each year there are nearly 795,000 individuals who suffer from a new or recurrent stroke ; 10% of these are cases of intracerebral hemorrhage .
stroke is the 4th leading cause of mortality according to the latest cdc statistics . among all strokes ,
the case fatality rate for hemorrhagic strokes ( 37 - 38% mortality ) is the highest , and most survivors have poor functional outcomes .
female gender has been recognized as an important risk factor for stroke , with nhanes reporting that women between 45 and 54 years of age were almost twice as likely to suffer from a stroke than males .
a greater decline was also seen in stroke - related deaths among males as compared to females between 1980 and 2005 .
a recent review concluded that although the incidence of stroke was higher in males , females were more severely ill .
internationally , it has been reported that the stroke burden is higher in females , because of a higher prestroke and poststroke disability [ 58 ] .
this difference in disability after stroke between men and women is seen not only physically but also psychologically .
no published literature , however , answers the question of gender differences specifically in acute hemorrhagic stroke . since acute nontraumatic intracerebral hemorrhage ( ich ) contributes greatly to the poststroke morbidity and mortality burden on the health system , we sought to determine gender differences in an exclusive cohort of first time hemorrhagic stroke patients presenting to our emergency department .
this was an institutional review board approved , consecutive cohort study , conducted in the emergency department ( ed ) of our academic institute with an annual census of 75,000 visits .
all adult patients who presented with a diagnosis of spontaneous nontraumatic intracerebral hemorrhage ( ich ) , from january 2006 to december 2008 , were eligible for inclusion in the study cohort .
all pediatric patients , patients with subdural , extradural , or subarachnoid hemorrhage , and patients with a recurrence of intracerebral hemorrhage were excluded from the final cohort .
written consent was obtained for use of medical records from patients at admission to the hospital .
the medical records of these patients were reviewed by two independent abstractors for demographics , arrival characteristics , vitals , symptoms , signs , laboratory parameters on presentation , past history of risk factors , treatment , and discharge status .
the stroke severity was obtained in the form of nihss scores , calculated on the basis of the examination notes of the neurologist on call [ 10 , 11 ] .
the clinical interpretation program of the ge / marquette mac-8 digital ecg chart determined the intervals on the ecg .
the functional outcome at discharge was noted as the modified rankin score ( mrs ) at discharge .
this was stratified into two categories  good outcome ( mrs < 3 ) and bad outcome ( mrs  3 ) .
the ct scans of these patients were studied to calculate the volume of hemorrhage using the abc/2 method . the topographic area affected by the hemorrhage and the intraventricular extension of the hemorrhage were also noted .
a close network of primary care and a single unified hospital system , in our county , enabled us to collect data on mortality outcomes on all patients in the study .
abstractors met periodically to discuss possible ambivalent data and to ensure uniformity in data collection .
all associations between nominal variables were analyzed using the pearson chi - square test or fisher 's test wherever applicable .
multivariate logistic regression was performed to adjust for potential confounding factors to evaluate the association between gender and stroke outcome .
survival analysis based on time to death for each of the genders was also performed .
of the 261 adult patients with ich who presented to the ed , 13 declined to consent for research ; for 3 patients , this was a recurrence of ich , and hence these patients were excluded from the cohort . in the final cohort of 245 patients , there were 125 ( 51.0% ) females ( f ) and 120 ( 49.0% ) males ( m ) .
the median age for the females was 77 years ( interquartile range iqr 65 to 83 years ) , which was significantly higher than the median age for males ( median age 69 years , iqr 59 to 80 years ; p = 0.007 ) .
only 12.6% of the patients were < 50 years of age ( 12.5% females , 12.8% males ) . from the cohort , 57.6% females and 56.7% males were referred to our academic ed , from elsewhere ( p = 0.883 ) .
there was also no difference ( p = 0.46 ) in the proportion of females and males who were brought in by ambulances ( 59.2% f , 51.7% m ) , helicopters ( 28.8% f , 32.5%  m ) , or private vehicles ( 12% f , 15.8% m ) .
