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This chapter should be cited as follows:
Malhamé I, Legault C, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.416443

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 8

Maternal medical health and disorders in pregnancy

Volume Editor: Kenneth K Chen, MD, Alpert Medical School of Brown University, USA Originating Editor: Professor Sandra Lowe

Chapter

Stroke and Pregnancy

First published: August 2021

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INTRODUCTION

Stroke refers to the sudden loss of neurological function due to neuronal injury caused by a cerebral vascular incident. Specifically, stroke is an infarction of the brain, central cord, or retina attributable to ischemia based on radiological or pathological findings, in a defined vascular distribution.1 Additionally, stroke may be diagnosed in the presence of clinical evidence of focal ischemic injury lasting for 24 hours.1 This broad definition includes ischemic strokes, strokes caused by intracerebral hemorrhage, and strokes caused by cerebral venous thrombosis (CVT).1

Strokes are responsible for 37% of all cardiovascular deaths in women globally.2 Pregnancy increases the risk of ischemic and hemorrhagic strokes threefold.3 Pregnancy-associated strokes represent 4.2% of strokes in women and 18% of strokes in those below the age of 35.4 Strokes in pregnancy are associated with significant disability,5 high case fatality,6 and account for 7.6% of all pregnancy-related deaths in the United States (USA).7

EPIDEMIOLOGY

During the antenatal period, pregnancy-associated strokes are estimated to affect 1.5 per 100,000 deliveries in the United Kingdom (UK).8 When accounting for the postpartum period, the incidence of pregnancy-associated strokes increases to 13.4, 34.2, and 46.2 per 100,000 deliveries in Canada, the USA, and Taiwan, respectively.3,9,10 These regional variations in the incidence of stroke may be explained by differences in case-finding strategies, stroke and postpartum period definitions, as well as differences in the geographic study settings. In Canada, the incidence of pregnancy-associated strokes increased from 10.8 per 100,000 deliveries in 2003–4 to 16.6 per 100,000 deliveries in 2015–16.10 In the USA, postpartum readmissions for stroke rose by 83% from 1994–5 to 2006–7.11 Although the observed increased incidence of stroke may be due to improvements in diagnostic and reporting methods, it may actually reflect important transformations within the obstetric population, now comprising more women with advanced maternal age, obesity, and chronic medical conditions.12 The risk of pregnancy-associated strokes has not decreased from 2007 to 2015 in the USA, and maternal mortality associated with strokes remains high.13

RISK FACTORS FOR STROKE IN PREGNANCY AND THE POSTPARTUM PERIOD

Risk factors for pregnancy-associated strokes may be present prior to conception or may develop during pregnancy in the antepartum, peripartum, or postpartum periods.

Risk factors present prior to pregnancy

Maternal age above 35 years is consistently reported as a risk factor for pregnancy-associated strokes.14 Traditional medical stroke risk factors remain relevant during pregnancy, including diabetes, chronic hypertension, dyslipidemia, and tobacco smoking.13,15,16,17 Given that 29% of women with pregnancy-related ischemic stroke have had a stroke prior to pregnancy, a history of stroke is an important risk factor for stroke recurrence in pregnancy.18 Cardiac conditions in pregnancy, including atrial fibrillation, congenital heart disease, cardiomyopathy, and rheumatic heart disease, can lead to cardioembolic strokes.9,19,20Hematological disorders such as thrombophilia (inherited and acquired), thrombocytopenia (including thrombotic thrombocytopenic purpura [TTP]), and sickle cell disease may result in acute ischemic stroke.10,14,21,22 Systemic autoimmune rheumatic diseases, including rheumatoid arthritis and systemic lupus erythematosus (with or without antiphospholipid syndrome) are risk factors for stroke in pregnancy.3,13,19,22 A personal history of migraine (especially migraines with aura) is also a risk factor for pregnancy-associated strokes, as migraines may predispose women to impaired vascular compensation of physiologic cardiovascular stress.14,23,24,25 Moreover, connective tissue disorders (e.g. vascular Ehlers–Danlos Syndrome),26 vascular disorders such as non-atherosclerotic occlusive disease (i.e. moyamoya disease) and intracranial vascular lesions (i.e. arteriovenous malformations [AVMs], aneurysms, and cavernomas),14 as well as recreational drugs9,22 are associated with pregnancy-associated strokes.

Pregnancy-associated risk factors

There is a trend towards an increased long-term risk of stroke in women undergoing hormonally assisted reproductive therapies (ARTs) (hazard ratio [HR] 1.25, 95% confidence interval [CI] [0.96, 1.63] following ovulation induction compared with women not receiving fertility treatment).27 However, during pregnancy and the postpartum period, ARTs were not associated with strokes on either crude (odds ratio [OR]0.5, 95% CI [0.2, 1,3]) or adjusted (adjusted OR[0.3], 95% CI [0.1, 0.7]) estimates.10 Nevertheless, arterial strokes have been described in ovarian hyperstimulation syndrome,28,29 a potential complication of fertility treatments characterized by intravascular volume depletion and hypercoagulability associated with an increased risk of venous and arterial thrombotic events.30

Additional risk factors may arise with the pregnant state including multiple physiologic changes. First, a pregnancy-induced increase in the synthesis of prothrombotic factors VIII, IX, and X, and reduction in antithrombotic factors such as protein S, induce a prothrombotic state.19 This prothrombotic state may be heightened by vomiting leading to dehydration in early pregnancy, as well as hemorrhage at time of delivery.19 Moreover, in the peripartum and immediate postpartum periods, cesarean section delivery, postpartum hemorrhage, and peripartum infections are also recognized risk factors for pregnancy-associated strokes, including cerebral venous thrombosis.3,17,20,31

In addition to pregnancy-induced physiologic changes, several pathologic conditions in pregnancy may increase the risk of stroke. These conditions include gestational diabetes, hypertensive disorders of pregnancy, peripartum cardiomyopathy, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), and CVT.14 Metastases from gestational trophoblastic disease are rare causes of stroke in pregnancy,19 and will not be further reviewed in this chapter.

