Pregnancy and stroke …

Elizabeth Anderson MD

Stroke & Vascular Disorders

Updated 12.03.2025
Released 06.03.2003
Expires For CME 12.03.2028

Pregnancy and stroke

Author: Elizabeth Anderson MD

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Editor: Steven R Levine MD

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Pregnancy and stroke

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Introduction

Overview

Acute stroke is a medical emergency characterized by a sudden onset of focal neurologic deficits resulting from underlying cerebrovascular disease (124). During pregnancy, stroke is an uncommon but serious cause of morbidity and mortality (137). In this article, the author discusses the etiologies, diagnostic approaches, and therapeutic challenges of pregnancy-specific ischemic and hemorrhagic strokes. This updated article includes revised epidemiologic data, the potential mechanism of preeclampsia, peripartum infection as a risk factor for stroke, Moyamoya disease in pregnancy, and the treatment of antiphospholipid syndrome.

Key points

	• Stroke is a rare but feared complication of pregnancy.
	• Patent foramen ovale closure may prevent ischemic stroke in young patients, but insufficient data exist on the best approach for women desiring pregnancy or already pregnant.
	• Routine testing for hypercoagulable state is not indicated.
	• An overlap exists between the mechanism, clinical presentation, and complications of preeclampsia, eclampsia, posterior reversible encephalopathy syndrome (PRES), and reversible cerebral vasoconstriction syndrome (RCVS).
	• Primary CNS vasculitis is extremely rare during pregnancy.
	• Patients with ischemic stroke may benefit from intravenous thrombolysis.
	• Endovascular thrombectomy may be useful in acute ischemic stroke due to large vessel occlusion.
	• Decompressive craniotomy may be lifesaving in patients with venous sinus thrombosis, even in patients with severe edema, herniation, or coma.

Historical note and terminology

Stroke can be defined as a sudden onset of focal neurologic deficit within a specific vascular territory that affects the brain, retina, or spinal cord and is caused by underlying cerebrovascular disease (124). Although rare, stroke during pregnancy and puerperium accounts for significant morbidity and mortality, with approximately 30 per 100,000 women delivering being affected. Moreover, of those women with high-risk features delivering (such as hypertensive disease), stroke incidence may be as high as 1 in 500 deliveries (137) For this review, pregnancy-related stroke refers to all ischemic and hemorrhagic events occurring during the three trimesters of pregnancy and the first 6 weeks after delivery or puerperium.

Clinical manifestations

Presentation and course

	• All types of strokes may occur during pregnancy.
	• The symptoms and clinical findings of stroke reflect the brain region affected.
	• Preeclampsia and eclampsia are stroke risk factors typical for pregnancy.
	• Preeclampsia is associated with posterior reversible encephalopathy syndrome (PRES), reversible vasoconstriction syndrome (RCVS), hemolysis, elevated liver function, and low platelets (HELLP).
	• Headache, visual disturbances, and seizures should raise the suspicion of either PRES or RCVS.

Ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, dural sinus thrombosis, and cerebral venous thrombosis can all be seen during pregnancy and puerperium. The neurologic manifestations depend on the brain region affected and may include weakness, numbness, clumsiness, imbalance, disturbance of vision, language, cognition, alertness, or a combination of these.

Preeclampsia and eclampsia. Preeclampsia and eclampsia are unique to pregnancy. Along with pregnancy-induced hypertension and gestational diabetes, they are risk factors for cardiovascular disease (187; 109). Further, preeclampsia and other hypertensive disorders of pregnancy can now be diagnosed in one out of every 10 pregnancies in the United States (137).

Preeclampsia is defined as systolic blood pressure (SBP) greater than 140 mmHg or diastolic blood pressure (DBP) greater than 90 mmHg, measured twice at least 4 hours apart, associated with proteinuria (300 mg/24h) after the twentieth week of pregnancy in a woman previously normotensive. In the absence of proteinuria, preeclampsia is diagnosed as hypertension associated with new onset of any of the following: thrombocytopenia (< 100,000/microliter), elevated liver enzymes more than twice the normal concentration, increase of creatinine more than twice normal or greater than 1.1 mg/dL, pulmonary edema, new-onset headache, or visual disturbances.

Preeclampsia with severe features occurs when systolic or diastolic blood pressure is greater than 160 or 110 mmHg, respectively, and it is associated with end organ damage as described above. In this situation, the confirmatory measurement should be performed after a few minutes to expedite treatment. When seizures or coma develop, the term eclampsia is applied. The neurologic deficits are usually reversible.

The effects of preeclampsia on the brain during normal pregnancy are less understood. One study by Yuan and colleagues suggests that there is a significant increase in carotid stiffness (in healthy controls) during the third trimester of normal pregnancies compared to nonpregnant controls (216). This then results in higher systolic blood pressure and resolves over time postpartum. To match these changes, the cerebral vasculature also adapts to maintain brain perfusion, with adaptive remodeling of cerebral arterioles and change in resistance to systemic vasoconstrictors and permeability factors. Complications may arise if this degree of cerebral autoregulation does not occur, such as that seen in preeclampsia, including vasogenic edema and cerebral vasoconstriction (137).

Posterior reversible encephalopathy syndrome (PRES). PRES is characterized by headache, encephalopathy, visual disturbances, and seizures associated with reversible vasogenic edema visible on CT or MRI (85). However, most neurologic deficits are reversible as they are caused by vasogenic edema, not by infarction (184; 177). The clinical manifestations and imaging findings of PRES and eclampsia are similar (25).

Reversible cerebral vasoconstriction syndrome (RCVS). RCVS, characterized by thunderclap headaches, seizures, confusion, visual changes, focal neurologic deficits, and coma, can be defined as a transient disorder of multifocal/segmental nonvasculitic vasospasm of both large- and medium-sized cerebral arteries. Although RCVS can be triggered by drugs (serotonergic medications) or events (orgasm), it can also be triggered by the postpartum state (which is seen in up to 20% of the cases). Similar to PRES, it is more commonly seen in patients who also experience preeclampsia (potentially due to a shared dysfunction in the endothelium as well as inflammation and hyperactivity of the sympathetic pathway). If RCVS becomes severe, it can result in ischemic stroke, subarachnoid hemorrhage, or intracerebral hemorrhage (137).

Hemolysis elevated liver function and low platelets (HELLP syndrome). Preeclampsia may be associated with HELLP syndrome. This presents as generalized edema, right upper quadrant or epigastric pain, nausea, and vomiting that are typically worse at night (19). The focal neurologic deficits are related to severe cerebral edema, ischemic stroke from vasospasm, carotid artery occlusion during rebound thrombocytosis, or intracerebral hemorrhage (103; 132; 82; 205; 81). Subarachnoid hemorrhage without evidence of aneurysm or vasospasm on angiography may also occur (183).

Cerebral vasculitis is characterized by less severe headaches and focal neurologic deficits due to ischemic stroke or intracerebral hemorrhage.