on analyzing symptoms on presentation to the ed 37.6% females presented with headache versus 29.2% males , 28.8% females presented with vomiting / nausea versus 12.5% males , 7.2% females presented with syncope versus 5.8% males , and 46.8% females presented with weakness versus 51.3% males .
further analysis revealed that females had 2.8 times higher odds of presenting with vomiting / nausea than males ( 95%  ci 1.45 to 5.51 ; p = 0.002 ) .
about 58.9% females and 34.4% males presented with left - sided weakness , and 37.5% females and 62.5% males presented with right - sided weakness ( p = 0.002 ) , implying that there might be a significant difference in the area of affection , which we analyzed on ct scans .
we also looked at the glasgow coma scale ( gcs ) evaluation of patients in our cohort .
there was no difference between the proportion of females ( 26.4% ) and males ( 25% ) who arrived comatose ( p = 0.802 ) .
there was also no difference in the stroke severity on arrival as defined by nihss between females ( median nihss 7 , iqr 2 to 23 ) and males ( median nihss 8 , iqr 2 to 19 ; p = 0.76 ) .
on assessing the ct scans on arrival of these patients , we found that there was no significant difference between the volumes of hemorrhage between females ( median volume 30  cc , iqr 5.2 to 135.7  cc ) and males ( median volume 22.9  cc , iqr 6.5 to 85.8  cc ; p = 0.415 ) .
there was also no difference ( p = 0.886 ) in the prevalence of intraventricular extension of hemorrhage between females ( 47.6% ) and males ( 46.7% ) .
on analyzing the topographic distribution of the hemorrhage in the brain , we found that 60% of the females had a right - sided hemorrhage as compared to 41% males .
males were more likely to have a left - sided hemorrhage ( 56% ) as compared to females ( 38% ) .
the odds of having a cerebellar hemorrhage were 4.2 times higher in females than males ( 95% ci 1.63 to 10.75 ; p = 0.002 ) .
this association remained significant even after controlling for nausea / vomiting as the latter has been reported to be associated with higher incidence of cerebellar hemorrhage ( odds ratio 3.42 , 95%  ci 1.16 to 10.04 , p = 0.02 ) .
we compared history of ischemic stroke , coronary artery disease , hypertension , diabetes mellitus , dyslipidemia , atrial fibrillation , cancer , coagulation abnormalities , seizures , head trauma , smoking , and cessation of smoking between the genders .
females had 0.51 times odds for having coronary artery disease ( p = 0.024 ) as compared to males . also , only 30.4% females from the cohort had a past history of smoking as compared to 61.7% males ( odds 0.27 , 95%  ci 0.16 to 0.46 ; p < 0.0001 ) .
there was , however , no difference between the proportions of females ( 25.6% ) and males ( 36.5% ) who stopped smoking ( p = 0.243 )
. associations between past history of other diseases and gender did not reach statistical significance .
on analyzing past medication use , there was also no statistically significant difference between the class of antihypertensive medication , anticoagulants , antiplatelets , steroids , and statins ( all of which are known to influence ich ) used by males and females .
there was no difference in the skin temperature ( p = 0.467 ) , heart rate ( p = 0.725 ) , and systolic blood pressure ( p = 0.271 ) recorded on arrival to the ed between males and females .
the women , however , did have a lower diastolic blood pressure on arrival ( median 81  mmhg , iqr 71 to 95  mmhg ) when compared to the men ( median 87  mmhg , iqr 75 to 102  mmhg ; p = 0.011 ) . on analyzing the ecg intervals ( pr , qrs , and qtc )
, we found a significantly lower qrs interval in females ( median 90  ms , iqr 82 to 98  ms ) when compared to males ( median 94  ms , iqr 88 to 106  ms ; p = 0.0125 ) .