ETIOLOGIES OF STROKES IN PREGNANCY

Stroke in pregnancy may occur as a result of arterial ischemia, intracranial hemorrhage, or venous thrombosis. Acute ischemic strokes are most common in the third trimester and the early postpartum period.14 Hemorrhagic strokes from vascular lesion rupture may occur in the second half of pregnancy,14 and the period at highest risk for AVM rupture has previously been described from 34 weeks of gestation and at time of delivery.32,33 Hemorrhagic strokes from RCVS most commonly occur postpartum.14,34 Of note, the association between stroke and induction of labor because of severe pre-eclampsia may be a confounder in the association between stroke and the peripartum period. Distinct pathophysiologic mechanisms are outlined in Table 1.

1

Most common etiologies of pregnancy-associate stroke and their investigations.

Stroke mechanism

Stroke etiology

Associated conditions

Investigations

Ischemic

Cardiac


Valvulopathy/mechanical heart valves

Intracardiac thrombus

Patent foramen ovale

Arterioseptal defect

Atrial fibrillation

Transthoracic

±

transesophageal echocardiography

ECG

Prolonged cardiac Holter monitoring

Vascular

Cervical (vertebral and carotid) artery dissection

Atherosclerotic disease

Nonatherosclerotic intracranial stenosis

RCVS

Vasculitis

MR angiography

CT angiogram

Conventional angiography in specific indications

Atherosclerotic disease: cardiometabolic work-up including HbA1C, lipid profile

Hematologic

Hypercoagulable state of pregnancy

Antiphospholipid syndrome

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura: ADAMTS13

Antiphospholipid syndrome: lupus anticoagulant, anticardiolipin IgM and IgG, B2-glycoprotein IgM and IgG

Hemorrhagic

Lesional

Arteriovenous malformation

Aneurysm

Cavernomas

CT angiogram

MR angiography

Conventional angiography

Non-lesional

Hypertensive disorder of pregnancy

RCVS

PRES

Coagulopathy

INR, PTT, platelets

Pre-eclampsia work-up

CT angiogram

MR angiography

Central venous thrombosis

MR venography

CT venogram

CT, computed tomography; ECG, electrocardiogram; HbA1C, glycated hemoglobin; INR, international normalized ratio; PTT, partial thromboplastin time; MR, magnetic resonance; PRES, posterior reversible encephalopathy syndrome; RCVS, reversible vasoconstrictive cerebral syndrome.

Hypertensive disorders of pregnancy

Hypertensive disorders of pregnancy are associated with 20–50% of all peripartum strokes,25,35 and increase the risk of pregnancy-associated stroke fivefold.3,36Pre-eclampsia is the greatest single risk factor for pregnancy-associated stroke.37 Mechanisms by which this hypertensive disorder may lead to stroke include diffuse arterial vasospasm and severe hypertension, as well as increased capillary permeability, platelet activation, and thrombin/fibrin production.19 Thrombocytopenia and disseminated intravascular coagulation may also contribute to the pathophysiology of stroke with pre-eclampsia. Among women with pre-eclampsia, those with advanced maternal age, black ethnicity, smoking, lack of private insurance, concurrent infection, prothrombotic states, congenital heart disease, migraine, systemic lupus erythematosus, coagulopathies, and chronic hypertension are at highest risk of stroke.15,16,17

Reversible cerebral vasoconstriction syndrome

Reversible cerebral vasoconstriction syndrome is characterized by severe, often thunderclap, headaches with or without seizures or other focal neurologic symptoms in the presence of reversible, diffuse, segmental constriction of cerebral arteries on vascular imaging.34,38 In the context of pregnancy, RCVS is strongly associated with pre-eclampsia and usually develops in the week following delivery.14,34 In addition to headaches, which may be accompanied by nausea, photophobia, or encephalopathy, RCVS can manifest with focal neurologic deficits and seizures in 8–43% and 1–17% of cases, respectively.34,39 Transient focal deficits are typically visual, but sensory, dysphasic, and motor deficits may occur.34,39 Persistent deficits indicate a probable stroke.34,39 Mechanisms for stroke in RCVS include ischemia from severe vasoconstriction, and bleeding leading to subarachnoid or intraparenchymal hemorrhage.14,34,39

The diagnosis of RCVS is made with angiographic imaging, including CT angiography and MR angiography, or transfemoral catheter angiography, demonstrating areas of multifocal vasoconstriction in large and medium vessels.22,40 Treatment for RCVS is mainly supportive and consists of removal and avoidance of any vasoactive medications, blood pressure reduction, analgesia, and seizure management.34,39 Magnesium sulfate should be given in the context of hypertensive disorders of pregnancy because of its demonstrated superiority in the prevention and treatment of eclamptic seizures.41,42,43. Additionally, verapamil, nimodipine, nicardipine, and magnesium sulfate have been suggested as reducing RCVS-related arterial narrowing.34,39 While most patients fully recover within 1–3 weeks, some may experience recurrence of symptoms.39