Prognosis and complications

Ischemic and hemorrhagic stroke. Analysis of the nationwide inpatient sample from the United States for the years 2000 to 2001 showed a mortality rate of stroke of 1.4 per 100,000 deliveries. Twenty-two percent of survivors were discharged to another facility (93). In the UK, the mortality rate was 0.3 per 100,000 deliveries, and the case fatality rate was 20% of all strokes and 50% of hemorrhagic strokes (181).

In the U.S., stroke accounts for 7.7% of maternal deaths (35). Worldwide, approximately 7.7% to 15% of all maternal deaths can be attributed to stroke, with the highest mortality secondary to intracerebral hemorrhage (which has an estimated case fatality rate of 13.8%). These patients then go on to have significant disability, with an estimated 30% to 50% having persistent neurologic deficit (88).

In a study of 441 French women aged 15 to 40 years with prior stroke, the risk of peripartum ischemic stroke increased to 1.8% (114). Only about half of these patients received antiplatelet therapy during pregnancy. A population-based study from Australia revealed that women who had a stroke were not more likely to have a stroke related to a subsequent pregnancy (12).

A nationwide register-based cohort study of 2,134,239 Swedish women revealed that all pregnancy complications studied, including preeclampsia or eclampsia, gestational hypertension, gestational diabetes, preterm birth, small for gestational age, and stillbirth, were associated with an increased risk of stroke (198).

Preeclampsia. Preeclampsia complicates 3% to 3.5% of pregnancies; 2.6% of these progress to eclampsia. The relative risk of death at 1 year is 5.1 compared to normotensive women (199), increasing the cost of care between 40 to 100 times that of a term pregnancy (188). Data from the Framingham Heart Study show that preeclampsia increases the risk of stroke, on average over 30 years, by 4-fold (44). Preeclampsia doubles the risk of cardiovascular disease in comparison to normal pregnancy (91). The higher cardiovascular risk is not only during the first few years following pregnancy but also long-term (28). A meta-analysis of 2,501,673 women found that preeclampsia is associated with a long-term risk of vascular dementia, but less clearly with Alzheimer and other types of dementia (34). Cardiac remodeling following hypertensive pregnancy disorders may be reversible after a short-term postnatal optimization of blood pressure through self-monitoring and physician supervision (108).

Cerebral venous sinus thrombosis (CVST). CVST occurs secondary to clot formation in the cerebral venous system, resulting in venous congestion, cerebral edema, and, in severe cases, venous infarct or hemorrhage. Of all pregnancy-related strokes, CVST accounts for approximately one third of cases, with the majority occurring in the postpartum period (about 75%). Presentation includes positional headache that increases over time and is often worse lying down, blurred vision, seizures, and focal neurologic deficits (137).

Cerebral venous thrombosis has a good long-term prognosis. In a pooled systematic review of 66 patients presenting with cerebral venous sinus thrombosis, 59% had a modified Rankin scale (mRS) of 0, and 94% had mRS of 0 to 2 at follow-up. Obtundation and coma, but not headache, predicted a poor outcome (101).

Although CVST diagnosed postpartum was more frequently associated with early complications than in nonpregnant women, outcomes at 90 days and 1 year were similar (62). Another pooled analysis of 13 studies showed that the risk of pregnancy-related venous thrombosis is low. The relative risk of noncerebral venous thromboembolism is 16-fold higher (2.7%) and the recurrence of cerebral venous thrombosis is 80-fold higher (0.9%) than in the general population. The miscarriage rate is similar to the general population (03). Treatment usually involves anticoagulation, although the duration is unclear. A history of pregnancy-related stroke is not a contraindication for subsequent pregnancy, although use of prophylactic anticoagulation in following pregnancies and in the immediate postpartum period may be suggested (137).

Posterior reversible encephalopathy syndrome (PRES). In a retrospective cohort of 70 patients with PRES, 94% had decreased consciousness, 81% had seizures, and 14% had ischemic stroke or intracerebral hemorrhage. Although most patients (56%) recovered well at 90 days, 16% died and 37% had marked functional impairment. However, patients with preeclampsia may have a better prognosis (118). Few patients with RCVS have neurologic sequelae after stroke, 9% had severe deficits, and 2% died (190). The prognosis of HELLP is similar to severe preeclampsia except for the hematologic variables (79).

Cerebrovascular malformations. Vascular brain lesions, arteriovenous malformations, and cavernous hemangioma occur in 5.3 per 100,000 deliveries. Their presence does not seem to carry additional risk to the mother and fetus. Seventy-nine percent of deliveries were performed via cesarean section (129), despite the fact that there is no evidence indicating that cesarean delivery decreases the risk of rupture (137).

Aside from obstetrical considerations, the complications of stroke in pregnancy resemble those seen in nonpregnant patients. Acutely, the most serious risk is herniation from cerebral edema. Seizures, status epilepticus, aspiration pneumonia, sepsis, decubiti, deep vein thrombosis, and pulmonary embolism contribute to poor outcomes. Long-term disability includes difficulty with childcare and return to work.

Clinical vignette

A 23-year-old woman had a sudden onset of blurred vision, occipital headaches, and dysarthria 5 days after delivery following an uneventful pregnancy. Her blood pressure was normal. She had dysarthria, left central facial weakness, subtle left arm weakness, and an extensor plantar response on the left. CT scan of the brain was normal. MRI showed areas of restricted diffusion in the frontal, parietal, and temporal lobes bilaterally. MRA was normal. MRV showed a filling defect in the superior sagittal sinus. CBC and complete metabolic panel were normal. Heterozygosity of the factor V Leiden mutation was found. Anticoagulation was started with intravenous unfractionated heparin and followed by oral warfarin. One month later her symptoms had completely resolved. Warfarin was continued for 6 months and then switched to aspirin. Prophylactic heparin therapy during subsequent pregnancies was recommended.

Biological basis

	• Pregnancy is associated with a hypercoagulable state.
	• Pregnancy-induced cardiovascular changes may unmask underlying heart vulnerabilities.
	• The highest risk of stroke is during the third trimester, delivery, and 6 weeks afterwards.
	• Most risk factors for ischemic stroke during pregnancy and in nonpregnant patients are similar.
	• Complications of pregnancy play a major role in stroke etiology.
	• Emboli may include blood clots, air, amniotic fluid, or metastatic tumor.
	• Dehydration, hyperviscosity, hemorrhage, anemia, and vasoconstriction are additional risk factors for stroke.
	• Cervical artery dissection is rare and should be suspected if head or neck pain occurs.
	• Most hemorrhagic stroke is caused by hypertensive disorders.

Etiology and pathogenesis

The risk of stroke is highest during the third trimester, around delivery, and up to 6 weeks postpartum (171). Physiological changes related to pregnancy are numerous and may increase the risk of cerebrovascular complications related to pregnancy. In addition, stroke may be caused by the cerebrovascular risk factors that occur outside pregnancy.

Cardiovascular adaptation to pregnancy. Increased levels of estrogen, progesterone, and relaxin decrease systemic resistance. At the same time, heart contractility and rate increase. Systemic blood pressure decreases in most, but not all, studies. This is counteracted by sympathetic activation and increased cardiac stroke work. However, the vasoconstrictor response is blunted during normal pregnancy (68). If excessive, this response may unmask cardiac pathology and lead to preeclampsia or RCVS.

