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Stroke In Women DR: Mahmoud Mohamad Hassan MD,Neurologist 2014 Introduction• --Stroke is a recognized complication of pregnancy, contributing to more than 12% of all maternal deaths. --The majority occurring in the third trimester or puerperium, however the incidence of stroke during the antenatal period alone, excluding stroke during the puerperium, may be similar to the incidence in nonpregnant women of childbearing age. -- Women also have poorer outcomes in terms of disability and dependency. -Although pregnancy clearly increases the risk of venous thrombosis, most cerebral infarctions are due to arterial occlusion. -Pregnancy is associated with an increased risk of both ischaemic and haemorrhagic stroke. Maternal Changes during Pregnancy Predisposing to Ischemic Stroke Hemodynamic adaptation Hemostatic adaptation . Hemodynamic Adaptations • • In the first 10 weeks of pregnancy: -Increase of total body water, that remains stably increased until 1 to 2 weeks after delivery, after which it gradually returns to normal. • +circulatory demands of fetus and placenta results cardiac output, stroke volume, and heart rate. in a rise of 30% to 50% of • • -During labour there is a dramatic change in cardiac output which increases progressively as labour advances. • • -Then, in the first days after delivery, there is a strong fall of stroke volume and heart rate and cardiac output gradually decreases and returns to normal by 6 to 12 weeks. Hemodynamic Adaptations • -As a consequence of decrease in systemic vascular resistance(A reduction in collagen and elastin contents ), blood pressure starts to lower around the 7th week, hits the lowest levels at 24 to 32 weeks, and then increases progressively to pre-pregnancy levels at term. • -Venous compliance increases throughout pregnancy, leading to decreased blood flow, increased stasis, and a tendency toward orthostatic pressure drops. Changes of Coagulation and fibrinolytic systems • Coagulation and fibrinolytic systems undergo major alterations during pregnancy so leans towards hypercoagulability, representing physiological preparation for delivery • These changes are more marked around term and in the immediate postpartum period, presumably related to the expulsion of the placenta and release of thromboplastic substances at the site of separation. • Blood coagulation and fibrinolysis get back to those of the nonpregnant state approximately 3 weeks after delivery. • • These changes are • 1- Increased concentrations of most coagulation factors, especially von Willebrand factor, factor VIII and fibrinogen. • 2- Progressive resistance to protein C activity and a decrease in protein S • 3- Increased concentrations of plasminogen activator inhibitors 1 and 2. • 4- Platelet aggregation secondary to hyperprolactinaemia Venous stasis • * Anatomical changes in pregnancy lead to venous stasis which is likely to be a consequence of iliac vein compression by the gravid uterus. • * Instrumental delivery and caesarean section may result in prolonged bed rest, reducing blood flow in the legs and contributing to venous stasis. •* Infection and dehydration secondary to blood loss after delivery may also worsen this state. Endothelial injury • Although normal pregnancy itself is not associated with endothelial injury, some degree of damage to pelvic vessels may occur during the course of vaginal or abdominal delivery, and increase the risk of developing venous and arterial thromboembolism. Pregnancy-Specific Causes of Stroke SPECIFIC STROKE SYNDROMES IN WOMEN - Migraine related Stroke. • - Pre-eclampsia and eclampsia. • - Postpartum cerebral angiopathy (PCA). • - Cerebral aneurysm rupture and SAH. - Central venous thrombosis (CVT). - Peripartum cardiomyopathy (PPCM). -Other • • • • Migraine related Stroke Migraine related Stroke - -The weight of evidence from case-control studies suggests that migraine, particularly migraine with aura, is associated with an increased risk of ischaemic stroke in young women under 45 years of age. -The relative risk may be . As high as 3-fold in those who experience migraine with aura . >3-fold in women who experience migraine with aura that smoke, . >4-fold in those who use the oral contraceptive pill Migraine related Stroke - Infarct tends to affect the posterior circulation. - Stroke occurs secondary to cerebral hypoperfusion during the aura phase. Pre-eclampsia and eclampsia Preeclampsia and Eclampsia • -Preeclampsia-eclampsia(toxemia) is a multisystem disorder that occurs in the later stages of pregnancy and in the first 6 to 8 weeks after delivery -Pre-eclampsia is characterized by the presence of hypertension, proteinuria, and oedema. The onset of seizures or coma defines eclampsia -Affecting 2–10% of pregnancies. Preeclampsia and Eclampsia -Although this condition is usually