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. Pregnancy-Associated CVT Pregnancy and the puerperium period are times of increased risk for venous thrombosis for women, including CVT. The incidence of CVT during pregnancy and the puerperium is estimated at 1 in 2500 deliveries to 1 in 10000 deliveries in Western countries, with increased odds ranging from 30% to The greatest risk periods for CVT include the third trimester and the first 4 postpar- Up to 73% of CVTs in women occur during Cesarean delivery appears to be associated with a higher risk of CVT after adjustment for age, vascular risk factors, presence of infections, hospital type, and location (OR, 3.10; 95% CI, 2.26 4.24). Future Pregnancies and Recurrence Prior guidelines have summarized the studies examining the outcome and complication rates of pregnancy in women who These studies found that the risk of complications during future pregnancies was low. There was a high propor- tion of spontaneous abortion, consistent with emerging obser- On the basis of the available evidence, CVT is not a contraindication for future pregnancies; however, many of the patients followed up for recurrences were main- tained on preventive antithrombotic medication. Considering the additional risk that pregnancy confers to women with a history of CVT, prophylaxis with LMWH during future preg- nancies and the postpartum period may be beneficial.200 CVT: Summary and Gaps There is a striking sex difference in CVT incidence that is related to hormonal factors and pregnancy. Long-term oral anticoagulation is recommended for patients at high risk of recurrence because of thrombophilia, but overall recurrence rates are low, even with subsequent pregnancy. Long-term data on sex differences in recurrence and on functional out- comes are lacking. CVT: Recommendations 1. In patients with suspected CVT, routine blood stud- ies consisting of a complete blood count, chemis- try panel, prothrombin time, and activated partial thromboplastin time should be performed (Class I; Level of Evidence C). 2. Screening for potential prothrombotic conditions that may predispose a person to CVT (eg, use of con- traceptives, underlying inflammatory disease, infec- tious process) is recommended in the initial clinical assessment (Class I; Level of Evidence C). 3. Testing for prothrombotic conditions, including protein C, protein S, or antithrombin deficiency; antiphospholipid syndrome; prothrombin G20210A mutation; and factor V Leiden can be beneficial for the management of patients with CVT. Testing for protein C, protein S, and antithrombin deficiency is generally indicated 2 to 4 weeks after completion of anticoagulation. There is a very limited value of test- ing in the acute setting or in patients taking warfarin (Class IIa; Level of Evidence B). 4. In patients with provoked CVT (associated with a transient risk factor), vitamin K antagonists may be continued for 3 to 6 months, with a target interna- tional normalized ratio of 2.0 to 3.0 (Class IIb; Level of Evidence C). 5. In patients with unprovoked CVT, vitamin K antago- nists may be continued for 6 to 12 months, with a tar- get international normalized ratio of 2.0 to 3.0 (Class IIb; Level of Evidence C). 6. For patients with recurrent CVT, VTE after CVT, or first CVT with severe thrombophilia (ie, homo- zygous prothrombin G20210A; homozygous factor V Leiden; deficiencies of protein C, protein S, or antithrombin; combined thrombophilia defects; or antiphospholipid syndrome), indefinite anticoagula- tion may be considered, with a target international normalized ratio of 2.0 to 3.0 (Class IIb; Level of Evidence C). 7. For women with CVT during pregnancy, LMWH in full anticoagulant doses should be continued through- out pregnancy, and LMWH or vitamin K antagonist with a target international normalized ratio of 2.0 to 3.0 should be continued for 6 weeks post par- tum (for a total minimum duration of therapy of 6 months) (Class I; Level of Evidence C). 8. It is reasonable to advise women with a history of CVT that future pregnancy is not contraindicated. Further investigations regarding the underlying cause and a formal consultation with a hematologist or maternal fetal medicine specialist are reasonable (Class IIa; Level of Evidence B). 9. It is reasonable to treat acute CVT during pregnancy with full-dose LMWH rather than unfractionated heparin (Class IIa; Level of Evidence C). 10. For women with a history of CVT, prophylaxis with LMWH during future pregnancies and the post- partum period is reasonable (Class IIa; Level of Evidence C). Oral Contraceptives On the basis of a US Department of Health and Human Services survey conducted from 2006 to 2008, 10.7 million women aged 15 to 44 years in the United States used the pill form of contraception.214 As alternative forms of hormonal contraception such as the transdermal patch, vaginal ring, and intrauterine devices are increasingly used, the risk of stroke with these formulations also needs to be evaluated. The risk of stroke is very low in the age group of women who use contraception, but the incidence rises steeply from 3.4 per 100000 at ages 15 to 19 years to 64.4 per 100000 in women IS Risk The cumulative risk of stroke in women using OC pills has been summarized in 4 different meta-analyses, with many of the same individual cohort or case-control studies included in each. A meta-analysis of 16 case-control and cohort studies between 1960 and 1999 estimated a 2.75-fold increased odds (95% CI, 2.24 3.38) of stroke associated with any OC use.215 A later meta-analysis of 20 studies published between 1970 and 2000 that separated the studies by design (case-control versus cohort) found no increased risk of stroke in the cohort studies but an increased risk with OC use in case-control stud- Importantly, only 2 of the 4 cohort studies reported strokes by subtype, and risk was increased for IS but not hemorrhagic strokes.216 An additional meta-analysis of studies from 1980 to 2002 limited only to low-dose combined OCs (second and third generation only) also showed a comparable increased risk with OC use (OR, Lastly, a systematic review of progestogen-only OCs revealed no significant increased risk of stroke with