Cerebral autoregulation. A protective mechanism against the hyperdynamic changes is decreased reactivity of cerebral arteries to vasoconstrictors and arterial remodeling leading to extension of the autoregulation curve towards both lower and higher blood pressure values. This is realized by selective arterial remodeling outwards of the parenchymal arterioles triggered by activation of peroxisome proliferator-activated receptor gamma (PPARγ) by relaxin. The same receptor is responsible for the increased capillary density in the occipital regions predisposing this area to hypertension-induced vasogenic edema. This vulnerability is further increased by the prevention of inwards remodeling by decreasing the expression of angiotensin type 1 receptor.

Blood-brain barrier. Despite increased secretions of vascular endothelial factor and placental growth factor, the blood-brain barrier permeability remains constant due to transient increased secretion of p-glycoprotein and multidrug resistance-associated protein1, the main efflux transporters (96).

Intravascular fluid balance. Increased plasma volume results from increased thirst under the influence of vasopressin stimulated by relaxin. Simultaneously, kidneys reabsorb more water under the influence of the renin-angiotensin-aldosterone system. Closer to term, increasing amounts of maternal atrial natriuretic peptide facilitate postpartum diuresis (173). Increased systemic pressure leads to forced dilatation of cerebral arteries and arterioles, decreased cerebrovascular resistance, and maintenance of blood flow.

Coagulopathy. Pregnancy results in a hypercoagulable state necessary to prevent bleeding complications (36). The coagulation activity seen during pregnancy doubles when compared with the nonpregnant state (195). During pregnancy, there is an increase in factors I, VIIm, VIII, IX, X, XII, XIII, and vWF, which promotes coagulation. Further, factors that inhibit coagulation, such as protein S and C are decreased. Finally, there is a decrease in fibrinolytic activity (which increases risk of thrombosis and stroke overall) (128). Hemostasis returns to baseline within 4 to 6 weeks after delivery (84).

Immunological response. The physiological immune response to pregnancy consists of a distinct activation of T and B cells but without exhibiting aberrant activation leading to an autoimmune response (45). Nuclear factor kB induces transcription of proinflammatory genes required for implantation and delivery. This factor is induced by cytokines, growth factors, hormones, and various infections. Its suppression during the rest of pregnancy allows fetal maturation and prevents premature delivery (74).

Complications of pregnancy. Complications of pregnancy contributing to stroke are hypertensive disorders of pregnancy, preeclampsia, eclampsia, gestational hypertension, gestational diabetes, postpartum hemorrhage, blood transfusions, and peripartum infection (93; 120; 142; 126).

Additional pregnancy-related risk factors are nulliparity, stillbirth, assisted reproductive technology, greater parity, cesarean delivery, multiple pregnancy loss, stillbirth, and preterm delivery (169; 125; 162; 43; 121; 209). Postpartum uterine hemorrhage may result in systemic hypotension watershed infarctions, postpartum pan-hypopituitarism, and posterior ischemic encephalopathy.

Delivery associated with assisted reproductive technology has been associated with an increased risk of preeclampsia and eclampsia, heart failure, cardiac arrhythmia, ischemic stroke, hemorrhagic stroke, and thromboembolism (217).

Posterior reversible encephalopathy syndrome (PRES). PRES may mimic ischemic stroke and requires imaging for diagnosis. There is a strong overlap of clinical manifestations and imaging findings between PRES and eclampsia (25).

Reversible cerebral vasoconstriction syndrome (RCVS). RCVS is a transient spasm of medium- and large-sized arteries triggered by a surge in sympathetic activation. It occurs in patients with preeclampsia or eclampsia, sympathomimetic drugs (eg, cocaine, antidepressants), as well as in normal pregnancy and delivery (189). It was also described in patients with cervical artery dissection (10). RCVS should be differentiated from cerebral vasculitis, a rare cause of stroke in pregnant women. Although transient, it may cause ischemic stroke or subarachnoid or intracerebral hemorrhage.

Hemolysis elevated liver function and low platelets (HELLP syndrome). HELLP syndrome is associated with preeclampsia and may cause either ischemic stroke or intracerebral hemorrhage, depending on the number of platelets present in circulation.

Air and amniotic fluid embolism. Amniotic fluid embolism is a phenomenon that occurs when there is a breech in the maternal-fetal physiological barrier during labor. This then results in a proinflammatory response. Although rare, stroke has been documented to be related to amniotic fluid embolism. In an Australian study with 600,000 deliveries, 20 cases of amniotic fluid embolism were reported; of those cases, four had resultant stroke (128). It is hypothesized that it is the related hypercoaguable state that is responsible.

Dilated cardiomyopathy. Dilated cardiomyopathy rarely develops during the second trimester. Ventricular arrhythmias, heart failure, stroke, and death may occur in up to 60% of high-risk patients. Hypertrophic cardiomyopathy leads to similar complications (178). Peripartum cardiomyopathy is uncommon during the last month of pregnancy and up to 5 months postpartum. Associated risk factors include older age, hypertension, and tocolytics use during pregnancy (59).

Choriocarcinoma. Choriocarcinoma arising from fetal trophoblastic tissue frequently metastasizes to the brain (67). This highly vascular tumor often presents as intracerebral hemorrhage at the gray-white matter junction or as subarachnoid hemorrhage (65). Intracranial aneurysms have also been described (147). Treatment is by chemotherapy or surgical resection (156; 182).

Cerebrovascular risk factors. Stroke during pregnancy may be triggered by the risk factors present independent of pregnancy: smoking, drug use, hypertension, diabetes mellitus, and ischemic heart disease as well as other rare causes like hypercoagulable states and vasculitis (109). Black and Hispanic pregnant women have higher risks of stroke than non-Hispanic whites (144). Additional risk factors include advanced age, systemic lupus erythematosus, chronic kidney disease, and, rarely, family history and trisomy 13 fetus (162). In a smaller study, stroke during pregnancy was associated less often with the typical vascular risk factors and more often with cerebral venous sinus thrombosis and RCVS (143).

Cardioembolism. Most cardioembolism is due to prosthetic heart valves or atrial fibrillation. The association of the prothrombotic state of pregnancy with changing intrathoracic pressures during pregnancy and delivery may favor paradoxical embolism of a venous thrombus through a patent foramen ovale (112; 73). In contrast to other stroke etiologies, patent foramen ovale–related stroke occurs more often during the first two trimesters (37).

Cervical artery dissection. Cervical artery dissection rarely occurs, usually after delivery, as headache and neck pain (185). The associated risk factors are advanced maternal age and hypertensive disorder of pregnancy (104; 127).