asymptomatic, patients may complain of headaches, visual abnormalities, confusion, and impairment of consciousness. -The proportion of patients with pregnancy-related stroke who have pre-eclampsia or eclampsia is 25–45% - Some studies found eclampsia to be associated with both cerebral haemorrhagic and non-haemorrhagic stroke. • Preeclampsia and Eclampsia • The risk of ischaemic stroke associated with pre-eclampsia appears to persist even beyond pregnancy and the puerperium. • Women with a history of pre-eclampsia are 60% more likely to have a non-pregnancy-related ischaemic stroke. • About 2% to 12% of patients with eclampsia develop a HELLP syndrome HELLP syndrome • • • • a life-threatening condition characterized by Hemolytic anemia (H), Elevated liver enzymes (EL), Low platelet count (LP). Pathophysiology of pre-eclampsia • The pathogenesis is complex and not completely understood. • -Endothelial cell dysfunction leading to vasospasm in various organs. instability of vascular tone with • -Activation of the coagulation system with microthrombi formation in many organs. • -Disturbance of cerebral autoregulation resulting in higher cerebral perfusion pressures as a result of chronic hyperventilation. • -Haemoconcentration . -MRI show subcortical white • matter lesions often affecting the parietooccipital region. -Consistent with the presence of • reversible vasogenic edema. As a consequence of disturbed cerebral autoregulation in the setting of severe hypertension. • These findings are similar to those • found in other vasculopathies associated to pre-eclampsia such as the posterior reversible encephalopathy syndrome (PRES). MR angiography may also show reversible vasospasm of the large and medium-sized vessels The management of pre-eclampsia • The management of pre-eclampsia is aimed at: • -Delivery of the fetus and placenta • -Drug therapy of hypertension. • - Magnesium sulphate should be used for the treatment of seizures. Postpartum cerebral angiopathy (PCA) Postpartum cerebral angiopathy (PCA) • Postpartum cerebral angiopathy is characterized by - -Prolonged but reversible vasoconstriction of the cerebral arteries,it belongs to a group of disorders termed reversible cerebral vasoconstriction syndrome (RCVS). • -It has been described using various labels, including postpartum angiopathy , postpartum angiitis , and puerperal cerebral vasospasm. • - Presenting features include : • sudden (thunderclap) headache, photosensitivity, vomiting, altered consciousness, seizures and transient or permanent focal neurological symptoms. Postpartum cerebral angiopathy (PCA) Postpartum cerebral angiopathy (PCA) • -Although the pathophysiology is not understood. • - Some cases of PCA have occurred in association with the use of vasospastic drugs and bromocriptine during pregnancy. • -Most patients have a history of uncomplicated pregnancy and normal labor followed within days to a few weeks by acute onset of headache with or without various neurologic signs and symptoms. • -The brain MRI in patients with postpartum angiopathy may show areas of hyperintensity in any location, but especially in watershed areas between vascular territories. • .(MRA) and CT angiography may show Multifocal segmental narrowing of large and medium-sized cerebral arteries, with reversibility and complete resolution 4–6 weeks later. - .Diagnostic uncertainty may arise because of overlapping clinical and angiographic features with cerebral vasculitis. - .Examination of the cerebrospinal fluid may be helpful, as this is often normal in PCA. - .Occasionally brain biopsy may be necessary when uncertainty exists, as the distinction between PCA and vasculitis has important therapeutic and prognostic implications. Treatment of PCA -The process is usually self-limiting. Although it generally runs a benign course with complete resolution of symptoms and angiographic findings. - -Vasodilators and glucocorticoids have been used, --Cerebral haemorrhage, maternal death and recurrence in subsequent pregnancies have all been reported. Cerebral Aneurysm rupture and SAH * SAH is a leading cause of non-obstetric-related maternal death..Most cases of SAH are due to ruptured cerebral aneurysms . * The incidence of SAH from aneurysmal rupture in pregnancy ranges from 3 to 11 per 100 000 pregnancies. * 50% of all aneurysmal ruptures in women below the age of 40 years are pregnancy-related. * Aneurysms are most likely to rupture in the later stages of pregnancy, and up to 6 weeks post partum. Haemodynamic changes related to pregnancy are likely to contribute to aneurysm instability and the increased risk of SAH Blood volume increases by more than 50% by the third trimester, with an associated increase in cardiac output, placing further stress on potentially weakened vessel walls. Pregnancy is also associated with hyperplasia of arterial wall smooth