this form of contraceptive.218 Two additional large cohort studies have been published since these meta-analyses. The first is the Women s Lifestyle and Health Cohort Study. This cohort comprised 49259 Swedish women who were followed up from 1991 to 1992 In the 285 cases of incident stroke that included ischemic, hemorrhagic, and unknown types, there was no significant association between OC use, duration, or type of OC. Reproductive factors, such as age at first birth, duration of breastfeeding, age at menarche, mean menstrual cycle days at age 30 years, and parity, were not associated with stroke after adjustment for cigarette smoking, hypertension, diabe- tes mellitus, alcohol, body mass index (BMI), education, and The second study estimated rates of IS only (excluding hemorrhagic stroke and transient ischemic attacks [TIAs]) in women aged 15 to 49 years and the RRs associated with use of various doses and formulations of hormonal contracep- tion in Denmark.144 In this population-based cohort of 1.6 million women, the crude incidence of IS in contraceptive users was 21.4 per 100000 person-years. The adjusted RR for ethinyl estradiol doses from 30 to 40 g ranged from RR for the 20- g dose ranged from 0.88 (0.22 3.53) to 1.53 (1.26 1.87). Progestin-only formulations were not associated with IS. The transdermal patch was associated with a nonsig- nificant increased risk in a small number of cases (RR, 3.15; 95% CI, 0.79 12.60), whereas the vaginal ring was associ- ated with a 2.49-fold increased risk (95% CI, 1.41 4.41). In addition, duration of use did not change the risk estimates.144 Although this study followed a very large number of women, it is limited because risk factors and stroke cases were based Bushnell et al Guidelines for Prevention of Stroke in Women 1559 on administrative data. The authors concluded that the RR of IS with intermediate-dose ethinyl estradiol and different pro- gestin types was lower than that reported in other studies and that the transdermal and vaginal ring routes of contraception conferred a similar risk as pills.144 Hemorrhagic Stroke Risk Data regarding risk with OC use have been less consistent for hemorrhagic stroke. The World Health Organization reported an overall slightly increased risk of hemorrhagic stroke (both intracerebral and subarachnoid) with OC use; however, this risk was present in developing countries but not in Europe.220 Also, European women >35 years of age were at increased risk of SAH, whereas women in developing nations were at increased risk of both ICH and SAH. Women with hyperten- sion and who smoked cigarettes were also at increased risk.221 In the Swedish Women s Lifestyle and Health Cohort, there was a significant decrease in hemorrhagic stroke among women who were parous (versus nulliparous; HR, 0.5; 95% CI, 0.2 0.8) and a nonsignificant increase in women who started OC use after 30 years of age (HR, 2.3; 95% CI, 0.8 6.8) and stopped using OCs based on doctor recommendation for medical reasons (adjusted HR, 2.1; 95% CI, 0.9 5.0).219 Hemorrhagic stroke in young women is relevant in Asia, where the risk of this type of stroke is disproportionately higher than in Europe and North America. A recent case- control study of Chinese women evaluated the association between the single-nucleotide polymorphisms rs10958409 GA/AA (located near SOX17, a transcription factor that modulates cardiovascular development and endothelial cell biology) and rs1333040 CT/TT (located near CDKN2A, CDKN2B, and ANRIL, which regulate p53 activity) and risk of ischemic and hemorrhagic stroke in OC users and nonus- Women with the rs10958409 GA/AA or rs1333040 CT/TT genotypes (associated with susceptibility of intracra- nial aneurysm) had an increased overall risk of stroke, which increased to an OR of 6.06 (95% CI, 1.69 21.81) and 14.48 (95% CI, 1.56 134.43), respectively, in OC users <50 years of age. The rs1333040 single-nucleotide polymorphism was a significant risk with OC use only for hemorrhagic stroke, This study is important because it demonstrates not only the gene-drug interaction but also some potential mecha- nisms for how OCs might lead to hemorrhage in specific at- Additional Risk Factors for Stroke in Women Using OCs Besides the well-established risk associated with older age, cigarette smoking, hypertension, and migraine head- the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study from the Netherlands showed that women who were obese (OR, 4.6; 95% CI, 2.4 8.9) and had a history of hypercholesterolemia (OR, 10.8; 95% CI, 2.3 49.9) were also at an increased risk from OC use compared with women with these risk factors who did not use OCs.224 The RATIO investigators have performed multiple anal- yses to identify prothrombotic mutations in women with stroke who were and were not OC users (Table 8). They found that women using OCs who were heterozygous for factor V Leiden (OR, 11.2; 95% CI, 4.2 29.0) and methyl tetrahydrofolate reductase or MTHFR 677TT mutation (OR, 5.4; 95% CI, 2.4 12.0) were at increased risk of IS. There may have been some synergism between OCs and these mutations, because the increased risk was not evident in nonusers with these mutations.225 In addition, this study also showed an association with a genetic variation of fac- In the assessment of acquired antiphospholipid antibodies, the presence of 2 glycoprotein-1 antibodies was associated with 2.3-fold increased odds of stroke (95% CI, 1.4 3.7), but there was no association with anticardiolipin or antiprothrombin antibodies. The prevalence of lupus anti- coagulant was 17% in women with IS, and the OR was very The OR increased to 201 (95% CI, 22.1 1828.0) in women who were also using OCs, although this was based on a very small number of outcomes. This is another example of the amplification of IS risk in a condition that is already associated with arterial thromboembolism and VTE.227 The RATIO investigators also assessed the association between OC use and endothelial dysfunction. They reported that an increase in von Willebrand factor levels and low ADAMTS13 levels were associated with increased odds of IS and MI in young women in the RATIO cohort, with a further Table 8. Odds of Ischemic Stroke With the