Cerebral venous sinus thrombosis (CVST). Cerebral venous thrombosis occurs in 10 to 20 per 100,000 deliveries in the developed countries (33). More than 80% of these patients had a hypercoagulable state (30). Increased blood viscosity associated with sickle cell anemia, malignancy, polycythemia, and paroxysmal nocturnal hemoglobinuria can also precipitate cerebral venous thrombosis. Systemic infection, anemia, and severe dehydration help explain the significantly higher frequency of this condition in the developing world. Other risk factors include cesarean delivery, hypertension, and infections other than pneumonia and influenza (115).

Intracerebral hemorrhage. Intracerebral hemorrhage has similar causes as in nonpregnant patients. Hypertension, pregnancy-induced hypertension, preeclampsia, and eclampsia are the most common causes (109). Intracerebral hemorrhage occurs more commonly during the third trimester and first 12 weeks postpartum (135). Migraine and RCVS are more commonly seen in pregnancy-associated hemorrhagic stroke than the typical cerebrovascular risk factors and underlying lesions present in nonpregnant women (141). Pathology shows fibrinoid necrosis of small penetrating vessels (167).

Arteriovenous malformations. Data on the risk of rupture of arteriovenous malformations during pregnancy are conflicting. A single center’s data over 50 years did not show an increased risk of hemorrhage (123). However, considering the amount of exposure to pregnancy, 40 weeks per pregnancy, 6 weeks for each puerperium, and 6 weeks for each abortion, the annual hemorrhage rate was 1.3% in nonpregnant women versus 5.7% in pregnant women. Analysis for reproductive age patients (15 to 50 years) shows a bleeding rate of 1.3% versus 7.0% (159). Moreover, analysis of the Healthcare Cost and Utilization Project State Inpatient Databases for California, Florida, and New York over 9 years revealed a 3-fold increase in intracerebral hemorrhage in women with arteriovenous malformations (116).

Cavernous malformations. Pregnancy does not increase the risk of hemorrhage from cavernous malformations (100). In a prospective registry of brain and spinal cavernoma enrolling 160 women, there was no increased risk of hemorrhage. Vaginal delivery is appropriate for most women (98).

Subarachnoid hemorrhage. Subarachnoid hemorrhage mostly results from aneurysmal rupture and is associated with high morbidity and mortality. Other causes include rupture of other vascular malformations, trauma, and RCVS. Intracranial aneurysms do not have an increased risk of bleeding during pregnancy and puerperium (107; 47). Aneurysmal rupture usually occurs in the third trimester, during labor and delivery. The incidence of ruptured aneurysms is one to five in 10,000 pregnancies. They are more likely to rupture in patients with advanced gestational age, primiparity, and hypertension (50; 151).

Moyamoya disease and syndrome. The risk of moyamoya-related stroke during pregnancy, delivery, and the postpartum period appears to be similar to or lower than in the prior studies of natural history (154). In a study of 20 patients with moyamoya disease, intracerebral hemorrhage tended to occur antepartum whereas ischemic stroke postpartum (89). In a study of 77 women, 19.2% of women developed hypertensive disorders of pregnancy, 60% of which required cesarian section because of a sudden increase in blood pressure (08). In another study of 71 pregnancies in 54 women with moyamoya disease, the risk of stroke was higher before bypass surgery than after (39).

Preeclampsia and eclampsia. Preeclampsia is triggered by the presence of the placenta but may occur even after delivery and is associated with long-term cardiovascular morbidity. Subclinical cardiovascular dysfunction is present before and after delivery, suggesting a more pervasive disruption of the cardiovascular system homeostasis, namely a gestational cardiorenal syndrome (78).

In the early stages, poor placentation due to ineffective trophoblast invasion of the uterine wall may be caused by certain natural-killer cells and HLA-C combinations (145). Placental hypoperfusion results from inadequate remodeling of uterine spiral arteries (164). In later stages, placental ischemia leads to the release of cytokines and other agents causing endothelial dysfunction (165). TNF-alpha stimulates endothelin-1, a potent vasoconstrictor, and IL-6, the renin-angiotensin system (113). Matrix metalloproteinases, soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin, and agonistic autoantibodies to the angiotensin type 1 receptor (AT1-AA) stimulate the production of endothelin-1, which seems to be the common pathway in the pathogenesis of preeclampsia and a potential target for treatment (14). Hypertension is related to increased cardiac output and mild systemic vasoconstriction (46). During late pregnancy, the cardiovascular parameters are determined by the status of the systemic circulation rather than by inadequate placentation or remodeling of the spiral arteries (155). Glomerular endothelial dysfunction leads to renal injury, proteinuria, and hypertension (191).

An umbrella review found serum iron level, chronic kidney disease, polycystic ovary syndrome, mental stress, infections, smoking, oocyte donation, obesity, and primiparity highly suggestive of an association with preeclampsia (72). In women with preeclampsia, the risk of stroke is increased by infection on admission, prothrombotic state, coagulopathy, and chronic hypertension (140).

Posterior reversible encephalopathy syndrome (PRES). In eclampsia, PRES is an important component of pathogenesis (25). It is caused by altered cerebral autoregulation due to endothelial dysfunction (180), leading to vasogenic edema in the vulnerable regions of the posterior brain where the sympathetic innervation is less robust. This syndrome occurs more often in the presence of hypertension, but not always (13). Status epilepticus is not uncommon in these patients (69).

Reversible cerebral vasoconstriction syndrome (RCVS). RCVS can develop in the puerperium in the absence of preeclampsia or hypertension. Two thirds of patients develop symptoms within a week postpartum, even after a normal pregnancy (52). The etiology is not clear, although several drugs have been implicated, such as ergot derivatives, cocaine, serotonin reuptake inhibitors, and immunosuppressive drugs (94; 77; 52). Pregnancy-associated arterial intimal hyperplasia (27) and arterial spasm have been suspected. CSF studies are usually normal or show mild pleocytosis. Mild hyperplasia without inflammation was found in one fatal case. Brain biopsy in one severe case found microangiopathic inflammatory infiltrates and fibrinoid necrosis without meningeal involvement (31). Although eclampsia, PRES, and RCVS are distinct entities that can occur independently, there is an overlap between them due to common pathophysiology.

Cerebral vasculitis. Cerebral vasculitis during pregnancy is rare; it may be isolated to the central nervous system or part of a systemic illness. Arterial inflammation leads to stenosis and ischemic stroke or intracerebral hemorrhage. Decreased exacerbation of polyarteritis nodosa and Bechet disease during pregnancy (110) and protection against giant cell arteritis after multiple pregnancies have been described (53). The autopsy of a fatal case of vasculitis described in a woman who developed systemic lupus erythematosus during pregnancy showed polyarteritis nodosa-like necrotizing vasculitis of the small muscular arteries and arterioles, with acute and healing lesions in the leptomeninges, brain parenchyma, and visceral organs (196).

Hemolysis elevated liver function and low platelets (HELLP syndrome). HELLP syndrome is characterized by microangiopathic hemolytic anemia, elevated liver enzymes, and thrombocytopenia. On liver biopsy, the classic lesion is periportal or focal parenchymal necrosis in which hyaline deposits of fibrin-like material can be seen in the sinusoids. Fibrin microthrombi and fibrinogen deposits in the sinusoids, in areas of hepatocellular necrosis, and the sinusoids of the histologically normal parenchyma are also seen (19).