on analyzing hemogram characteristics , we noted that females had lower hemoglobin ( median 13.2  mg / dl , iqr 12.3 to 14.1 ) as compared to males ( median 14.1  mg / dl , iqr 12.7 to 15.3  mg / dl ; p < 0.0001 ) , higher leukocyte counts ( median 10.7  10/cc for females versus 9.4  10/cc for males ; p = 0.039 ) , and higher platelet counts ( median 244  10/cc for females versus 223  10/cc ; p = 0.0031 ) , but all these were within normal limits .
there were no differences between the genders with regard to the coagulation parameters inr ( p = 0.532 ) and aptt ( p = 0.096 ) .
females also had higher total cholesterol levels ( median 199  mg / dl iqr 174 to 211  mg / dl ) when compared to males ( median 168  mg / dl , iqr 146 to 208  mg / dl ; p = 0.033 ) .
women also had higher measured blood glucose on arrival to ed ( median 146  mg / dl iqr 115 to 191  mg / dl ) when compared to men ( median 129  mg / dl , iqr 106 to 157  mg / dl ; p = 0.0096 ) .
there were also statistically significant differences that were noted between serum sodium ( p = 0.0386 ) , serum potassium ( p = 0.0045 ) , and serum creatinine ( p < 0.0001 ) levels between females and males , with females having lesser values than males .
a total of 12.8% females had a craniotomy / surgery as compared to 10.8% of the male subjects , and nearly 10.4% females had an extraventricular drainage ( evd ) as compared to 8.3% males . however , there was no difference in proportion of the females undergoing surgery / craniotomy and evd as compared to the males ( craniotomy / surgery p = 0.62 , ivd , p = 0.58 ) .
there was no difference in the median length of hospital stay between females ( median 4 days , iqr 2 to 10 days ) and males ( median 5 days , iqr 3 to 13 days ; p = 0.179 ) .
females had a worse functional outcome on discharge ( median mrs 4 , iqr 2 to 6 ) when compared to males ( median mrs 4 , iqr 0 to 5 ; p = 0.0062 ) .
females had 1.94 times the odds of having a poor outcome as compared to males ( 95% ci 1.12 to 3.3 ) .
there were also more deaths within 7 days in the female subset ( n = 38 , 30.4% patients ) as compared to the males ( n = 23 , 19.2% patients ) .
the odds of dying within 7 days were 1.84 times higher in females than in males ( 95%  ci 1.02 to 3.33 ; p = 0.0421 ) .
new dnr orders were instituted over a period of 113 days from the date of admission .
overall , 62 ( 49.6% ) females had dnr orders versus 36 ( 30% ) of males . despite having no differences between the stroke severity , volume of hemorrhage , and past history of diseases ,
females were also more likely to have dnr ( do not resuscitate ) orders instituted after admission to the hospital with ich ( odds ratio 2.33 , 95%  ci 1.37 to 2.97 ; p = 0.0016 ) .
, we first made a subcohort of all patients who had dnr orders instituted within 24 hours ( n = 44 ) . in this subcohort , we excluded any patients who received any operative or interventional procedures after arrival to the ed ( n = 2 ) , because it was assumed that these patients were only made dnr after significant interventional albeit futile , efforts .
the final subcohort ( n = 42 ; females 28 , males 14 ) was then omitted from our initial cohort of 245 patients . this final subset of nonearly dnr patients ( n = 203 ) consisted of 97 females ( 47.8% ) and 106 males ( 52.2% ) . on analysis of association of gender with early mortality
, we still found that females were 2.6 times ( or ) more likely to die within 7 days of presentation with ich than males ( 95%  ci 1.3 to 5.4 ; p = 0.006 ) .
it is a known fact that increasing age , stroke severity , cerebellar hemorrhage , and intraventricular extension of hemorrhage are associated with poor outcome and death after ich .
we ran a logistic fit incorporating all these variables in a multivariate analysis and found that female gender remained an independent predictor of poor outcome at discharge ( adjusted or = 2.30 , 95%  ci 1.04 to 5.25 ; p = 0.0398 ) and death within 7 days of ich ( adjusted or 3.03 , 95% 1.24 to 7.79 ; p = 0.0144 ) .