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy is defined by the presence of vasogenic cerebral edema leading to focal neurologic symptoms.44 Increased vascular permeability from endothelial dysfunction and increased capillary filtration from hypertension may be mechanisms contributing to the crossing of fluids from the intravascular to the interstitial space in PRES.41 Accordingly, PRES is closely related to hypertensive disorders of pregnancy and RCVS. Indeed, PRES was present on the neuroimaging of 9.1% of patients with RCVS,45 19.2% of women with pre-eclampsia,46 and 92.3–97.9% of patients with eclampsia.46,47

Since PRES preferentially involves the occipital lobe, visual symptoms are commonly reported.44 PRES may also manifest with acute headaches and altered mental status.44 MRI is a more sensitive diagnostic modality, but CT scan of the head may also be used. Typical neuroimaging findings include subcortical white matter and cortical vasogenic edema in the bilateral parietal and occipital lobes.22 Although PRES in the obstetric population may have better clinical outcomes than PRES in the non-obstetric population,48 some women may develop hemorrhage leading to posterior cerebral artery infarcts.19,22 The mainstay of therapy for obstetrical PRES includes management of pre-eclampsia, blood pressure reduction, and anticonvulsant therapy.19,22 Except in women at very early gestation, PRES is an indication for delivery because of the significant risk of associated intracranial hemorrhage.47

Cerebral venous thrombosis

CVT may be found in the intracranial venous sinuses, the deep venous system, and the cortical veins draining into the major intracranial sinuses.49 Stroke may occur as a result of venous stasis or hemorrhage secondary to occlusion of venous structures.49 Women have a higher risk of cerebral venous thrombosis than men, and more than half of patients with this disorder present during pregnancy or the puerperium.50 CVT accounts for 2% of all pregnancy-associated strokes,3 and the risk is highest during the third trimester, the puerperium, and the first 4 weeks postpartum.51

In the presence of parenchymal lesions – including adjacent infarction, hemorrhage, or edema – headaches, partial seizures, focal neurologic deficits, and decreased level of consciousness may occur. In the absence of parenchymal lesions, symptoms may include diffuse headache and papilledema with possible vision loss. In a systematic review, headaches (74%), seizures (50%), comatose/obtunded mental status (45%), motor weakness (38%), and visual disturbances (24%) were the most common features at presentation.52

The diagnosis of cerebral venous thrombosis is made by cerebral imaging. While CT venography is more sensitive in detecting smaller thrombi, MR venography allows for better visualization of the surrounding parenchyma.49 The mainstay of treatment is anticoagulation, even if intracerebral hemorrhage is present at baseline,49 which has been associated with a non-statistically significant reduction in death and dependency.53 Heparins, including low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH), are the anticoagulation modality of choice for cerebral vein thrombosis in pregnancy. Vitamin K antagonists may safely be used in the postpartum period, including during breastfeeding.49 Direct oral anticoagulants have not been studied in this condition and are not recommended.49 In most cases, a limited course of anticoagulation for 3–12 months is preferred.49

The recurrence risk of cerebral venous thrombosis following discontinuation of anticoagulation in patients without additional risk factors has been reported to be of 0.53/100 person-years after a median anticoagulation duration of 12 months.54 Treatment with prophylactic LMWH during subsequent pregnancy and the puerperium is recommended in these women, based on indirect evidence in women with other forms of venous thromboembolism.51,55

Arteriovenous malformations

The prevalence of AVM is estimated at 1.3 per 100,000 person-years, and intracranial hemorrhage occurs in 2.3% of cases annually.56,57 AVMs may be congenital, genetic (hereditary hemorrhagic telangiectasia being the most common genetic cause), or develop de novo through childhood and adulthood.56,58 Lesions are typically diagnosed prior to the age of 40.59 Up to 50% of AVMs may manifest with hemorrhage, and 34% are followed by the development of epileptic seizures.56 AVMs are a leading cause of hemorrhagic stroke in pregnancy.60 Accordingly, in a population-based study including 423 women with pregnancy-associated hemorrhagic strokes, 30 (7.1%) were found to have cerebrovascular malformations.61 Plasma volume expansion, increased cardiac output, and structural changes in the vascular wall may potentially alter the risk of intracranial hemorrhage from intracranial vascular lesions leading to hemorrhagic strokes.37,62 However, whether pregnancy increases the risk of AVM rupture remains controversial.62 While some studies have failed to detect an increased risk of intracranial bleeding during pregnancy among women with AVMs,61,63 several recent studies have in fact reported an increased risk of hemorrhagic strokes during pregnancy and the postpartum period.64,65,66,67,68 A contemporary review of studies assessing the risk of hemorrhagic stroke with AVMs in pregnancy is found in Table 2.

2

The risk of hemorrhagic stroke associated with pregnancy in women with arteriovenous malformations.