Infection. Any infection on the admission day for delivery increased the risk of stroke. The risk was even higher for genitourinary infections and sepsis. This suggests that infections may contribute to peripartum stroke (139).

Placental pathology. Placental abruption is also associated with an increased risk of ischemic and hemorrhagic stroke, particularly if delivery is before 34 weeks, when accompanied by placenta ischemia and in women with more than one abruption (06).

A certain proportion of strokes during pregnancy and puerperium do not have a clear etiology. However, these must be categorized as a stroke of unknown etiology rather than caused by the pregnant state.

Epidemiology

	• The incidence of stroke varies with its definition, the population studied, the duration of postpartum monitoring, and the epoch.
	• The incidence of stroke during pregnancy and postpartum is slightly increased compared to the nonpregnant state.
	• The risk of stroke is increased during peripartum and postpartum periods.
	• The risk of recurrent stroke is similar in pregnant and nonpregnant women without risk factors but is higher in pregnant women with risk factors.

Ischemic and hemorrhagic stroke. A systematic review and meta-analysis of 11 studies demonstrate a pooled rate of stroke of 30 per 100,000 pregnancies (when analyzing high-income countries), of which 19.9 were arterial and venous thrombosis and 12.2 were hemorrhagic. The crude stroke rate for antenatal and perinatal stroke was 18.3, and it was 14.7 for postpartum stroke (197).

Interestingly, studies involving low- and middle-income countries (although not robustly powered) show a much higher rate of maternal stroke. In one study of 5500 deliveries in Tanzania (from 2009 to 2010), the incidence of maternal stroke was 89 per 100,000 deliveries (57). An additional study (from 2006 to 2008) of over 39,000 deliveries in India showed that the incidence of cerebrovascular complications was 66 per 100,000 deliveries.

A nationwide study from France showed that in pregnant women aged 15 to 49, the incidence was 42.9% for ischemic stroke, 41.9% for hemorrhagic stroke, and 17.4% for cerebral venous thrombosis (131). Compared to nonpregnant women, pregnancy was associated with a similar rate of ischemic stroke, a slightly increased rate of hemorrhagic stroke, and an 8-fold increased risk of cerebral venous thrombosis.

In the United Kingdom, stroke incidence was 1.5 strokes (0.9 ischemic and 0.6 hemorrhagic) per 100,000 deliveries. The risk factors were migraine, gestational diabetes, and preeclampsia or eclampsia (181). In another open cohort study from England of 2,046,048 women aged 15 to 49 years, nonpregnant women had an incidence rate of first stroke of 25.0 per 100,000 person-years. Antepartum, the incidence rate was lower (10.7 per 100,000 person-years), but the incidence of stroke was 9-fold higher peripartum (161.1 per 100,000 person-years). Early postpartum (first 6 weeks), the incidence was 3-fold higher (47.1 per 100,000 person-years). The rate of ischemic and hemorrhagic stroke was increased both peripartum and early postpartum (16).

Analysis of a National Inpatient Sample revealed that stroke occurred in one of 2222 pregnancy-related hospitalizations and has not changed between 2007 and 2015. During the same period, the prevalence of risk factors for stroke (obesity, smoking, hyperlipidemia, migraine, and gestational hypertension) increased, but in-hospital mortality among pregnant women with stroke has decreased from 5.5% in 2007 versus 2.7% in 2015 (58).

The incidence of stroke in the general U.S. population has decreased in recent years, likely due to better control of cardiovascular risk factors. However, the same cannot be said for maternal stroke (with an upward trend being recognized in studies over time). Stroke rates also appear to be higher in the U.S. when compared to other developed nations. This can be partly attributed to increasing maternal age at birth and higher prevalence of cardiovascular risk factors. However, health disparities seen amongst different races and ethnicities also play a significant role (57).

Risk of recurrent stroke. The risk of recurrent ischemic stroke is not increased during pregnancy, but during the postpartum period (114). The risk of stroke recurrence during pregnancy is less than 1%, similar to the risk of women without risk factors but is higher in women with known cerebrovascular risk factors like type 1 diabetes mellitus, large artery atherosclerosis, heart failure, previous transient ischemic attack, and increasing age (160). Unfortunately, the older epidemiological studies suffer not only from the variability of methods used but also from the use of an outdated definition of stroke introduced several decades ago, which was only recently updated (170).

Preeclampsia. In the United States, preeclampsia complicates 3.4% of pregnancies, with maternal age at the extremes and birth dates in the 1970s as the major risk factors (07). Inpatient data from the New York State Department of Health reveal that approximately 0.2% of women with preeclampsia had a stroke. Severe preeclampsia, eclampsia, infection on admission, prothrombotic state, coagulopathy, or chronic hypertension were associated with stroke (140).

Moyamoya disease. A systematic review of pregnant patients with moyamoya disease (MMD) shows that the mean gestational age at diagnosis due to stroke was 28.7 weeks, and 69.5% presented with cerebral hemorrhage. Of those diagnosed with moyamoya disease postpartum, 46.6% had a stroke within 3 days of delivery, of which 78.3% were ischemic (130).

Moyamoya disease is more prevalent in women and often first presents in early adulthood when women are in their childbearing years. If diagnosed before pregnancy, females often have good pregnancy outcomes. In a systematic review of 54 articles, 95% of those diagnosed with Moyamoya before pregnancy had good outcomes (57). However, of those diagnosed during pregnancy, more than two thirds had intracerebral hemorrhage as a complication, with associated high rates of morbidity and mortality. Postpartum, the stroke diagnosis was often ischemic.

Cerebral venous sinus thrombosis (CVST). The CVST rate was 9.1 per 100,000 pregnancies in a systematic review and meta-analysis of 11 studies published between 1990 and 2017 (197). Another systematic review of women with a history of cerebral venous thrombosis shows that the absolute risk of pregnancy-related venous thrombosis is low. However, the relative risk of noncerebral venous thromboembolism is 16-fold higher and the recurrence of cerebral venous thrombosis is 80-fold higher than in the general population. The rate of miscarriage is not significantly increased (03). Cerebral venous thrombosis is a more important cause of pregnancy-associated stroke in developing countries (152).

Prevention

	• High blood pressure should be closely monitored and treated.
	• Magnesium sulfate helps prevent eclampsia.
	• Aspirin prevents stroke in women with hypertensive disorder of pregnancy.
	• Mechanical valves require careful and continuous anticoagulation.
	• Warfarin is teratogenic.
	• Low-dose aspirin for secondary stroke prevention is safe during the second and third trimesters.
	• PFO closure during pregnancy is of unclear benefit.
	• The optimal preventive strategy in women with antiphospholipid syndrome is unclear.
	• Uncertainty persists in choosing the best management of moyamoya disease, unruptured aneurysm, or arterio-venous malformation during pregnancy.

Pregnancy-related strokes are difficult to prevent, as the contributing factors are usually identified after the event or result from pregnancy itself. Moreover, there are insufficient data on the safety of some medications used for prevention in nonpregnant patients.