Presence of Genetic or Acquired Prothrombotic Factors With and Without OC Use in the RATIO Cohort Adjusted OR (95% CI) Study Case/Control, n Biomarker (Genetic or Acquired) Non-OC Users OC Users Slooter et al225 Pruissen et al226 Urbanus et al227 175/628 Lupus anticoagulant (Ratios/c Andersson et al228 ADAMTS13 indicates a disintegrin and metalloproteinase with the thrombospondin type I repeat 13; CI, confidence interval; FVL, factor V Leiden mutation; FXIII, factor XIII; MTHFR, methylenetetrahydrofolate reductase; OC, oral contraceptive; OR, odds ratio; RATIO, Risk of Arterial Thrombosis in Relation to Oral Contraceptives; Ratios/c , normalized ratios for lupus anticoagulant screen and lupus anticoagulant confirm coagulation times; and vWF, von Willebrand factor. *Adjusted for age, residence area, and index year. Adjusted for age at index date, index year, area of residence, hypercholesterolemia, hypertension, diabetes mellitus, and smoking. Adjusted for age, year of event/index year, area of residence, hypercholesterolemia, hypertension, diabetes mellitus, and smoking. increase in the OR with OC use.228 The largest effect of OC use was in women with von Willebrand factor levels >90th percentile, for whom the OR for stroke was 1.6 (95% CI, 0.8 3.5) in nonusers and increased to 11.4 (95% CI, 5.2 25.3) in OC users. The results of this study demonstrate that OC use appears to further increase the risk of stroke in the set- ting of endothelial dysfunction. Additional research should be focused on the validation of von Willebrand factor and ADAMTS13 as risk factors for stroke with OC use in other racial/ethnic and geographic populations, as well as explora- tion of the value of measuring these biomarkers in women before initiation of OCs. Should women be screened for thrombophilia before hor- monal contraception is prescribed for them? This question has been addressed in a large systematic review and meta- analysis of the risk of VTE in the high-risk settings of OC use Although there are 15-fold odds of VTE in women with the factor V Leiden mutation who are using OCs (95% CI, 8.66 28.15), the absolute risk is low because of the low prevalence of this and other thrombophilias and VTE. For other hereditary thrombophilias, including prothrombin gene mutation, as well as protein C and antithrombin defi- ciencies, the odds of VTE increased in combination with OC use, but the odds of VTE stayed the same with protein S defi- IS and CVT are much less common than VTE,144 so the yield of routine screening would be even lower for these conditions. Selective screening based on prior personal or family history of VTE is proposed to be more cost-effective than universal screening in women who initiate OCs or desire to become pregnant.229 The cost- effectiveness analysis in this meta-analysis was designed for prevention of VTE, but adaptation to stroke screening in young women should also include obesity, diabetes mellitus, hyperlipidemia, hyperten- sion, and cigarette smoking. Another very important risk factor for stroke in young women is migraine aura, which has some evidence sup- porting a further increase in risk for women who also use OCs. An analysis of the Stroke Prevention in Young Women study, a population-based, case-control study of 386 women aged 15 to 49 years with incident stroke and 614 age- and ethnicity- matched control subjects, showed that women with probable migraine with visual aura were at 1.5-fold increased odds (95% CI, 1.1 2.0) of stroke compared with Women with this migraine type who also smoked cigarettes and used OCs had 7.0-fold higher odds (95% CI, 1.3 22.8) of stroke than women with probable migraine with visual aura who did not smoke or use OCs; however, women with probable migraine with visual aura who were OC users but nonsmokers did not have a signifi- cantly increased odds of stroke, which suggests the risk with both OC use and smoking in women with probable migraine with visual aura is additive.230 This was a biethnic cohort of black (representing a higher proportion of cases) and white women, whereas many of the large cohorts were limited to a northern European population. A consensus statement from both headache and stroke experts suggests screening for and treatment of all traditional stroke risk factors in women with migraine but does not state that low-dose OC use is Hormonal Contraception and BP The impact of OC use on BP, an important stroke risk fac- tor, and other hemodynamic parameters is somewhat contro- versial. A study of BP and hemodynamic measurements in young women (mean age 20 years) in the United Kingdom (ENIGMA Study) showed that women using OCs had a mar- ginal but significantly higher systolic BP (mean 112 12 ver- sus 110 11 mmHg in nonusers; P=0.04) and an increased arterial pulse wave velocity, a measure of aortic stiffness232 ; however, in the multivariate model, mean arterial pressure, age, and heart rate were associated with arterial pulse wave velocity but not OC use.232 Several systematic reviews cover the topic of OC use and hypertension in women. Summarizing the data through 2005, one review estimated the odds of IS for women with hyperten- sion using OCs were 1.73 (95% CI, 0.83 3.60) and concluded that there was no synergistic increase in risk because the odds of stroke in normotensive women using OCs were similar.233 A systematic review of studies that examined BP after ini- tiation of OCs demonstrated mixed results from studies of follow-up BPs. Generally, the mean BPs were most often well below 140/90 mmHg. Importantly, only a very small percent- age ( 2%) of women developed hypertension.234 A systematic review of studies that collected outcomes based on measure- ment of BP before initiation of OCs235 found 2 case-control studies that met criteria for inclusion.220,236 Both studies dem- onstrated a higher OR of IS in women without versus with BP measurement before initiation of OCs, although the CIs A separate case-control study showed no difference in hemorrhagic stroke based on preinitiation BP Taken together, these limited data suggest that OCs appear to marginally increase BP, albeit infrequently leading to hypertension, and that measurement of BP before OC initiation may be an