the adjusted or for mrs for males was 0.44 ( 95%  ci 0.19 to 0.96 ) and for death within 7 days was 0.33 ( 95%  ci 0.13 to 0.81 ) .
we also ran a survival analysis based on time to death for each of the genders .
the curves were near similar and the statistical analysis of difference did not reach significance on the wilcoxon test ( p = 0.4403 ) . a closer look at the curves did show a clear separation between the mortality trends among females and males between 10 and 150 days after ich ( figure 1 ) .
in this research , we have reported important differences between males and females who presented with first time intracerebral hemorrhage ( ich ) .
our demographic finding of women being older than men at the time of ich concurs with the findings of roquer et al . who reported that women were on an average 6 years older than men at the time of stroke .
although there were no differences between the modes of arrival of patients for both genders , or their state of consciousness and orientation ( measured by gcs ) , we did find that women were more likely to have nausea / vomiting as a symptom on presentation .
investigators have previously reported some differences in the presentation symptoms between males and females with stroke , with regard to ability to walk , aphasia , visual field disturbances , dysphagia , and coma .
the most important difference that we noted however , was that women were more likely to be affected in the right hemisphere , causing left - sided weakness .
we also noted that though the volume of hemorrhage was similar in both genders , females had nearly 4 times the odds to have a cerebellarhemorrhage when compared to males .
this actually steps away from previous reports on ischemic stroke , which state that infra - tentorial strokes are less prevalent in females [ 7 , 14 ] .
previous experience with subarachnoid hemorrhage ( sah ) patients has revealed that females with sah may be more prone to hypokalemia and qt prolongation .
females also had lower hemoglobin , higher leukocyte , and platelet counts as compared to males , but again these were all within normal limits .
women did have higher glucose levels on arrival to the emergency department , although there was no difference in the prevalence of diabetes mellitus between males and females .
it has been reported in the past that hyperglycemia on presentation can lead to worse early outcome in patients with spontaneous ich .
we concentrated on studying the early mortality outcomes for our cohort , as we wanted to negate influences of complications that arise due to the morbidity and disability after stroke .
we found that , despite having similar premorbid status , similar prior medication use , similar hemorrhage volumes and frequency of intraventricular extension , women still experienced higher 7-day mortality post ich .
the higher odds of cerebellar ich and hyperglycemia at presentation , could be contributory factors to this phenomenon .
it is known that hyperglycemia early on in the course of spontaneous ich does influence the early outcome in these patients .
the long - term mortality experience for males and females was , however , similar , as we saw on the survival curves . at discharge from the hospital , females were almost twice as likely as males to have bad functional outcome .
this association held true even after adjusting for predictors of worse outcome in a multivariate model .
higher inflammatory response in hemorrhagic stroke has been associated with poor outcomes [ 17 , 18 ] ; studies have reported that females tend to have more robust inflammatory response in some diseases . this could have led to poor outcome in females , although we were not able to capture data regarding inflammatory measures such as midline shift , perihematomal edema , or herniation .
for example , it has been reported that progesterone and estrogen may be important neuroprotective agents in ischemic stroke [ 2023 ] .
research has suggested that estrogens may serve this purpose by a way of stimulating growth factor supply , attenuating inflammatory processes , free radical scavenging , stimulation of intrinsic antiapoptotic pathways , and other interactions with intrinsic cell - cell pathways [ 2426 ] .
some researchers have also suggested the mitochondria as a possible site of estrogen - mediated , neuronal survival .
other studies have reported that women experience worse functional outcome and early mortality after ischemic stroke [ 8 , 28 ] .
still others , however have credited the female gender for conferring a survival advantage after ischemic stroke , consistent with the notion that female sex hormones are candidates for neuroprotective therapy .
some researchers have reported that gender differences in outcome are not seen in hemorrhagic stroke .
our study reports the first comprehensive gender differences in a cohort of exclusively first time hemorrhagic stroke patients .
the significant differences outcomes and early mortality , with female sex driving bad outcome , may indicate that unlike in ischemic stroke , female sex hormones might not present a survival advantage in ich .
