Treatment of acute ischemic arterial stroke in pregnancy is controversial. No data are available from clinical trials about the use of thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) in pregnancy, and the experience is limited to case reports and series, including not just ischemic stroke but various other thromboembolic conditions. Randomized clinical trial evidence from non-pregnant patients demonstrates that if rtPA is administered within 3 h of ischemic stroke onset, it significantly reduces the risk of mortality and improves outcome at 90 days post stroke compared with placebo [24]. However, there is an approximately 6 % risk of hemorrhage, and this risk increases with rtPA administration more than 3 h after onset of the stroke symptoms [24]. Thrombolytic agents can be administered intra-arterially for proximal middle cerebral artery occlusion effectively and relatively safely [25]. In addition, certain devices have been approved for mechanical thrombectomy [26]. In some cases, intra-arterial rtPA can be combined with mechanical thrombectomy. Patients tend to have an optimal outcome if whatever method is used leads to partial or complete recanalization of the occluded artery. rtPA does not cross the placenta and there has been no evidence of teratogenicity in animal studies [27]. It is listed as a category C drug and pregnancy is considered a relative contraindication for administration [28], but there are multiple case reports of successful use in pregnant women, and the risk of placental abruption appears small. The risks and benefits should be carefully considered, but it appears that thrombolytic therapy can be used both intravenously and intra-arterially in pregnancy with successful outcomes [27].

The American Heart/American Stroke Association (AHA/ASA) stroke secondary prevention guidelines [20] and American College of Chest Physicians guidelines (ACCP) [29] recommend antiplatelet treatment for secondary prevention of non-cardioembolic ischemic stroke or TIA. The National Institute of Health and Care Excellence (NICE) in England recommends the following for secondary prevention of ischemic stroke [30] in patients where stroke is confirmed by imaging: aspirin 300 mg daily should be given for 2 weeks, starting immediately. Clopidogrel 75 mg daily is then given long-term if it can be tolerated and is not contraindicated. If clopidogrel is contraindicated or not tolerated, a combination of modified-release dipyridamole (200 mg twice daily) and LDA is recommended. If both clopidogrel and modified-release dipyridamole are contraindicated or not tolerated, aspirin alone should be given. Clopidogrel crosses the placenta and, although there are no reliable safety data available for its use during pregnancy, case reports and anecdotal evidence suggest that it may be safe [31, 32]. There are no safety data available for the use of dipyridamole during pregnancy, but it has been used in combination with aspirin or warfarin, during both pregnancy and breastfeeding [33]. The guidance also recommends optimal management of atrial fibrillation, diabetes and hypertension if present, and to offer a statin. In a systematic review of both human and animal studies on the teratogenic effects of statins during pregnancy, most of the available data suggested that statins are unlikely to be teratogenic [34]. However, because of the disruption of gonadal stem cell development and theoretical long-term fetal neurological damage [35], statins are classified as Category X (contraindicated) for pregnancy by the FDA and contraindicated during pregnancy and lactation in the Summary of Product Characteristics (SPC) in the UK [36]. In view of this, they should not be commenced until after pregnancy and lactation are completed.

A PFO is an embryonic defect in the inter-atrial septum. PFO is common, present in up to 15–25 % of the adult population [37, 38]. The meta-analysis by Overell et al. [39] published in 2000 concluded that PFO and atrial septal aneurysm were significantly associated with an increased risk of stroke in patients below the age of 55. However, older data showed no differences in rates of recurrent stroke in those with or without PFO (2 year event rate 14.8 and 15.4 %, respectively) as well as no demonstrated effect on outcomes based on PFO size or presence of atrial septal aneurysm. Overall, the importance of PFO with or without atrial septal aneurysm for a first stroke or recurrent cryptogenic stroke remains in question [20]. The American Heart Association/American Stroke Association (AHA/ASA) guidelines on secondary prevention of stroke and TIA suggest antiplatelet therapy for patients with ischemic stroke or TIA and a PFO [20]. There are insufficient data to establish whether anticoagulation is equivalent or superior to aspirin for secondary prevention in patients with PFO, and also insufficient evidence to make a recommendation regarding PFO closure in patients with stroke and PFO [20].

The management of anticoagulation to prevent cardiac and systemic thromboembolism, including ischemic stroke, in patients with a mechanical heart valve is covered in Chap. 10.

Antiphospholipid syndrome (APS) is a major acquired risk factor for pregnancy-associated stroke, both arterial or venous [40]. Ischemic stroke due to arterial thrombosis is the most common neurological manifestation, accounting for over 50 % of central nervous system complications in APS which presents during pregnancy or the puerperium.