important preventive measure to detect women at risk of stroke. OCs: Summary and Gaps The relative increase in stroke risk with low-dose OCs is small, approximately 1.4 to 2.0 times that of non-OC users.144 On the basis of the longitudinal data from the Danish popu- lation-based study, among 10000 women who use the 20- g dose of desogestrel with ethinyl estradiol for 1 year, 2 women will have arterial thrombosis and 6.8 will have venous throm- The risk of stroke with OC use also appears to be lower than the risk associated with pregnancy ( 3 per 10000 Despite the overall low risk of stroke from hormonal con- traception, certain subgroups of women, particularly those who are older, smoke cigarettes, or have hypertension, dia- betes mellitus, obesity, hypercholesterolemia, or prothrom- botic mutations, may be at higher risk for stroke. Estimates are based primarily on case-control studies and a smaller number of cohort studies primarily from northern European countries, which limits generalizability to other populations. Further research is needed to better understand the subgroups of women who may be at risk for hemorrhagic stroke associ- ated with OCs based on age, race/ethnicity, genetic makeup, and parity. In addition, research assessing the value of specific biomarkers of endothelial function, such as von Willebrand Bushnell et al Guidelines for Prevention of Stroke in Women 1561 factor and ADAMTS13, before and during OC use, as well as after an arterial thrombotic event, is warranted. OCs: Recommendations 1. OCs may be harmful in women with additional risk factors (eg, cigarette smoking, prior thromboembolic events) (Class III; Level of Evidence B).224,225 2. Among OC users, aggressive therapy of stroke risk factors may be reasonable (Class IIb; Level of 3. Routine screening for prothrombotic mutations before initiation of hormonal contraception is not useful (Class III; Level of Evidence A).229 4. Measurement of BP before initiation of hormonal contraception is recommended (Class I; Level of Menopause and Postmenopausal HT Menopause Onset Exposure to endogenous estrogen has been hypothesized to be protective for stroke in premenopausal women; however, given logistical difficulties in collecting longitudinal data on endogenous hormones and the large sample sizes that would be required to study stroke in younger women, no study has investigated the relationship between endogenous hor- mones and stroke as women transition through menopause. The association between onset of menopause and stroke risk has been the subject of 2 recent reviews, one focusing on the association of age at menopause and stroke risk and the other focusing on the association of premature or early meno- pause and stroke risk.237,238 In the first review by Lisabeth and the authors concluded that the few studies that considered the association between age at menopause and incident stroke had inconsistent findings. The findings of these studies were summarized briefly. Hu et al239 found that age at natural menopause was not associated with risk of total stroke, IS, or hemorrhagic stroke among 35616 women in the Nurse s Health Study who reported no use of HT. In a cohort study of 5731 postmenopausal Korean women who did not use HT, no association was found between age at natural menopause and risk of total stroke, IS or hemorrhagic Lisabeth et al,241 using data from the Framingham Heart Study (n=1430), found that women with natural meno- pause before age 42 years had twice the IS risk (RR, 2.03; 95% CI, 1.16 3.56) as women who had natural menopause at 42 years of age after adjustment for age, risk factors, and postmenopausal estrogen use. Results from a Japanese cohort also suggested that women who underwent meno- pause before 40 years of age were more likely to have an IS than those with menopause between 50 and 54 years of age after adjustment for age and risk factors (RR, 2.57; 95% CI, 1.20 5.49); however, findings appeared to be largely driven by women with surgical menopause.242 A case-control study conducted in Spain found no association between menopause at <53 years of age and the odds of noncardioembolic stroke after accounting for age and risk factors.243 In the review by Rocca et al,238 7 observational cohort stud- ies were summarized to determine whether early or premature menopause is associated with stroke. The findings from 3 of the studies not yet discussed previously are briefly summarized.244 Using data from the Nurse s Health Study, Parker et al245 found that after multivariable adjustment, women with hysterectomy with bilateral oophorectomy had a slightly elevated risk of total stroke compared with women with hysterectomy with ovarian conservation (HR, 1.14; 95% CI, 0.98 1.33), and this associa- tion did not reach significance. In further analysis of these data limited to women with hysterectomy who had never used estro- gen therapy, the authors found a larger statistically significant association between oophorectomy and total stroke (HR, 1.85; 95% CI, 1.09 3.16) in all women and in women with hyster- ectomy before age 50 years (HR, 2.19; 95% CI, 1.16 4.14). A more recent analysis of a Swedish cohort found that women who underwent an oophorectomy before age 50 years had an increased risk of total stroke (HR, 1.47; 95% CI, 1.16 1.87) compared with women with no hysterectomy and no oopho- Finally, in a recent analysis of data from the WHI focused on women with a history of hysterectomy (without capture of age before natural menopause), no association was found for oophorectomy versus ovarian conservation and risk of total stroke in all women (HR, 1.04; 95% CI, 0.87 1.24) or those women without a history of hormone use (HR, 1.31; 95% CI, 0.92 1.87) after multivariable adjustment.247 Menopause Onset: Summary and Gaps Results of existing studies of the association between age at menopause or premature or early menopause, whether natural or surgical, and stroke risk appear to suggest increased risk of stroke with earlier onset of menopause, although the evi- dence is not entirely consistent. Few data on the association of other surrogate markers for endogenous hormone exposures, such as lifetime estrogen exposure, duration of ovarian activ- ity, or