Author, year, country

Study design

Key findings

Conclusion

Bateman61 2005, USA

Cohort study using the nationwide inpatient sample

Incidence of hemorrhagic stroke related to cerebrovascular malformations:

  • 0.50/100,000 person-years in pregnancy
  • 0.33/100,000 person-years outside of pregnancy

No increased risk of hemorrhagic stroke with pregnancy in women with cerebrovascular malformations

Gross65 2011, USA

Single-center. case-crossover study

Among 54 women with AVMs, the annual risk of hemorrhagic stroke was of 1.1% during the non-pregnant period and 10.8% during the pregnant period

There is an increased risk of hemorrhagic stroke associated with pregnancy in women with AVMs

Liu63 2014, China

Single-center, case-crossover study

Among 393 women with ruptured AVMs and between the age of 18 and 40 years, the annual risk of hemorrhagic stroke was of 4.14% during the non-pregnant period and 3.32% during pregnancy and the puerperium

No increased risk of hemorrhage was found in patients with cerebral AVM during

pregnancy and the puerperium

Porras66 2017, USA

Single-center, case-crossover study

Among 270 women with AVMs, the annual risk of hemorrhagic stroke was of 1.30% during the non-pregnant period and 5.7% during pregnancy and the puerperium (relative risk [RR][4.43], 95% CI[1.98–8.65], P < 0.001)

There is an increased risk of hemorrhagic stroke associated with pregnancy in women with AVMs

Zhu67 2017, China

Single-center, case-crossover study

Among 264 women with AVMs, the annual risk of hemorrhagic stroke was of 2.92% during the non-pregnant period and 5.4% during pregnancy and the puerperium

There is an increased risk of hemorrhagic stroke associated with pregnancy in women with AVMs

Van Beijnum64 2017, Netherlands and UK

Case-crossover study and self-control case series using a multicenter, hospital-based Dutch cohort and a Scottish AVM registry

Dutch cohort:

among women with AVM, the RR of hemorrhagic stroke was 6.8 (95% CI[3.6,13]) according to the case-crossover method and 7.1 (95% CI[3.4,13]) using the self-controlled case-series method.

Scottish cohort:

among women with AVM, the RR of hemorrhagic stroke was 1.3 (95% CI[0.39,4.1]) using the case-crossover method and 1.7 (95% CI[0.0,4.4]) according to the self-controlled, case-series method

There was an increase in relative rate of AVM rupture during pregnancy in the Dutch cohort but not in the Scottish cohort

Lee68 2020, USA

Cohort-crossover study using Healthcare Cost and Utilization Project State Inpatient Databases for California, Florida, and New York

Among women with AVMs the risk of hemorrhagic stroke increased 3.27-fold (RR[95%]. CI[1.67–6.43]) during pregnancy and puerperium compared with a non-pregnant period

There is an increased risk of hemorrhagic stroke associated with pregnancy in women with AVMs

AVMs can be diagnosed using MR angiogram and CT angiography, with arteriography remaining the gold standard for assessment of anatomy as well as functional and physiological data potentially influencing clinical decision making.59 While there is currently no published guidance for neuroimaging follow-up of women with AVMs in pregnancy, the need for repeat imaging in pregnancy must be individualized depending on time elapsed since prior imaging, AVM characteristics, and the need for reassessment of AVM growth, remodeling, or regression. In a systematic review and meta-analysis, the following parameters were significantly associated with an increased risk of hemorrhage: prior hemorrhage (HR 3.2, 95% CI [2.1, 4.3]), deep AVM location (HR 2.4, 95% CI [1.4, 3.4]), exclusively deep venous drainage (HR 2.4, 95% CI [1.1, 3.8]), and associated aneurysms (HR 1.8, 95% CI [1.6, 2.0]).69 Additionally, infratentorial location, single draining vein, venous varices, and all types of venous anomalies affecting flow have been highlighted as potential risk factors for hemorrhage.70 Whether size is a predictor of hemorrhage remains controversial.56 As such, the risk of hemorrhage of brain AVMs in pregnancy must be carefully evaluated by a multidisciplinary team with neurosurgical or neuro-interventional expertise. Options for treatment of unruptured AVMs include conservative management, surgical resection, stereotactic radiosurgery, endovascular embolization, or combinations of these treatments.56 The treatment of ruptured AVMs in pregnancy should be based on best available option for the patient, irrespectively of pregnancy status.62 The risk of recurrence in patients with previous intracranial hemorrhage is estimated at 4.8%.57 Obstetric management, as well as primary and secondary prevention for hemorrhagic strokes associated with AVMs, are addressed in the sections below.

Cervical artery dissection

Cervical artery dissection (CAD) is defined by the presence of a mural hematoma in the arterial wall.71 Dissection may occur in the internal carotid artery, more than 2 cm after the bifurcation, and can also affect the vertebral artery.71 Pregnancy-associated CAD accounts for 6% of CAD <50 years.72 The pathophysiology of CAD is poorly understood. The presence of an underlying vasculopathy, including fibromuscular dysplasia or connective tissue disorder (such as vascular Ehlers–Danlos syndrome and Marfan’s syndrome), has been reported.71,73 In pregnancy and the postpartum period, increased hemodynamic forces to vessel walls, hormone-mediated changes in vasoactive substances, collagen metabolism, and vessel integrity, as well as hypercoagulability, are potential mechanisms for the development of CAD.74 While an association with Valsalva maneuvers has been hypothesized, CAD has been described after short second stage of labor and primary cesarean section delivery.74 Vascular instability from pre-eclampsia may be a contributing factor to the development of CAD, although most cases do not present with concomitant hypertension.74 An association with migraine and RCVS has been reported.75