Ten to twenty-five percent of women with thrombotic thrombocytopenic purpura (TTP) or other thrombotic microangiopathies (see Chap. 17) present during pregnancy or in the postpartum period [50–52]. TTP may present with a wide variety of neurological manifestations including stroke, TIA, fluctuating neurological symptoms, headaches, seizures and confusion. The diagnosis should be considered in pregnant women who develop thrombocytopenia and anemia. Laboratory investigations may show red cell fragmentation on the blood film indicative of microangiopathic hemolytic anemia (MAHA), and other evidence of intravascular hemolysis: reticulocytosis, elevated bilirubin and lactate dehydrogenase (LDH). It is useful to distinguish between congenital and acquired antibody-mediated TTP as this influences management. In congenital TTP, activity levels of ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) are under 5 % and in acquired TTP ADAMTS 13 activity under 5 % and anti-ADAMTS 13 IgG autoantibodies are diagnostic [51]. Early diagnosis is crucial as intensive treatment with plasma exchange (PEX) may be life-saving [53]; and pregnant women presenting with thrombocytopenia, MAHA, and neurological features including stroke or TIA, should be treated with PEX until the diagnosis of TTP is excluded [47]. In acute acquired TTP with neurological pathology, which is associated with a high mortality, rituximab should be considered on admission, in conjunction with PEX and steroids [47]. Adjunctive LDA and prophylactic dose LMWH may reduce the risk of pregnancy loss and late placenta-mediated vascular pregnancy morbidity such as intrauterine fetal growth restriction.

Heritable thrombophilic defects that are associated with an increased risk of thrombosis include factor V Leiden, prothrombin (factor II) G20210A gene mutation, deficiency of protein C, protein S and antithrombin. However, observational studies have not demonstrated a clear association between inherited thrombophilia and ischemic stroke [54–58]. Two meta-analyses have addressed the potential relationship between prothrombotic disorders and stroke. The first found a significant association between stroke and factor V Leiden, MTHFR C677T variant and the prothrombin G20210A mutation [59]. The risk of an individual suffering from a stroke associated with this polymorphism in the general population is low. The second meta-analysis [60] could not verify a significant association between stroke and factor V Leiden, but found a slight association between stroke and the prothrombin G20210A mutation and the MTHFR C677T polymorphism. These findings were more evident in younger individuals (<55 years) including women of childbearing age. There is insufficient evidence to support specific recommendations in patients with inherited thrombophilia for primary or secondary stroke prevention. With regard to secondary prevention, it appears prudent that women are investigated for DVT and a PFO, with prophylactic anticoagulation during pregnancy and 6 weeks post-partum, or long-term depending on clinical and hematological factors [20].

Stroke is a frequent and severe complication in adults with sickle cell disease (SCD), which confers an increased risk of ischemic stroke. Ischemic stroke often causes physical and cognitive disability, while hemorrhagic stroke has a high mortality rate. As more children with SCD survive into adulthood, the number of strokes in adults is increasing, yet stroke in this patient population remains poorly understood [61].

For adults with SCD, the risk of having a first stroke can be as high as 11 % by age 20, 15 % by age 30, and 24 % by age 45 years. An analysis of administrative data from California, USA, which included individuals of all ages with SCD, identified the greatest absolute number of ischemic and hemorrhagic strokes and the highest incidence rates of ischemic stroke in adults 35–64 years of age (740/100,000 person-years), which includes women of childbearing age. The incidence is significantly higher than for ischemic stroke (excluding TIA) seen in African–Americans overall (270/100,000 person years) [62]. Numerous clinical and genetic risk factors for stroke in SCD have been identified, with the most consistently identified clinical risk factors for ischemic stroke in adults including genotype (with the risk greatest for HbSS), increasing age, increased systolic blood pressure or hypertension, lower baseline hemoglobin during pregnancy, and concomitant thalassemic syndromes [63–65].

Currently, there are no validated methods to screen for an increased risk of stroke in adults with SCD. Transcranial Doppler ultrasound (TCD) can identify children with HbSS at increased risk of stroke, and the Stroke Prevention trial in Sickle Cell Anaemia (STOP) demonstrated the efficacy of regular transfusion to maintain hemoglobin S (Hb S) <30 %, to decrease the absolute risk of stroke over 30 months from 30 to 3 %. Women with stroke associated with SCD should have an evaluation for other, potentially modifiable, risk factors for stroke. Exchange transfusion should be undertaken for all pregnant women with SCD and prior stroke or TIA to reduce the risk of stroke during pregnancy. Women with SCD and stroke should be treated in dedicated stroke units with input from both neurologists and hematologists [20].