time since menopause, and stroke risk exist. Additional studies are needed to determine the influence of the onset of menopause on stroke risk. Studies should aim to determine whether the association between menopause onset and stroke is limited to ischemic events and whether and how the type of menopause (natural or surgical) may impact this association. Postmenopausal HT Early observational evidence suggested a potential benefit of HT on cerebrovascular disease248 ; however, even as early as 2002, evidence was emerging that HT may have detrimental effects. A review of 29 observational studies found no clear evidence that HT use benefited stroke risk in postmenopausal Subsequent randomized clinical trials for both the primary and secondary prevention of stroke in women ran- domized to HT have been universally negative (Table 9). Two large clinical trials examined women with established vascular disease: the Heart and Estrogen/Progestin Replacement Study (HERS) and Women s Estrogen for Stroke Trial (WEST).250,251 Stroke events (including any stroke and IS) were similar for women allocated to an estrogen or to placebo. Findings from the WHI HT trials were reported soon after those from HERS and WEST. The multicenter WHI random- ized women into groups according to use of conjugated equine estrogen (CEE) and medroxyprogesterone or CEE alone, based on hysterectomy status.253 256 These women, unlike those in previous randomized trials, did not have documented vascular disease (no self-reported history of acute MI, stroke, or TIA in the previous 6 months); however, they were considerably older than women in previous observational trials, with a mean age of 63 years. Additional analyses of the WHI focused on specific subgroups of women to determine those at particularly high risk; the subgroups were outlined in previousAHA guidelines.19 The risk of stroke with CEE was limited to IS (HR, 1.55; 95% CI, 1.19 2.01) and not hemorrhagic stroke (HR, 0.64; 95% CI, 0.35 1.18). There was no difference based on stroke pathogenic subtype, severity, or mortality. Women with no prior history of CVD were at higher risk (HR, 1.73; 95% CI, 1.28 2.33) than women with a prior history (HR, 1.01; 95% CI, 0.58 1.75). Women using HT who were 50 to 59 years of age had a lower of age (HR, 1.72; 95% CI, 1.17 2.54) or those 70 to 79 years of age (HR, 1.52; 95% CI, 1.02 2.29) compared with nonusers. These risk estimates did not vary by race or other baseline risk factors, including aspirin or statin use or BP.19 There is also little compelling evidence that HT is effective at preventing deterioration of cognitive function in postmeno- pausal women. The Women s Health Initiative Memory Study (WHIMS), a subgroup of women enrolled in the WHI, found that for women 65 years of age, HT did not reduce the inci- dence of either dementia or mild cognitive impairment.260,261 HT had an adverse effect on global cognitive function,262,263 which was greater among women with lower cognitive func- tion at initiation of treatment. Subsequent magnetic resonance imaging studies in a subset of these women found greater brain but not a significantly higher volume of subclini- cal cerebrovascular lesions in treated women.265 The adverse effects were most evident in women experiencing cognitive deficits before initiation of HT. Similar results have been reported in randomized clinical trials for selective estrogen receptor modulators and other hormonally active compounds (including raloxifene266,267 and a commonly used therapy in Europe with both estrogenic and androgenic properties). Raloxifene (60 mg ver- sus placebo) had no effect on the risk of nonfatal stroke (HR, 1.10; 95% CI, 0.92 1.32) but increased the risk of fatal strokes (HR, 1.49; 95% CI, 1.00 1.24; P=0.05). There has been an increasing recognition that the timing of HT initiation may play a critical role in the overall effect of An analysis of the WHI subjects was performed to test this hypothesis, and interestingly, women <10 years from menopause had no increased risk of coronary heart disease events with any CEE (alone or CEE plus medroxyproges- years post menopause had an elevated risk (HR, 1.28; 95% Table 9. Association Between HT Use and Stroke Risk in Randomized Controlled Trials of Perimenopausal and Postmenopausal Women Trial Total No. Average Age, y HT Regimen Vascular Disease Follow-up Any Stroke, HR mg of MPA (n=1380) vs vs placebo Yes (CVD); nondisabling ischemic stroke or TIA within preceding 90 d (CVD) mg of MPA (n=1380) vs Yes (CAD) 6.8 y (2.7-y unblinded follow- up to HERS) Open HT, 494; open control, 494; blind HT, 404; blind Open HT, 58.6; open control, 58.9; blind HT, 58.5; blind placebo, 59 CEE 0.625 mg/d plus 2.5 mg/d MPA or CEE 0.625 mg/d plus 5 mg/d MPA, if <3 y had passed since menopause at recruitment Randomly allocated (open label, n=1006) to HT (n=502) or no 49.7 Intact uterus: 2 mg of synthetic 17 -estradiol for plus 1 mg of norethisterone acetate for 10 d, and 1 mg of 17 -estradiol for 6 d. Prior hysterectomy: 17 - estradiol 2 mg/d. Enrolled within 24 mo of last menses. No* 11 y (randomized treatment phase) and continued observational follow-up (16 y) CAD indicates coronary artery disease; CEE, conjugated equine estrogen; CI, confidence interval; CVD, cardiovascular disease; DOPS, Danish Osteoporosis Prevention Study; HERS, Heart and Estrogen/Progestin Replacement Study; HR, hazard ratio; HT, hormone therapy; MPA, medroxyprogesterone acetate; WEST, Women s Estrogen for Stroke Trial; and WHI, Women s Health Initiative trial for women with a uterus (CEE+MPA) or without a uterus (CEE). *Self-reported as no history of acute myocardial infarction, stroke, or transient ischemic attack in the previous 6 months.259 Bushnell et al Guidelines for Prevention of Stroke in Women 1563 CI, 1.03 1.58; P for trend=0.02). There was, however, no trend for increased stroke based on years since menopause.267 The Estonian trial of HT, a study of women 50 to 64 years of age, also confirmed the findings of the WHI, with a trend toward an increase in cerebrovascular events in women taking (Table 9). The Kronos Early Estrogen Prevention Study (KEEPS) is an ongoing trial of women 42 to 58 years of age who are within 36 months