Among women with pregnancy-associated CAD, maternal age above 35 is common, and 75% of cases occur within 2 weeks postpartum.74 Clinical manifestations include headaches (often unilateral and fronto-temporal), cervical pain, tinnitus, dysgeusia, monocular blindness, Horner’s syndrome, and focal neurologic deficit from stroke.72,73,74 Although MR angiographic imaging is the preferred imaging modality, CAD may also be diagnosed using CT angiogram or conventional angiography.71,76 On radiologic imaging, CAD can present as a long, tapered stenosis, a tapered occlusion, or a dissecting aneurysm, and the most typical sign is an enlarged artery with a crescent-shaped rim of hyperintense signal surrounding a narrowed lumen.71,76

Treatment consists of antithrombotic therapy with either antiplatelet therapy or anticoagulation. A randomized controlled trial of antiplatelet therapy (including aspirin, clopidrogrel, dipyridamole, or dual-antiplatelet therapy) or anticoagulation (with unfractionated heparin or LMWH followed by warfarin) for 3 months did not show any difference in the combined end-point of ipsilateral stroke and death between groups, and there was no difference in residual narrowing or occlusion during 12 months of follow-up,77 confirming results from a previous Cochrane review.78 Whether antithrombotic therapy should be continued beyond 3–6 months is unclear, and repeat imaging may help to guide treatment duration.71 Although the risk of stroke recurrence in the general population was estimated at 2.4%,77 the risk of recurrence for pregnancy-associated CAD in future pregnancy is unknown.

Amniotic fluid embolism

Amniotic fluid embolism is thought to originate from entry of material from the fetal compartment into the maternal circulation activating a generalized inflammatory response, with resulting maternal vascular collapse, respiratory failure, and coagulopathy during the peripartum or immediate postpartum period.79 Increased pulmonary vasoconstriction can lead to acute right ventricular failure, decreased left-sided filling pressures, and shock.79,80 Acute strokes occurred in 4/20 women with amniotic fluid embolism and may be attributable to the characteristic hypercoagulable state.81 In addition, a paradoxical embolism with right to left shunting through a patent foramen ovale (PFO) has also been described.81 As such, survivors of amniotic fluid embolism must be carefully evaluated for stroke, and stroke may contribute to maternal mortality reported with this life-threatening condition.

INVESTIGATION OF STROKE IN PREGNANCY (SEE CHAPTER ON RADIATION AND PREGNANCY)

Rapid presentation and prompt neuroimaging are key to confirming or excluding the diagnosis of stroke and to differentiate between ischemic and hemorrhagic events. Prompt imaging may allow the early identification of cases that may benefit from intravenous thrombolysis or acute endovascular thrombectomy. As far as possible, the management of pregnant women should be the same as in non-pregnant patients to achieve optimal maternal and fetal outcomes. If cranial imaging is not available and the patient presents with symptoms of stroke, efforts should be focused on urgent transfer to a healthcare facility with neuroimaging capacity and neurological and interventional expertise.

All standard neuroimaging exposes the fetus to very low doses of radiation.82 Both MRI and CT imaging may be used for the diagnosis of stroke. While MRI is a more sensitive tool to evaluate the ischemic core, CT with arterial contrast is a better option to assess rapidly evolving large-vessel occlusions, which are an indication for thrombectomy. In a large population-based study, MRI exposure during pregnancy was not associated with any adverse fetal outcomes.83 However, an additional analysis of this database limited to MRI of the abdomen, pelvis, or spine in the first trimester identified a possible association with an increased risk of childhood (up to 4 years of age) vision loss (inverse probability weight-adjusted HR 2.28, 95% CI 1.09, 4.77) when MRI was performed at  5–10 weeks gestation.83 This has not been replicated in other studies.

Iodinated contrast agents may be given at all stages of pregnancy and while breastfeeding.62,84 Gadolinium for MR imaging, however, should be avoided whenever possible. Gadolinium crosses the placenta and accumulates in the fetal urinary tract and amniotic fluid. While inadvertent administration of gadolinium in the first trimester is not associated with teratogenesis, it is associated with an increase in rheumatologic and skin conditions, including nephrogenic systemic sclerosis and stillbirth in the offspring.83 Thus, gadolinium should be administered only after careful consideration by the clinical and radiology physicians when the potential benefit to the pregnant patient outweighs the possible risks to the fetus.85

ACUTE MANAGEMENT OF STROKE IN PREGNANCY

When caring for the pregnant patient with suspected ischemic stroke, coordinated care between all key stakeholders is necessary. Ideally, the patient should be transferred urgently to a comprehensive stroke center with access to advanced imaging, neurological and neuro-interventional or neurosurgical expertise, neonatology, and anesthesia, as well as advanced obstetrical care with maternal–fetal medicine and obstetric medicine where available. The patient should monitored in a specialized stroke unit or neurologic intensive care unit.86

Treatment of arterial ischemic stroke

Treatment of ischemic stroke has changed drastically in the last 20 years with the advent of thrombolysis and, more recently, thrombectomy. Both treatments have clear evidence for acute stroke treatment in select groups of patients. Thrombolysis use in acute stroke started after the landmark National Institute of Neurologic Diseases and Stroke (NINDS) trial.87 The treatment consists in giving a systemic dose of recombinant tissue-type plasminogenic activator (rt-PA) with the goal of dissolving intra-arterial thrombi.87 Thrombolytic treatment is time dependent and needs to be given promptly to decrease the risk of hemorrhage and provide optimal benefit.88 Although rt-PA is a large molecule that does not cross the placental circulation,89 placental hemorrhage/abruption may occur.90