muscle and loss of the normal elastic fibre alignment contributing to weakness of the vessel wall. Metabolic and endocrine factors have also been implicated. Central venous thrombosis (CVT) The risk of pregnancy-related venous infarction is significantly higher in -Puerperium,- pre-eclampsia, -advancing maternal age, -caesarean delivery, -associated infections and -excess vomiting during pregnancy Peripartum cardiomyopathy (PPCM) * Peripartum cardiomyopathy unknown cause occurring in characterised by symptoms of ventricular systolic dysfunction existing heart disease. (PPCM) is a disorder of the peripartum period, heart failure due to left in women without pre- * Cardiomyopathy is an established risk factor for cardioembolic stroke. * It remains a diagnosis of exclusion. Diagnostic following criteria include the - Development of congestive heart failure in the last month of pregnancy or within the 5 months after delivery. - The absence of pre-existing cardiac dysfunction. - The absence of a determinable cause of the cardiomyopathy. The cause and pathogenesis of PPCM remains unclear, although a number of aetiological factors have been proposed, including: - Myocarditis - Nutritional deficiency - Abnormal immune response - Stress-activated cytokines and viral antigen persistence. -The presence of left ventricular thrombus ( common in PPCM). -Myocardial infarction, Choriocarcinoma • Choriocarcinoma is a malignant neoplasm that arises from placental trophoblastic tissue, usually following a molar pregnancy but also term delivery, abortion, and ectopic pregnancy. • It has a tendency to early metastasize, especially to the lungs, brain, liver, and vaginal . • Brain metastases are relatively common complication involving about 1/5 of patients. Choriocarcinoma • The clinical presentation of cerebral involvement includes headache, focal neurological deficits, seizures, encephalopathy, signs of elevated intracranial pressure, and excessively elevated serum β human choriogonadotrophic hormone level Choriocarcinoma • Choriocarcinoma is a highly vascular tumor and is extremely prone to hemorrhage. • In the brain, trophoblasts may invade blood vessels, just as they would in the uterus resulting in cerebral ischemic damage as a result of thrombotic process in damaged vessels or consequence of trophoblastic • cerebrovascular embolism Amniotic fluid embolism (AFE) • Is a rare complication of pregnancy, related more frequently to advanced age and multiparity. • AFE occurs in the setting of a disrupted barrier between the amniotic fluid and maternal circulation. • Why this entry into maternal circulation occurs in some women and not in others is not clearly understood. Amniotic fluid embolism (AFE) • Paradoxical cerebral amniotic fluid embolism is possible . Seizures is present in 10%–20% of cases and may be at times the first manifestation. Treatment of Stroke during Pregnancy Treatment of Stroke during Pregnancy • The choice of therapy for an ischemic stroke in pregnancy is complicated by potentials of fetal toxicity, in particular during the first trimester when the risk of teratogenicity is the highest. Treatment of Stroke during Pregnancy • • • According to(AHA) guidelines for pregnant women with ischemic stroke or TIA and at high-risk thromboembolic conditions such as coagulopathy and mechanical heart valves: 3 possible therapeutic alternatives may be considered: (a) adjusted-dose unfractionated heparin (UFH) throughout pregnancy, • • (b) adjusted-dose low molecular weight heparins (LMWHs) throughout pregnancy, • (c) either UFH or adjusted-dose LMWHs until week 13, then restarted from the middle of the third trimester until delivery and warfarin at other times . Treatment of Stroke during Pregnancy • For lower risk conditions, either UFH or LMWH therapy is recommended in the first trimester, followed by low dose of aspirin for the remainder of the pregnancy Anticoagulant Treatment • -UFH and LMWH do not have teratogenic effects since they do not cross the placenta and are not cause of fetal hemorrhage, although bleeding at the utero-placental junction is possible. • -Several studies strongly suggest that UFH/LMWH therapy is safe for the fetus . By contrast, warfarin cross the placenta and can cause bleeding and malformation in the fetus . Therefore, warfarin is best avoided during pregnancy. Anticoagulant Treatment • -Since the use of UFH prior to labor may complicate the delivery and increasing the risk of bleeding and contraindicates epidural analgesia. • -By contrast, LMWH therapy is rarely related with bleeding complications and in particular, it is not associated with an increased risk of severe peripartum bleeding . Anticoagulant & lactation • Heparin and LMWHs do not reach the maternal milk and can be safely given to nursing mothers . • The use of warfarin is also safe during breastfeeding . Antiplatelet Treatment • Whether treatment with aspirin during the first trimester of pregnancy is safe remains unclear. • A meta-analysis of eight studies (seven observational and one randomized) evaluated whether aspirin use during the first trimester of pregnancy and found no evidence of an overall increase in rates of major congenital malformations, suggesting that aspirin is safe even when used early in pregnancy . Antiplatelet Treatment • A meta-analysis of 14 randomized studies including a total of 12,416 women, there is no evidence of fetal and maternal adverse effects of low-dose aspirin therapy (60 to 150 mg/d) administered during the second and the third trimester of pregnancy in women at risk for pre-eclampsia . • This analysis, however, showed that exposure to aspirin in early pregnancy may be associated with an increased risk of gastroschisis • Potential complications of aspirin therapy in late pregnancy include fetal and maternal bleeding, premature closure of the ductus arteriosus, prolongation of labour, and delay in the onset of labor. Antiplatelet Treatment • Clopidogrel has not been found to cause significant feto-toxicity in animal studies , but there are no adequate and wellcontrolled studies in pregnant women so far. Thus, there are insufficient data to evaluate its safety in this setting. • Although dipyridamole has not been found to cause significant fetal adverse effects, there are no adequate data regarding safety or effectiveness of dipyridamole in humans during pregnancy. Sex Differences in Platelet Biology • Platelets from women bound more fibrinogen in response to low and high concentrations of ADP and showed more spontaneous aggregation with greater prothrombotic tendency compared with men after adjustment for risk factors such as smoking,hypertension, diabetes, hyperlipidemia, and aspirin use. Clinical Evidence of Sex Differences in Response to Antiplatelet Therapy • In a meta-analysis of 6 randomized primary prevention trials, aspirin therapy was associated with significantly reduced stroke risk in the 51,342 women studied over a mean 6.4 years of follow-up. • For clopidogrel treatment a significant interaction between treatment and sex was observed for trials of GP IIb/IIIa inhibitors as women had worse outcomes with such treatment Thrombolytic Treatment • No data are available about the use of thrombolytic treatment in pregnancy since this conditions was an exclusion criteria from clinical trials that validated these therapies. • Due to its large molecular size, recombinant human tissue plasminogen activator (rt-PA) does not cross the placental barrier and studies on animal model have not shown teratogenic effects . However, fetal adverse effects remain largely unknown. • Obstetric concerns are also raised by the possible effects on the placenta resulting in premature labor, placental abruption, or fetal demise. Thrombolytic Treatment • Thrombolysis for acute ischemic stroke in pregnancy has been described in only 11 patients . In most cases, patients received thrombolysis during the first trimester, 4 patients did not have complications, 3 had cerebral hemorrhage with clinical worsening in one case. Intrauterine hematoma in one case . 2 women had an elective therapeutic abortion and one a spontaneous miscarriage. • Moreover, thrombolysis in the postpartum period was also reported, within fifteen hours after a cesarean delivery in one case and after six days from delivery in another one, without complications . Thrombolytic Treatment • It is difficult to draw any conclusion regarding safety or effectiveness although favorable maternal outcome was shown in many cases. • Therefore, thrombolytic therapy should not be withheld for potentially disabling stroke during pregnancy, but in each clinical situation, the ultimate choice of therapies must be based on careful assessment of the maternal and fetal risks and benefits. Prognosis and Recurrence • A multicenter study on a group of 489 consecutive women aged 15 to 40 years with a first-ever arterial ischemic stroke or cerebral venous thrombosis showed that the risk of stroke recurrence associated with subsequent pregnancies is relatively small . • The postpartum period, not the pregnancy itself, is associated with an increased risk of recurrent stroke Oral Contraception Following a stroke event oral contraceptives should be stopped . Non –hormonal methods of contraception should be considered. Hormon Therapy • Postmenopausal hormone therapy is not effective for reducing the risk of a first stroke. and is not effective for reducing the risk of a recurrent stroke or death among women with established vascular disease. Among women taking hormone replacement therapy, there may be an increased risk of fatal stroke. • So,Hormone therapy should not be initiated to prevent vascular disease among postmenopausal women.