Preeclampsia. Screening for preeclampsia by measuring blood pressure throughout pregnancy is recommended (203). Treatment is recommended if systolic blood pressure is 160 mmHg or higher and diastolic blood pressure is 105 mmHg or higher. If lower blood pressure values are not accompanied by end organ damage, no treatment is recommended. Decreasing the threshold blood pressure from 140/90 to 120/80 mmHg does not increase the number of women who might be at higher risk of adverse outcomes (192).

Blood pressure control. Labetalol, long-acting nifedipine, verapamil, and methyldopa may be used both during pregnancy and lactation. Angiotensin-converting enzyme inhibitors, angiotensin receptor inhibitors, renin inhibitors, and mineralocorticoid receptor antagonists are not recommended.

Although treatment of blood pressure values of 140-159 / 90-109 mmHg does not influence the risk of fetal death, preterm delivery, or small for gestational age, it may halve the risk of subsequent severe hypertension (02) and may be considered (29). However, a meta-analysis showed that for each 10 mmHg of mean arterial pressure reduction, birth weight decreased by 145 g, regardless of the agent used (206).

Magnesium sulfate is recommended for blood pressure greater than 160/110 mmHg or severe preeclampsia intrapartum or postpartum. In a Cochrane review, parenteral magnesium sulfate prevented eclampsia by more than 50% versus placebo (54).

Recurrent early-onset preeclampsia and preterm delivery may benefit from daily low-dose aspirin (60 to 80 mg) beginning in the late first trimester (55).

After discharge, blood pressure should be monitored at 3 days and at days 7 to 10. Women should be educated regarding the signs and symptoms to monitor regardless of history of preeclampsia.

The California Teachers Study, a prospective cohort study including 83,749 women, showed that hypertensive disorder of pregnancy increased the risk for stroke before the age of 60, but not in aspirin users. Statin use did not modify this risk (138). Recurrent preeclampsia or a combination of preeclampsia and preterm delivery should prompt yearly evaluations of blood pressure, lipids, fasting blood glucose, and body mass index (05).

Several studies suggest that prophylactic use of aspirin may be beneficial in reducing the risk of preeclampsia. A meta-analysis of five trials including 556 women showed that aspirin use at or before 16 weeks of pregnancy was associated with a major reduction in risk of preterm preeclampsia. This was further validated by a meta-analysis of 13 studies demonstrating that low-dose aspirin use showed a 24% reduction in preeclampsia when started at 12 to 16 weeks’ gestation (57).

Vitamin D3 deficit may increase the risk of preeclampsia; however, there is no evidence to support supplementation (23). Calcium supplementation greater than 1 g/day during pregnancy was also found to reduce the relative risk of hypertension (86).

Anticoagulation. The recommendations for anticoagulation during pregnancy developed by the writing group of the ACCP are based on two scenarios: (1) a high-risk condition that requires anticoagulation, or (2) a low-risk condition that requires antiplatelet therapy.

Artificial heart valves represent one of the highest stroke risks and require anticoagulation throughout pregnancy. Anticoagulation can be achieved in three ways: (1) low molecular weight heparin (LMWH) or unfractionated heparin (UFH) until the 13th week with substitution of vitamin K antagonists until close to delivery when LMWH or UFH is resumed; (2) adjusted-dose UFH administered subcutaneously every 12 hours to keep mid-interval aPTT at least twice control throughout pregnancy; or (3) adjusted-dose of LMWH twice daily throughout pregnancy. If the risk of thromboembolism is very high, eg, older mitral prosthesis or history of thromboembolism, vitamin K antagonists throughout pregnancy except close to delivery when administration of UHF or LMWH is preferred. The addition of 75 to 100 mg aspirin to anticoagulation is also suggested (21).

With that in mind, it is important to remember that warfarin (a vitamin K antagonist) is able to cross the placenta and, therefore, is a category X medication. This medication is not recommended for use by the U.S. Food and Drug Administration as it is associated with warfarin embryopathy in the first trimester and further neurologic sequelae (including seizures, hypotonia, intracranial microhemorrhages, etc.) if used in the second and third trimesters. Therefore, the anticoagulation of choice remains LMWH or UFH (106).

Women requiring long-term anticoagulation for other indications should be switched as soon as pregnancy is determined to UFH or LMWH for the duration of pregnancy. A discussion of risks and benefits with the patient is important.

Antiplatelet agents. Use of aspirin in the treatment of acute ischemic stroke is recommended within the first 24 to 48 hours of onset. If thrombolysis is utilized, initiation should be delayed for 24 hours, at which time intracerebral hemorrhage should be ruled out with imaging. If the patient has either minor stroke or high-risk transient ischemic attack, the use of dual antiplatelet therapy with aspirin and clopidogrel should be considered and started within 24 hours of presentation. This should be continued for 21 days, with aspirin monotherapy thereafter. Although significant evidence has pointed towards the safety of aspirin in pregnancy, the safety of clopidogrel is less clear, and, therefore, it is currently a U.S. Food and Drug Administration category B medication. If clopidogrel is being used, it should be stopped 7 to 10 days before a scheduled delivery, if possible, due to bleeding risk. If spontaneous labor occurs, neuroaxial anesthesia should be avoided to prevent risk of spinal or epidural hematoma (106).

Postpartum prevention. In the postpartum period, nursing mothers may safely take warfarin, but they may also take UFH (21) and even LMWH (168). During breastfeeding, low-dose aspirin seems to be safe for the infant (92; 17), with limited evidence placing clopidogrel as a category B medication (106).

Cerebral venous sinus thrombosis. Prophylactic treatment with low-dose heparin beginning after delivery and lasting for 6 weeks postpartum should be considered for women with a prior history of cerebral venous thrombosis.

Patent foramen ovale. There are no data on closing patent foramen ovale in women who desire pregnancy or during pregnancy. In selected patients with cryptogenic stroke and large shunts, patent foramen ovale closure prevented more strokes compared to medical therapy alone. Rarely, serious device-related adverse events and atrial fibrillation occurred after patent foramen ovale closure (40; Gore REDUCE Clincial Study Investigators 2017; 166).

Antiphospholipid syndrome. Antiphospholipid syndrome increases the risk of recurrent ischemic stroke, preterm delivery, and preeclampsia during pregnancy. Specifically, the presence of lupus anticoagulant or past thrombotic events has been shown to have the strongest predictive factors for further thrombotic events during pregnancy in a prospective analysis study including 33 pregnant women (57).

A Cochrane analysis in women with antiphospholipid antibodies and recurrent pregnancy loss has not determined the best preventive strategy: a) aspirin with LMWH versus placebo or IVIG, or b) aspirin plus high-dose LMWH versus aspirin with low-dose LMWH or UFH. Further adequately powered studies are needed (15).