of their final menstrual period and who were randomized to estrogen replacement in low doses (0.45 mg of CEE), transdermal formulation (50 g/wk), or combined with cyclic oral, micronized progesterone 200 mg for 12 days each month.271 The primary outcomes are progres- sion of subclinical atherosclerosis as measured by carotid intima-media thickness and coronary calcium scores, rather than stroke; however, this study will directly assess HT initi- ated soon after menopause. This study has completed enroll- ment, and initial results were presented at the meeting of the North American Menopause Society on October 3, 2012 (http://www.keepstudy.org); however, until the full data are available, no statements can be made regarding the safety of HT in this subset of women. The effective duration of use for benefit is currently unknown. Prevention Study (DOPS),258 specifically examined healthy women aged 45 to 58 years who were recently postmeno- pausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle-stimulating hormone values (n=1006). Women had a mean time since menopause of 0.6 years, with last menstrual bleeding 3 to 24 months before study entry. Stroke was a designated (secondary) end point. A total of 502 women were randomly allocated to receive HT and 504 to receive no treatment (control; Table 9). Importantly, this study had an open-label design, and the patients in the control arm did not receive placebo, which could have influ- enced compliance in the HT arm. After 11 years, the trial was stopped secondary to concerns of potentially harmful effects of HT that had been seen in other trials, such as the WHI. Women were followed up as an observational cohort for an additional 5 years. There was no increase in stroke, VTE, or breast cancer in treated women. HT initiated in these recently postmenopausal, younger women significantly reduced the risk of the combined end point of mortality, MI, or heart fail- ure. Stroke rates did not differ between groups.258 Transdermal estradiol may represent a safer alterna- tive than oral estrogens, because treatment does not appear to increase the risk of VTE and stroke and may reduce the risk of MI compared with nonusers. In a nested case-control study examining patients in general practices in the United Kingdom that included 15710 cases of stroke and almost 60000 randomly selected, matched control subjects from women aged 50 to79 years, transdermal estradiol was not associated with an increased risk of stroke, whereas oral estro- gens significantly increased stroke risk.272 Importantly, dose effects, even from transdermal use, were seen in this popu- lation, because low-dose products that contained 50 g of estrogen did not increase stroke risk (rate ratio, 0.81; 95% CI, 0.62 1.05) compared with no use, but high-dose patches that contained >50 g did increase risk (rate ratio, 1.89; 95% CI, 1.15 3.11). Until randomized blinded studies are performed that demonstrate the safety of transdermal therapy, this treat- ment is not recommended for stroke prevention on the basis of available evidence, although this treatment is approved for relief of menopausal symptoms. Postmenopausal HT: Summary and Gaps An increased risk of stroke is associated with the tested forms of HT, which include CEE/medroxyprogesterone in standard formulations. A recent analysis and review of 9 random- ized controlled trials,273 a review of HT trials by Henderson and a Cochrane review that included 23 stud- all reached the conclusion that HT, in the formulations prescribed in prior studies, does not reduce stroke risk and may increase the risk of stroke. There are insufficient data to assess the risk of long-term HT use initiated in perimeno- pausal women or postmenopausal women <50 years of age; however, the data on this subject are often conflicting, and information regarding risk with newer HT regimens contin- ues to emerge. There is no benefit of raloxifene or tamoxifen for stroke prevention, and raloxifene may increase the risk of fatal stroke. Tibolone is also associated with an increased risk of stroke. Prospective randomized trials of alternative forms of HT are ongoing, although the primary outcomes are an intermediate measurement of subclinical atherosclerosis and not stroke. The use of HT for other indications needs to be informed by the risk estimate for vascular outcomes provided by the clinical trials that have been reviewed. HT is associated with a small to moderate improvement in sex- ual function, particularly in pain, when used in women with menopausal symptoms or in early postmenopause (within 5 years of amenorrhea), but this treatment cannot be recom- mended currently for stroke prevention in unselected post- Limitations of prior trials included low adherence, high attrition, inadequate power to detect risks for low-incidence outcomes such as stroke, and evalu- ation of few regimens. Further research is needed to better understand the subgroups of women who may be at risk for stroke associated with HT and to optimize the timing and route of administration, as well as the dose and type of hor- mone used. Much less is known about the use of HT and the risk of either ICH or SAH. Postmenopausal HT: Recommendations 1. HT (CEE with or without medroxyprogesterone) should not be used for primary or secondary preven- tion of stroke in postmenopausal women (Class III; Level of Evidence A). 