Most stroke guidelines use a cutoff time of a 4.5-h treatment window from symptom onset.91 Historically, pregnancy has been considered as a relative contraindication to rt-PA and pregnant patients were excluded from all major rt-PA trials. Therefore, there are no randomized data in this patient population and the only available evidence comes from case series. Recent reports estimate a hemorrhagic risk for thrombolysis of about 8% use for all indications combined among pregnant patients as compared to 6.5% in the general population.87,92 In the last few years, case reports of rt-PA use in pregnancy have shown overall safety of the medication when administered antepartum.89,93,94,95,96,97,98 Accordingly, both expert opinion and major stroke guidelines now support the use of thrombolysis in pregnancy in selected cases of acute stroke.99 Thrombolysis in the postpartum period, however, can result in uncontrolled bleeding, particularly in the setting of cesarean delivery, and should be reserved for life-threatening events.100

Thrombectomy has revolutionized treatment of acute stroke since 2015.101 This treatment consists of endovascular retrieval of symptomatic thrombus in the large vessels of the cerebral vasculature through clot aspiration and stent retrieval.101 It is offered in comprehensive stroke centers with access to interventional neuroradiology, neurosurgery, and neurovascular expertise and is considered the standard of care in acute stroke treatment.91,102 Thrombectomy has a very potent effect on patient survival and functional recovery after ischemic stroke,101 and has shown benefit for up to 24 h after symptom onset.103,104 Patients are selected for this therapy based on both timing from stroke onset and acute imaging findings, including the presence of a large mismatch between previously infarcted brain tissue and the penumbra, also called 'tissue at risk'.101 Few case reports describe the use of mechanical thrombectomy for stroke in pregnancy.94,105,106 In those cases, both anterior and posterior circulation thrombus location were described. The use of thrombectomy showed favorable outcomes in patients, with no intracranial hemorrhage or systemic complications. Fetal radiation exposure has been estimated at around 2.8 mGy in a general endovascular procedure, and may be lower with optimal protection and technical radiographic adjustments.107 This would be well within the limits considered safe.

Treatment of hemorrhagic stroke

Following the diagnosis of hemorrhagic stroke, angiographic imaging with MR angiography, CT angiogram, or catheter angiography must be urgently obtained to guide further management.62 Pregnancy should not delay treatment, and endovascular procedures can be performed if necessary, with abdominal shielding and judicious use of radiation.62 Ruptured aneurysms may be coiled or clipped, depending on the best available option for the patient.62 Ruptured AVMs may be embolized or resected as per modalities previously outlined.14 In addition, any coagulopathy should be corrected, including reversal of anticoagulation if applicable.40,62

While severe blood pressure elevations can contribute to further bleeding, adequate perfusion must be maintained in order not to worsen the ischemic injury.40 As such, blood pressure <160/110 in the acute setting is a reasonable target.62 Hemorrhagic stroke may result in several life-threatening complications including hydrocephalus, hematoma expansion, increased intracranial pressure, and herniation.14 The management of increased intracranial pressure is similar to that in non-pregnant adults, including elevation to 15–30°, maintenance of adequate cerebral perfusion pressure, sedation to prevent agitation, and ventilation to prevent hypercapnia and hypoxia.108 In the event of persistent intracranial hypertension, osmotic diuresis, permissive hypocapnia, and decompressive craniotomy may be required.108 Seizure prophylaxis is often indicated, and should not be withheld in pregnancy.40 Prevention of venous thromboembolism in patients with stroke can be performed with pneumatic compression, while intracranial bleeding precludes anticoagulation.40,109

Poststroke care

Rehabilitation after stroke should begin early in the acute care setting.62 Adequate intensity of therapy, task-oriented training, and excellent team coordination have been associated with better long-term functional outcomes.62 Rehabilitation goals should be tailored to the patient’s specific needs and social role, as the needs for rehabilitation in the young adult may differ from those in the older population.62,110 In addition, screening for peripartum depression with appropriate referral and proactive treatment is key, since depression after stroke is common and may impair functional recovery.62,111 Secondary prevention following stroke is reviewed below.

MANAGEMENT OF PREGNANCY AND BIRTH FOR WOMEN WITH STROKE

Stroke in pregnancy

Whether delivery is indicated for women with stroke in pregnancy depends on the underlying stroke mechanism and planned interventions. Stroke in the setting of hypertensive disorders of pregnancy is a severe manifestation of pre-eclampsia warranting emergent delivery.112 If the timing of hemorrhagic stroke from a ruptured vascular lesion corresponds to a viable gestational age, an interdisciplinary team may consider performing a concurrent cesarean delivery.62 On the other hand, if such timing corresponds to a previable gestational age, maternal safety and outcome must be prioritized regardless of pregnancy status.62 Additional neurological interventions performed after 28–32 weeks, such as craniotomy and osmotic diuresis, may pose significant risks to the fetus and require consideration for cesarean delivery.62

Where delivery is required, careful anesthetic planning should balance potential neuraxial anesthesia-related benefits and contraindications, as well as blood pressure and intracranial pressure targets.62 In women with very high risk of intracranial bleeding (e.g. acute ischemic stroke with hemorrhagic transformation), cesarean section delivery may a preferred option although this remains controversial.40,62 General anesthesia should be avoided where possible and, when performed, reflex hypertension during intubation or extubation should be anticipated.62 Since succinylcholine may cause a small increase in intracranial pressure, alternative regiments have been proposed for endotracheal intubation using rocuronium or high-dose remifentanil (in conjunction with ephedrine to prevent hypotension and bradycardia).14 Intrapartum fetal monitoring should follow local guidance, and continuous monitoring may be appropriate.62

Postpartum, stimulants for hypertension, such as pain, should be avoided. Importantly, women must receive adequate counseling on signs and symptoms of stroke recurrence and should be closely monitored in the first 12 weeks postpartum, as half of all pregnancy-associated strokes occurring during the postpartum period.3,10,62 Breastfeeding for women with pregnancy-associated stroke is not contraindicated, and most medications given for acute stroke treatment are safe in breastfeeding (see below).