Moyamoya disease. Of the patients diagnosed with Moyamoya disease, 80% delivered via cesarean section; however, no evidence exists to suggest that cesarean section is preferred. Moyamoya disease is often diagnosed before pregnancy (137). Of those women, 95% have good pregnancy outcomes. However, more than two thirds of the women who are diagnosed with Moyamoya during pregnancy present with intracerebral hemorrhage, resulting in high maternal and fetal morbidity and mortality. If presenting postpartum, the stroke is often ischemic rather than hemorrhagic.

Moyamoya disease does not seem to contraindicate pregnancy. It is unclear if bypass surgery before pregnancy or cesarean delivery after diagnosis of moyamoya disease improve outcome (130).

Cerebrovascular malformations. Pregnancy and puerperium do not seem to increase the risk of hemorrhage of cavernous hemangioma (100) or aneurysm (200; 107; 47), but the data on unruptured arteriovenous malformations are conflicting (123; 159; 116). An incidental lesion is not a contraindication for pregnancy or a reason to terminate it. The risk of hemorrhage from an unruptured arteriovenous malformation during pregnancy is approximately 3.5%, not significantly increased compared to 1% to 2% in the general population with arteriovenous malformations (87; 66). Moreover, interventional therapy of unruptured arteriovenous malformations was not superior to conservative management in patients followed up to 33 months (146). The risk of rebleeding of arteriovenous malformation is higher; however, the number of events during pregnancy is low, and there are insufficient data to guide a preventive approach.

In cases of asymptomatic aneurysms, the balance between the risks and benefits of intervention is crucial. The ISUIA-I and ISUIA-II studies on unruptured aneurysms suggest that stable asymptomatic anterior circulation aneurysms smaller than 7 mm have a low risk of rupture (90; 212). Whenever treatment for arteriovenous malformation or aneurysm is considered, the effect of radiation on the fetus needs to be weighed against the benefit of lower risk of rebleeding. Measures taken to avoid strenuous labor are reasonable. However, it is important to note that no evidence supports cesarean delivery with an attempt to decrease risk of rupture of vascular lesions (137).

Diagnostic workup

	• Testing for coagulopathy is reasonable but rarely helps changing therapy.
	• CT of the head with uterine shielding is reasonably safe during pregnancy.
	• MRI is safe during pregnancy, but gadolinium administration should be avoided.
	• Echocardiogram with bubbles helps to find a cardioembolic source.
	• Cerebral angiogram and CSF analysis may help distinguish vasospasm from vasculitis.
	• Transcranial Doppler helps monitor vasospasm.
	• Cerebral biopsy is needed for diagnosis of cerebral vasculitis.

In general, the diagnostic approach to suspected stroke during pregnancy resembles that of a nonpregnant young woman.

Laboratory studies. Laboratory studies for metabolic derangements, drug abuse, or coagulopathy should be routinely obtained, particularly in cases of cerebral venous thrombosis. Testing for protein C, protein S, or antithrombin III deficiencies, activated protein C resistance, factor V Leiden, MTHFR mutation, prothrombin gene G20210A mutation, elevated factor VIII, plasminogen activator inhibitor, and homocysteine levels, as well as anticardiolipin antibodies and lupus anticoagulant, is reasonable, but the impact on treatment is not clear (26). However, the impetus for routine coagulopathy testing has diminished as it does not provide useful information or alter the thrombophilia treatment (63; 09; 11). If tested for, it is recommended to do the thrombophilia screen 6 weeks postpartum to allow for accuracy of results (128).

Head CT. Head CT is reasonably safe in pregnancy if the uterus is shielded (179; 51), with the amount of radiation given for CTH being 50 milliradians, CTA giving 10 milliradians, and chest radiography giving 1 milliradian (all of which are considered safe) (128). CT angiography gives a dose of radiation to the fetus comparable to digital subtraction angiography and carries a lower risk of maternal complications (163). The use of iodinated contrast during the third trimester is considered safe, with only a slight risk of treatable fetal hypothyroidism (133).

MRI of the brain. Although MRI exposure during fetal development was shown to be safe, animal studies have demonstrated ocular deformities and growth retardation (83; 202). Nevertheless, MRI use has gained traction during pregnancy, particularly in the second and third trimesters (49). Moreover, MRI alongside MRV is considered the first-line imaging modality in terms of sensitivity when it comes to identifying cerebral venous thrombosis (128). Gadolinium crosses the placenta and should be avoided during pregnancy.

Catheter cerebral angiography. Catheter cerebral angiography is the gold standard for the diagnosis of vasculitis and the evaluation of subarachnoid hemorrhages, aneurysms, and arteriovenous malformations. It may also allow for endovascular intervention for ruptured vascular malformations, which is safer than surgery (179).

History is the most important form of screening for preeclampsia. If preeclampsia without severe symptoms is present, daily assessment of symptoms and fetal movements, biweekly blood pressure measurements, and weekly platelet count and liver enzymes are recommended. Ultrasound and antenatal testing for fetal growth monitoring and status are also suggested. If restricted fetal growth is suspected, umbilical artery Doppler velocimetry is recommended. Women with gestational hypertension should have weekly blood pressure and proteinuria measurements (05).

Posterior reversible encephalopathy syndrome (PRES). On brain MRI, T2 hyperintensities that are predominant in the occipital regions, without restricted diffusion on diffusion-weighted imaging, suggest vasogenic edema (184; 177). Edema may occur in other regions of the brain, including the brainstem of comatose patients (105). Catheter angiography or MR or CT angiography may reveal arterial constriction alternating with dilatation and even a beading appearance (20).

Reversible cerebral vasoconstriction syndrome (RCVS). CT or MRI of the brain reveals convexity subarachnoid hemorrhage, brain infarcts, intracerebral hemorrhage that may occur days after the initial negative scan, and cerebral edema. MRI may show hyperintense signal abnormalities on T2-weighted images and fluid-attenuated inversion recovery (FLAIR), without restricted diffusion changes, predominantly in the posterior parietal and occipital lobes (111). The lesions are often reversible, although patients may suffer permanent deficits or may have a fatal course (193). Intracerebral hemorrhages may occur (71). Cerebral angiography demonstrates diffuse smooth narrowing of large- and medium-sized cerebral arteries. Transcranial Doppler may be used for monitoring vasospasm (38). An overlap of vasoconstriction associated with vasculitis characterized by smooth arterial narrowing associated with perivascular inflammation was also described (31).

Cerebral vasculitis. Brain MRI may show several small, deep, or superficial infarcts of different ages, white matter abnormalities, and occasional enhancement of leptomeninges and intracranial lesions. Cerebral angiography may show alternating areas of smooth or irregular narrowing with arterial dilatation. High-resolution MRI may show enhancement with gadolinium of the inflamed blood vessel wall (80).

Lumbar puncture and biopsy. CSF studies are reserved for the diagnosis of subarachnoid hemorrhage or vasculitis. Brain biopsy is indicated when cerebral vasculitis is suspected to confirm the diagnosis and to exclude an alternative diagnosis that may exist in 39% of cases (04).

Echocardiogram. An echocardiogram with saline contrast bubble study should be obtained as for any young stroke patient, with particular attention paid to the presence of a patent foramen ovale or right to left shunt.