this may be due to intrinsic differences in the neuronal damage mechanisms in ich and ischemic strokes , which need to be studied extensively in the near future .
we noted that female patients in our cohort were more likely to have dnr orders instituted after admission for ich , despite the similarities to males on premorbid conditions , stroke severity and hemorrhage volumes .
the variation in the use of dnr orders has been studied extensively including differences by gender , race , insurance status , patient preference , hospital , and specialty [ 31 , 32 ] .
it might be suggested that dnr orders could have influenced the outcomes and could have been an important confounder in our study . by doing the subset analysis ,
wherein we excluded patients who had early dnr orders , a surrogate for no interventions , we believe that we tried to get an understanding of this influence . if anything , the female gender became more strongly associated with early mortality in this subcohort of nonearly dnr patients ( odds ratio increased from 1.84 to 2.33 ) .
for convenience , we looked at functional outcome at the hospital discharge , rather than at a fixed time the point from point of onset of ich itself .
this could have influenced our assessment of mrs , though we did not notice any statistically significant difference in hospital length of stay between the two genders .
in addition to this , we did not report long - term outcome for our patients .
although prospective large - scale stroke trials typically assess outcome at 36 months , due to the unavailability of data and the retrospective nature of our study , we were unable to do so .
we also could not assess the effects of hematoma expansion in our cohort , as the initial ct scan was done at different time points from onset of ich , and results of repeated ct scan were not looked at .
it is known that hematoma expansion can continue for up to 48 hours after stroke ; hence , we may have overestimated or underestimated the volume of hemorrhage in our patients .
referral of a large subset of patients from other hospitals and initial treatment given at other sites could have influenced our assessment of initial gcs .
since only 12.5% of our female subset was below the age of 50 years ( the median age for menopause ) , we might not be seeing the protective effects of estrogen on our cohort , which may truly hold true .
we also did not look at specific causes of mortality in our cohort of patients .
but since we are reporting early mortality after ich , we have fair reason to believe that death within 7 days was primarily related to the ich itself .
we have described important gender differences in patients with first episode of ich . we have concluded that unlike in ischemic stroke females are more likely to experience cerebellar hemorrhagic strokes , than males .
also , we have reported a greater inclination for females to experience a right hemispheric ich than males , which could influence functional recovery and mortality outcomes .
we found that females have nearly twice the odds to die within 7 days after an ich as compared to males .
female gender is an independent predictor of early mortality and bad functional outcome at hospital discharge , after adjusting for age , stroke severity , volume of hemorrhage , and intraventricular extension of hemorrhage , all of which are known to predict worse outcome .
 
 objective . to study whether gender influences outcome after intracerebral hemorrhage ( ich ) 
 . methods . 
 cohort study of 245 consecutive adults presenting to the emergency department with spontaneous ich from january 2006 to december 2008 . 
 patients with subarachnoid hemorrhage , extradural hemorrhage , and recurrence of hemorrhage were excluded . 
 results . 
 there were no differences noted between genders in stroke severity ( nihss ) at presentation , ich volume , or intraventricular extension ( i ve ) of hemorrhage . despite this 
 , females had 1.94 times higher odds of having a bad outcome ( modified rankin score ( mrs ) 3 ) as compared to males ( 95% ci 1.12 to 3.3 ) and 1.84 times higher odds of early mortality ( 95% ci 1.023.33 ) . analyzing known variables influencing mortality in ich , the authors found that females did have higher serum glucose levels on arrival ( p = 0.0096 ) and 4.2 times higher odds for a cerebellar involvement than males ( 95% ci 1.6310.75 ) . after adjusting for age , nihss , glucose levels , hemorrhage volume , and i 
 ve , female gender remained an independent predictor of early mortality ( p = 0.0127 ) . 
 conclusions . 
 female gender may be an independent predictor of early mortality in ich patients , even after adjustment for stroke severity , hemorrhage volume , i ve , serum glucose levels , and age . 