Women with a history of stroke

The obstetric care of women with a history of stroke in pregnancy should take place at a high-risk center, within a multidisciplinary team comprising neurological expertise.62 Antenatal fetal surveillance should follow local protocols.62 Planning for delivery is key, and a history of stroke is not a contraindication to vaginal delivery.62 In case of recent neurovascular interventions, the optimal mode of delivery is not clear.40 There are no data to address whether cesarean section helps to reduce the incidence of AVM-associated complications during delivery. In seven patients assessed at the time of AVM resection, Valsalva maneuvers increased in central venous pressure (8 ± 4 mmHg, P < 0.02), yet did not significantly increase in the draining venous pressure.113 Moreover, cesarean delivery is a risk factor for both postpartum hemorrhage potentially resulting in hemodynamic instability, and a predictor of stroke in the peripartum and postpartum periods.20,62 As such, mode and timing of delivery in women with vascular intracranial lesions should be assessed by a high-risk interdisciplinary team, and an individualized approach should be used to consider the risks and benefits of vaginal delivery with assisted second stage of labor versus cesarean delivery, as well as patient preferences and values.62

STROKE PREVENTION IN PREGNANCY

Primary prevention

Primary prevention of stroke is based on optimization and management of risk factors for pregnancy-associated stroke. Since hypertensive disorders are the most significant risk factor for stroke in pregnancy, women at increased risk of pre-eclampsia should receive adequate pre-conception counseling and appropriate pharmacologic prophylaxis.112 In the setting of an established hypertensive disorder, tight blood pressure control targeting a diastolic blood pressure of around 85 mmHg and a systolic blood pressure of around 140 mmHg is reasonable, and has been recommended.112,114,115 First-line oral antihypertensive agents for non-urgent blood pressure reduction include alpha-methyldopa, labetalol, and nifedipine. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers should be avoided in pregnancy due to their fetotoxic potential. Severe hypertension (i.e. >160 mmHg systolic and/or >110 mmHg diastolic) must be considered as a medical emergency.112 The risk of stroke may be decreased with better recognition of consistent blood pressure targets and more appropriate use of antihypertensive medication in women with hypertension in pregnancy.112,116 For urgent blood pressure management, intravenous labetalol and hydralazine, as well as oral nifedipine, are considered suitable agents.112

Women with known AVMs should be evaluated prior to conception and, if necessary, treated before pregnancy. Unruptured AVMs may be treated conservatively with or without surgical intervention, based on individual factors and AVM characteristics.62 Low-grade symptomatic AVMs amenable to surgical intervention should be resected in the same time-frame as in non-pregnant women, with efforts to reduce fetal risks during endovascular or surgical treatment.62 Treatment timing for high-grade AVMs requiring a combined approach should be determined by an interdisciplinary team with neurosurgical and neurological expertise.62 There is no favored neurosurgical technique during pregnancy – choice of resection, endovascular embolization, or stereotactic radiotherapy should be made on angiographic and neurosurgical grounds. Cases of cerebral AVM treatment during pregnancy have been reported.117

Women with high-risk conditions for cardioembolic events, including mechanical heart valves, require anticoagulation with close monitoring (see chapter Anticoagulation in Pregnant Women with Mechanical Heart Valves). Women with known intracardiac shunts should be carefully assessed for indications of thromboprophylaxis. Air-bubble filters should be used in all infusion lines during labor and delivery for women with congenital heart disease, intracardiac shunt, or extracardiac shunt, to avoid air emboli.118

Secondary prevention

Data on the recurrence rate of stroke in subsequent pregnancies remain relatively scarce, with 909 pregnancies described with prior history of stroke.119 Among this group, the risk of recurrence was 1%.119 Most women with stroke recurrence in pregnancy (seven of nine women) had antiphospholipid syndrome.119 In addition, four of nine women had pre-eclampsia.119 A systematic review reported 55 pregnancies following pregnancy-associated stroke.120 The risk of recurrence was 2%, and the incidence of pregnancy complications was similar to that in the general population.120

Pre-conception counseling for women with a history of stroke (both related and unrelated to pregnancy) should include an assessment of individual risk factors for stroke, as well as counseling on smoking cessation, dietary changes, exercise, weight optimization, and pharmacological measures.55 Pharmacologic secondary prevention must be tailored to the type of prior stroke and patient preferences.55 The use of antiplatelet agents and anticoagulation should be assessed on a case-by-case basis, and multidisciplinary consultation may be helpful in decision making.55 Table 3 outlines specific recommended secondary prophylaxis for stroke in pregnancy.55

3

Suggested pharmacological prophylaxis according to previous stroke mechanism.55

Prior stroke etiology

Recommended prophylaxis in pregnancy

Underlying mechanism resolved

No therapy or low-dose aspirin

Cryptogenic stroke

Low-dose aspirin

Cervicocephalic artery dissection

Low-dose aspirin

LMWH in women with prior dissection during highest prothrombotic period, or with remaining clot

Antiphospholipid syndrome

Low-dose aspirin

Therapeutic LMWH

Cerebral venous sinus thrombosis

Prophylactic LMWH during pregnancy and 6 weeks postpartum

Patent foramen ovale

Low-dose aspirin

Prophylactic LMWH should be considered if indications for venous thromboprophylaxis are present

Atrial fibrillation

Therapeutic anticoagulation with LMWH according to indication outside of pregnancy (including CHADS2, CHADS65, or CHA2DS2-VASc scores130,131,132,133)

Mechanical heart valve

Therapeutic LMWH

Sequential therapy with LMWH and vitamin K agonists

Vitamin K agonists throughout pregnancy

DVT, deep venous thrombosis; LMWH, low molecular weight heparin.