2. Selective estrogen receptor modulators, such as ral- oxifene, tamoxifen, or tibolone, should not be used for primary prevention of stroke (Class III; Level of Evidence A). Risk Factors More Common in Women Than Men Migraine With Aura The prevalence of migraine in the population is 18.5%, and for migraine with aura, it is 4.4%.277 Women are 4 times more likely to have migraines than men.277 Very rarely are migraines associated with stroke, however. Migraine with aura is defined as a typical migraine headache plus the presence of homony- mous visual disturbance, unilateral paresthesias or numbness, unilateral weakness, or aphasia or unclassifiable speech dif- ficulty that might typically precede the migraine headache.278 This type of migraine is associated with double the risk for IS based on meta-analyses of diverse cohorts of patients. The most recently published meta-analysis reported a increase in IS in patients with migraine with aura (OR, 2.51; similar to a previous analysis that showed an OR of 2.16 (95% CI, 1.53 3.03).280 The associa- tion between migraine aura and IS is higher in women than men. In women with migraine with aura, the risk increases even more in those using oral contraceptives (OR, 7.02; 95% CI, 1.51 32.68) and in cigarette smokers (OR, 9.03; 95% CI, The absolute risk of migraine-associated stroke is relatively low. On the basis of data from the Women s Health Study (WHS), migraine with aura accounted for 4 additional IS cases per 10000 women per year when migraine with aura was the assumed underlying cause of stroke.281 The risk is higher with increasing frequency of migraine282 and if the aura does not include nausea and vomiting.283 Data from the WHS suggest that migraine with aura is associated with increased risk of TIA (RR, 1.56; 95% CI, 1.03 2.36) and nondisabling stroke (RR, 2.33; 95% CI, 1.37 3.97) compared with women with no history of migraine284 and that the presence of migraine with aura does not modify the beneficial effects of aspirin.285 Therefore, migraine aura appears to be associated with a bet- ter prognosis because of the link to milder strokes and TIAs than with non migraine-associated strokes in the WHS. Migraines with aura have also been associated with a risk of hemorrhagic stroke in the WHS, but this association was stronger in the subset of women with fatal hemorrhagic stroke and in women <55 years of age.286 In pregnant women with an International Classification of Diseases, 9th Revision, hospi- tal code for migraine, there was a large association with hem- orrhagic stroke (OR, 9.1; 95% CI, 3.0 27.8); however, in the pregnant population, the risk of vascular diseases was closely associated with a concomitant diagnosis of preeclampsia/ Interestingly, there is an emerging literature on the asso- ciation between migraines and preeclampsia.288 290 The most recent analysis of the United Kingdom Obstetric Surveillance System found 30 cases of antenatal stroke, for an estimated incidence of 1.5 cases per 100000 women who delivered babies (95% CI, 1.0 2.1). Factors associated with increased risk of antenatal stroke were history of migraine (adjusted OR, 8.5; 95% CI, 1.5 62.1), gestational diabetes (adjusted OR, 26.8; 95% CI, 3.2 ), and preeclampsia or eclampsia Migraine With Aura: Summary and Gaps Migraine with aura (but not without aura) is associated with risk for IS and hemorrhagic stroke in women, especially those <55 years of age, although the absolute risk is low, and these women appear to have a good poststroke prognosis. Not only do the majority of studies with both men and women support this as a predominantly female issue, but the largest cohorts that have been studied are limited to women. There are not sufficient data to recommend specific approaches to treat migraine with the intention of lowering risk of stroke. Migraine treatment with triptans is contraindicated in patients with a history of cerebrovascular disease or coronary heart as explicitly stated in guidelines from the American Academy of Neurology. As for the risk of treatment with trip- tans in women with migraine with aura, there are no data to guide this decision other than the observational data related to higher risk of stroke among those who smoke cigarettes or use OCs (see Oral Contraceptives ). Given the number of stud- ies that consistently show a higher risk of stroke in younger women with migraine with aura, it may be reasonable to include this in a woman-specific risk profile. The general rec- ommendations for men and women with migraine with aura and stroke are as stated in the primary prevention guideline.19 Migraine With Aura: Recommendations 1. Because there is an association between higher migraine frequency and stroke risk, treatments to reduce migraine frequency might be reasonable, although evidence is lacking that this treatment reduces the risk of first stroke (Class IIb; Level of Evidence C). 2. Because of the increased stroke risk seen in women with migraine headaches with aura and smoking, it is reasonable to strongly recommend smoking cessation in women with migraine headaches with aura (Class IIa; Level of Evidence B). Obesity, Metabolic Syndrome, and Lifestyle Factors By the year 2030, an estimated 86% of Americans will be overweight or obese.292 Obesity affects a disproportionate number of women in the United States; in 2007 to 2008, the age-adjusted prevalence of obesity in the United States was 35.2% in women compared with 32.0% in men.293 Non- Hispanic black women have the highest prevalence of obesity The distribution of obesity has important cardiovascular coined the term android obe- sity to describe the high-risk form of obesity, at that time more frequently found in men, in which the body fat is concentrated in the abdominal area; he introduced the term gynoid obesity to describe the low-risk lower-body adiposity, more frequently found in premenopausal women. Abdominal obesity (defined as waist circumference >88 cm in women and >102 cm in men), however, is now far more prevalent in women than men, and android obesity is a misnomer. In fact, data from NHANES in 2007 to 2008 revealed that among adults 20 years old, age-adjusted prevalence of abdominal obesity was 61.8% in women compared with 43.7% in men.293 In addi- tion, premenopausal women are increasingly likely to have abdominal obesity; a recent study of women aged 35 to 54 years in the United States revealed that from 1988 1994 until 1999 2004, the prevalence of abdominal obesity increased The escalating obesity epidemic may counter the tremendous advances that have been made Bushnell et al Guidelines for Prevention of Stroke in Women 1565 in smoking cessation and hypertension and dyslipidemia awareness and control in the United States. Understanding the effects of obesity and abdominal adiposity on stroke risk, and the potentially differential impact of these conditions on women compared with men, may elucidate avenues for reduc- ing the incidence and morbidity of stroke. Association Between Obesity and Abdominal Adiposity and Stroke Risk and Outcomes