Myeloproliferative neoplasms (MPD) represent a group of hematological disorders caused by stem cell-derived clonal myeloproliferation. They include polycythemia (PV), essential thrombocythemia (ET), and myelofibrosis, which can all progress to acute myeloid leukemia. Thrombosis is the main cause of morbidity and mortality. The most common MPD in women of childbearing age is ET. In MPD, thrombosis can occur in any vessel, including the cerebral vasculature [66]. There is limited evidence in the literature on the management of PV in pregnancy. If the woman has a previous history of venous and arterial thrombosis (whether pregnant or not), or severe pre-eclampsia in the index pregnancy, the current pregnancy should be considered as high risk and should be managed by a multidisciplinary team including an experienced obstetrician and hematologist. All patients should receive LDA and 6 weeks of post-partum LMWH. If the patient has had previous venous or arterial thrombosis, thromboprophylaxis is indicated during pregnancy. The British Committee for Standards in Haematology (BCSH) guidelines state that LMWH should be started once the pregnancy test is positive. They recommend dalteparin 5,000 units or enoxaparin 40 mg initially once daily; at 16–20 weeks’ gestation, this should be increased to twice daily; and 3 days post-partum it can be reduced again to once daily for 6 weeks, if normal body weight, no renal impairment or previous VTE or fetal morbidity. If there is previous history of stroke or other arterial event, they recommend dalteparin 5,000 units or enoxaparin 40 mg twice daily throughout the pregnancy and, if there is evidence of recurrence, to consider increasing the LMWH dose or giving warfarin after 14 weeks’ gestation [67, 68]. Furthermore, regular fetal monitoring is required with serial growth scans, as well as uterine artery Doppler scan at 20 weeks (and 24 weeks, if abnormal).

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease of hematopoietic stem cells caused by a somatic mutation in the X-linked phosphatidylinositol glycan complementation class A (PIGA) gene. PNH is characterized by hemolytic anemia, bone marrow failure, and thromboembolism [69]. VTE constitutes the main cause of death in PNH. Cerebrovascular complications, primarily dural cerebral venous thrombosis, account for 25 % of deaths [70, 71]. Although some hypercoagulable disorders cause both venous and arterial in situ thrombosis, cases of ischemic stroke attributed to PNH may occur [72]. The diagnosis and management of PNH is discussed in detail in Chap. 19.

Homocysteine is a sulphur-containing amino acid produced during metabolism of methionine. Elevated plasma levels of homocysteine are associated with an increased risk of atherosclerosis and cardiovascular ischemic events. Several mechanisms by which elevated homocysteine impairs vascular function have been proposed, including impairment of endothelial function, production of reactive oxygen species (ROS) and consequent oxidation of low-density lipids [73]. Meta-analyses have confirmed the association between hyperhomocysteinemia and stroke [74, 75]. Several studies have analyzed the efficacy of folic acid or vitamin B supplements. Although vitamin supplements reduced homocysteine levels, this did not have any significant effect on vascular risk [76–78] and a systematic review confirmed that there is insufficient evidence to determine whether treatment affecting homocysteine levels can prevent stroke recurrence [79]. The AHA/ASA guidelines advise that, although folate supplementation reduces levels of homocysteine and may be considered for patients with ischemic stroke and hyperhomocysteinemia, there is no evidence that reducing homocysteine levels prevents stroke recurrence [20].

There are a few specific complications of pregnancy that may cause stroke. Pre-eclampsia/eclampsia constitutes one of the highest risk situations for a cerebral event during pregnancy and the puerperium [7, 8, 21, 80–82].

Typical presenting features of CVT include headache, disturbance of consciousness, focal neurological signs and seizures [19]. Papilledema has been reported in only around 50 % of cases and in this context is not a particularly reliable sign of raised intracranial pressure. Patients may present with headache and papilledema in isolation and be erroneously diagnosed as so-called ‘benign intracranial hypertension’. A very sudden onset headache at presentation may also occur and may be mistaken for a ruptured cerebral aneurysm. Involvement of cortical veins may lead to one or more areas of venous infarction, with or without hemorrhagic transformation. The presentation in such cases is often with localization related seizures and focal neurological deficit, depending on the territories involved. Deterioration in level of consciousness suggests either multiple lesions in the cerebral hemispheres, bilateral thalami or, more worryingly, transtentorial herniation and brainstem compression. A stroke-like presentation has been described as a manifestation of cortical vein thrombosis.

CVT should be seriously considered in any woman developing neurological symptoms in the immediate post-partum period, since up to 15 % of cases can occur within 2 days after uncomplicated childbirth. Cases can occur during pregnancy though these are much less common [19]. Despite the strong association with the post-partum state, it is still advisable that such patients have a thrombophilia screen to exclude any additional pro-thrombotic tendency such as APS.