Fetal safety of low-dose aspirin (80–150 mg daily) is well established for a wide range of indications during pregnancy and lactation. Thus, women requiring aspirin for stroke prevention prior to conception should continue this medication throughout pregnancy and lactation. The use of other antiplatelet agents has been reported in high-risk settings, such as recent coronary artery stenting or following PFO closure. 40,121,122,123 Given a paucity of safety data, other antiplatelet agents are not recommended for secondary prophylaxis of stroke during pregnancy and should be reserved for specific situations (e.g. in the setting of aspirin allergy). Aspirin 80–150 mg daily may be used as a substitute in those cases.

Low-molecular-weight heparin and unfractionated UFH do not cross the placenta and are safe anticoagulants in pregnancy. Prophylactic doses are usually given for prevention of venous thromboembolic events, while therapeutic doses are reserved for select indications including atrial fibrillation or antiphospholipid syndrome (see Table 3). Vitamin K antagonists are teratogenic and associated with increased fetal and neonatal risk of bleeding. In general, vitamin K antagonists should not be used for stroke prevention except in rare instances, such as previous embolic stroke associated with mechanical heart valves.55 Vitamin K agonists can be used in breast-feeding women. In the instance of stroke related to atrial fibrillation, women may be taking direct oral anticoagulants (DOAC) prior to pregnancy. Animal studies of DOACs in pregnancy have shown reproductive toxicity and their safety during lactation has not yet been established.124 Thus, women taking DOACs should be switched to alternative anticoagulation when planning pregnancy or as soon as they are pregnant, and therapy with DOACs should be resumed only after breastfeeding has been completed.55,124

In women with a history of stroke and hypertensive disorders, blood pressure should be maintained at a maximum around 140 mmHg systolic and 90 mmHg diastolic with appropriate antihypertensive agents.55 Women with prior stroke and pre-existing or gestational diabetes must be treated with tight blood targets, as recommended for all diabetic women in pregnancy.55 The role of statins for long-term secondary prevention following arterial ischemic stroke is well established, although controversy remains regarding their safety in pregnancy. Although reassuring data indicate that statins do not increase the risk of congenital malformations,125,126,127 current consensus statements do not recommend their use during pregnancy and lactation as they may interfere with fetal lipid metabolism.55,128

In the postpartum period, systemic estrogen-containing contraceptive should mostly be avoided in women with ischemic or thromboembolic stroke in favor of progesterone-only contraceptives or intrauterine devices, because of their higher association with stroke risk.55,129

CONCLUSION

Pregnancy-associated stroke is a complex disorder requiring a high degree of clinical suspicion, prompt diagnosis, and immediate management within an interdisciplinary team. Pregnant women have different risk factors for stroke than the general population, and stroke in pregnancy may result from distinct pathophysiologic mechanisms. Radiologic imaging should not be delayed, as required neuroimaging modalities are considered safe in pregnancy. The treatment of acute ischemic and hemorrhagic stroke follows similar guiding principles as in the non-pregnant population. However, additional therapies may be required for pregnancy-specific conditions. Obstetrical considerations include careful anesthetic planning and comprehensive risk assessment of different delivery modes. Following delivery, women must be counseled and monitored for the development of recurrent events. Preconception assessment prior to subsequent pregnancy must be sought to optimize the risk of future safe pregnancies.

PRACTICE RECOMMENDATIONS

  • Although the absolute risk of stroke in pregnancy is low, the relative risk is threefold in pregnancy and the incidence of pregnancy-associated stroke is increasing.
  • Traditional cardiovascular risk factors remain important in pregnancy and should be managed appropriately. Additional pregnancy-specific risk factors (e.g. pre-eclampsia) should also be addressed.
  • Hypertensive disorders of pregnancy, reversible cerebral vasoconstriction syndrome, posterior reversible encephalopathy syndrome, cerebral venous thrombosis, arteriovenous malformations, and amniotic fluid embolism are conditions that may lead to stroke in pregnancy. Therefore, these conditions require urgent medical attention.
  • Women with known arteriovenous malformations should be evaluated prior to conception and, if needed, treated before pregnancy.
  • Pregnant women who present with signs or symptoms consistent with stroke should be rapidly assessed and imaged (with adjustment of imaging techniques if necessary).
  • Thrombolysis and thrombectomy can be performed when indicated for the acute management of pregnancy-associated stroke. Decisions regarding neurosurgical or neuro-interventional management of ruptured intracranial vascular lesions should be taken irrespectively of pregnancy status.
  • Women with a prior history of stroke (whether pregnancy related or not) should be assessed prior to conception and secondary prevention measures applied in pregnancy.


CONFLICTS OF INTEREST

The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.

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