Obesity is an independent risk factor for stroke. Studies have revealed a graded association between BMI and stroke risk; the risk of total stroke or IS rises linearly with increasing BMI and in a stepwise fashion for higher BMI categories.297 299 Obesity affects stroke risk in both men and women, even after adjustment for factors such as age, physical activity, smok- ing, alcohol consumption, and comorbid conditions such as hypertension and diabetes mellitus297 307 (Table 10). There is no clear evidence that obesity has a stronger impact on stroke risk in women than in men (Table 10). Numerous epidemiological and metabolic studies have shown that abdominal obesity has a stronger correlation with insulin resistance, atherogenic dyslipidemia, diabetes mellitus, and CVD than other distributions of body fat.309 Abdominal obesity can be measured by use of waist circum- ference, waist-to-hip ratio, and waist-to-stature ratio. As with BMI, there is a graded association between abdominal obesity and stroke risk. A study of 67000 women found a 2% relative increase in total stroke risk with each 1-unit increase in waist Other studies have shown similar associa- tions between abdominal obesity and stroke risk.304,307,310,311 Although many studies have shown that abdominal obesity is associated with stroke in women, even after adjustment for age, lifestyle habits, and medical comorbidities,301,303,307,310 312 some studies have shown that the association is no longer sig- nificant in multivariable models300,313,314 (Table 11). Studies of sex differences in the effect of abdominal obesity on stroke risk have had conflicting results (Table 11). The impact of obesity on poststroke outcomes remains unclear. One retrospective analysis of cross-sectional and pro- spective data from a nationally representative survey of the US adult population followed up from survey participation in 1988 to 1994 through mortality assessment in 2000 revealed that the overall risk for all-cause mortality among stroke sur- vivors increased per 1 kg/m2 of higher BMI (P=0.030), but an interaction between age and BMI (P=0.009) revealed that the association of higher BMI with mortality risk was strongest in younger individuals and declined linearly with On the other hand, a post hoc analysis of the Telemedical Project for Integrative Stroke Care (TEMPiS) revealed that mortality risk was lower in overweight patients (HR, 0.69; 95% CI, 0.56 0.86) and lowest in obese (HR, 0.50; 0.66) patients compared with those with normal BMI.316 It is unclear whether obesity has a differential impact on stroke outcomes in women compared with men.317 Metabolic Syndrome Metabolic syndrome, a combination of cardiometabolic risk factors that tend to cluster together (insulin resistance, abdominal adiposity, dyslipidemia, and hypertension) affects approximately one third of the US adult population.318 Analysis of data from NHANES 2003 to 2006 revealed that 36.1% of men and 32.4% of women in the United States had metabolic Numerous studies have shown an association between metabolic syndrome and stroke in both men and women303,310,311,314,319 326 (Table 12). The exact mecha- nism whereby metabolic syndrome affects cardiovascular risk is unknown; it is thought that components of the syndrome synergistically increase vascular risk through mechanisms that include insulin resistance, hypercoagulability, endothelial dysfunction, and inflammation. Studies suggest that meta- bolic syndrome confers a higher stroke risk on women than and metabolic syndrome accounts for a larger percentage of stroke events in women than in men (30% ver- The mechanisms for this difference are not completely understood. Pathophysiologic Mechanisms of Obesity, Abdominal Adiposity, and Metabolic Syndrome That Affect Stroke Risk The pathophysiological mechanisms by which general obesity increases stroke risk remain unclear. One proposed mecha- nism is that obesity is associated with a prothrombotic and BMI is directly associated with fibrinogen, factor VII, plasminogen activator inhibitor, and tis- sue-type plasminogen activator antigen levels in both men and Similar associations are present between abdomi- nal obesity and hemostatic factors. These associations persist after controlling for age, smoking, total and high- density lipo- protein cholesterol, triglycerides, glucose level, BP, and use of In addition, higher levels of acute phase reactants such as C-reactive protein may decrease endothelial cell production of nitric oxide, which may in turn instigate a cascade of events leading to vasoconstriction, leu- kocyte adherence, platelet activation, oxidation, and thrombo- Attenuation of the protective effect of high-density attributable to general obesity may also play a role. The biological pathways by which abdomi- nal adiposity increases stroke risk are also not yet understood, but platelet activation, inflammation, endothelial dysfunction, or an overactive endocannabinoid system335 may all serve key roles in the process. In addition, increased very low-density lipoprotein production caused by the high lipolytic activity of abdominal adipose tissue304,312 may increase stroke risk. Lifestyle Lifestyle factors such as a healthy diet,336 338 physical activ- abstinence from smoking,344 346 moderate alcohol and maintenance of a healthy BMI299,308 reduce the risk of CVD and mortality. Adherence to a combination of healthy lifestyle practices has been shown to decrease stroke incidence in women327 and improve outcomes after stroke in both men and women.349 All-cause mortality after stroke decreases with higher numbers of healthy behaviors (1 3 factors versus none: HR, 0.12 [95% CI, 0.03 0.47]; 4 5 factors versus none: are observed for cardiovascular mortality after stroke (4 5 fac- tors versus none: HR, 0.08 [95% CI, 0.01 0.66]; 1 3 factors ver- A multitude of randomized controlled trials of lifestyle inter- ventions targeting individuals at high risk for diabetes mel- litus and CVD have been conducted.350 362 Although many of the studies have proved effective in improving lifestyle habits and vascular risk factors in the short term, it has proved more challenging to maintain such changes and reduce cardiovascu- lar events. 