities) have an increased risk of VTE The recurrent event is more often a VTE than a recurrent CVT, and provid- ers should have a high index of suspicion for other thrombotic complications (pulmonary embolism, deep venous thrombo- sis) in patients with a prior CVT. Sex Differences in Outcome Overall, patients with CVT have lower mortality and bet- ter functional outcomes than most stroke subtypes.191,192 Predictors for poor outcome include age, malignancy, central nervous system infection, and intracranial hemorrhage.191 The mortality rate was only 2.8% in the most recent large study, and in general, patients had good functional outcomes (89.1% of patients had a complete recovery, with a modified Rankin score of 0 1).199 A post hoc analysis of patients followed up in the ISCVT found that male sex was associated with poorer outcomes at follow-up (HR, 1.59; 95% CI, 1.01 2.52) and that significantly more women recovered completely after 6 This was driven in large part by improved outcomes in a subset of women who had an identified gender-specific risk factor (OC use, pregnancy, puerperium, and hormone replacement therapy), present in Women with other underlying risk factors for CVT unrelated to these sex-specific factors had similar outcomes as males. Logistic regression analysis confirmed that the absence of sex-specific risk factors was a strong and independent predictor of poor outcome in women with CVT (OR, 3.7; 95% CI, 1.9 7.4). Although there was a trend toward higher mortality in males, this was not significant.193 No association between sex and mortality rates was seen in the recent Nationwide Inpatient Sample of 3488 patients; however, the mortality was higher in that cohort (4.39%), which contained a surprisingly large number of patients with In a larger sample of 11400 records from the Nationwide Inpatient Sample data set, the most common condition associated with CVT was pregnancy/puerperium (seen in 24.6% of patients). These women had a low mor- tality rate (0.4%), but despite this, male sex was associated with decreased mortality (2.1%) on multivariate analysis The use of the Nationwide Inpatient Sample data is limited, because only inpatient data are recorded, results may be prone to coding errors, initial stroke severity is not recorded, and information on the presence of sex-specific risk factors is undoubtedly incomplete. Currently, data on sex specific functional out- comes are lacking. 