Management

	• Elevated blood pressure should be controlled promptly.
	• Preeclampsia is treated with delivery.
	• Seizures during eclampsia are best treated with intravenous magnesium sulfate.
	• Intracerebral hemorrhage treatment requires correction of coagulopathy and control of hypertension.
	• Aneurysmal subarachnoid hemorrhage is treated with either clipping or coiling; vaginal delivery is safe after the aneurysm is secured, but cesarean section may be needed if fetal distress develops before aneurysm control.
	• Bleeding from arteriovenous malformation is treated similarly to nonpregnant patients.
	• Ischemic stroke is treated with thrombolysis within 4.5 hours.
	• Mechanical thrombectomy may be needed if a large vessel occlusion is diagnosed.
	• Cerebral venous sinus thrombosis is treated with anticoagulation.

Preeclampsia. Preeclampsia may occur even in the absence of proteinuria. By definition, it is a disorder of pregnancy that typically occurs after 20 weeks’ gestation as a clinical manifestation of hypertension. It will either present with new-onset hypertension and proteinuria, or with new-onset hypertension and end-organ dysfunction (without proteinuria). By definition, hypertension is defined as a systolic blood pressure of greater than or equal to 140, with a diastolic blood pressure of greater than or equal to 90 (in a previously normotensive, pre-gestational female) (186).

Management of preeclampsia begins with antihypertensives (186). First-line agents include methyldopa, with the next best alternative being labetalol and slow-release nifedipine or hydralazine. If those agents are not available or effective, second-line agents include clonidine, hydrochlorothiazide, nicardipine (IV medication), or sodium nitroprusside. Other drugs to consider include verapamil, diazoxide, prazosin, and oxprenolol.

If preeclampsia evolves to eclampsia (which is the neurologic evolution to seizures–a common complication of preeclampsia), antihypertensive agents alone are not sufficient for control (186). Therefore, magnesium sulfate is necessary for neuroprotective effects. Criteria to use magnesium sulfate include systolic blood pressure of 160 mmHg or higher, diastolic blood pressure of 110 mmHg or higher (on at least two occasions 4 hours apart), thrombocytopenia, impaired liver function tests, pulmonary edema, new-onset headache (unresponsive to medications), and visual disturbance.

Delivery is recommended at 37 0/7 weeks or if severe preeclampsia at 34 0/7 weeks is complicated by any of the following: uncontrollable hypertension, eclampsia, pulmonary edema, abruption placentae, disseminated intravascular coagulation, nonreassuring fetal status, or intrapartum fetal demise. If delivery is imminent at 33 6/7 weeks, it should be postponed for 48 hours after administration of corticosteroids. Corticosteroids may be administered to promote fetal lung maturation at less than 43 0/7 weeks. Use of aspirin has been shown to have positive benefits on perinatal mortality, preterm birth, fetal growth restriction, and pulmonary embolism diagnosis in those at elevated risk of preeclampsia when daily aspirin is used throughout pregnancy (186). However, the timing of aspirin initiation appears to affect how well aspirin supplementation works. Low-dose aspirin should be initiated before 16 weeks of gestation, during the first trimester of pregnancy, to decrease the risk of preeclampsia. There is minimal benefit if started after 16 weeks’ gestation.

After discharge, patients with headache associated with blurry vision or preeclampsia with severe hypertension may benefit from parenteral magnesium sulfate. Systolic blood pressure greater than 150 mmHg and diastolic blood pressure greater than 100 mmHg should be treated if repeat measurements at 4 to 6 hours apart are still elevated. Persistent systolic blood pressure greater than 160 mmHg and diastolic blood pressure greater than 110 mmHg should be treated within 1 hour (05).

Intracerebral hemorrhage. Management of intracerebral hemorrhage in pregnancy is similar to a nonpregnant patient. Coagulopathy or thrombocytopenia should be corrected urgently. High blood pressure is controlled with labetalol, hydralazine, or nifedipine. Seizures should be treated. However, prophylaxis is best avoided in the absence of seizures. If the Glasgow Coma Scale is less than 8, or if there is evidence of herniation or acute hydrocephalus, intracranial pressure monitoring might be considered. Evacuation of intracerebral hemorrhage can be performed in life-threatening situations such as cerebellar hemorrhage with deteriorating neurologic status, brainstem compression, or hydrocephalus. If the intracerebral hemorrhage is supratentorial, the volume is greater than 30 cc, and the distance from the surface is less than 1 cm, hematoma evacuation may be beneficial (148).

Aneurysmal subarachnoid hemorrhage. Aneurysmal subarachnoid hemorrhage is controlled by clipping of the aneurysm or endovascular coiling. After the aneurysm is secured, vaginal delivery is safe (50; 157). If labor or fetal distress occurs before the aneurysm is secured, cesarean section followed by or coincident with treatment of the aneurysm is preferred (214).

Arteriovenous malformation. Predictors of untreated arteriovenous malformation bleeding are increased age, deep location, and exclusive deep venous drainage. Without these risks, the annual rate of first bleeding is 0.9% and is as high as 34.4% with all three predictors (194). If an arteriovenous malformation does rupture, the mortality rate following that hemorrhage is reported to be as high as 28% (134). Management of bleeding from arteriovenous malformation is similar in pregnant and nonpregnant women. However, the risk of re-bleed in patients who have already bled is much higher, estimated at up to 27% (134). Endovascular treatment, however, should be avoided before the twelfth week of gestation due to the potential radiation risk to the fetus (158). Excision of bled arteriovenous malformation during pregnancy does not seem to prevent rebleeding (50). A case-based systematic review of the literature published between 1955 and 2022 found that endovascular treatment of bleeding from arteriovenous malformation and aneurysms was safe, and the outcome was similar to the general population who underwent similar intervention (60).

Intravenous thrombolysis for acute ischemic stroke. The treatment of acute ischemic stroke during pregnancy was not studied in randomized trials as pregnancy is considered a relative contraindication (95). Recombinant tissue plasminogen activator (tPA) is currently the only drug approved for acute treatment of ischemic stroke within 4.5 hours from onset. tPA is category C, does not cross the placenta, and is not associated with animal teratogenicity. Several case reports demonstrated the successful use of rt-PA (56; 210; 97; 119; 149; 213). The complication rate following thrombolytic therapy was similar in pregnant and nonpregnant women. The fetal fatality rate was estimated at 8%. In patients younger than 60 years of age, the risk of symptomatic intracerebral hemorrhage is lower than in the general population, approximately 2.8% (136). The earlier the treatment, the higher the benefit and the lower the risk of complications (175).

Endovascular thrombectomy for large vessel occlusion. Several clinical trials demonstrated the benefit of endovascular thrombectomy in patients with large vessel occlusion, but pregnancy was an exclusion criterion (22; 32; 76; 99; 176). In a case series of seven patients, endovascular thrombectomy was safe and effective (122). Both penumbra and stent retriever were used successfully (01; 24). Although the intraarterial intervention is associated with increased upfront costs, the potential life-year gains make this intervention cost-effective (70).

There is also evidence from a meta-analysis of randomized controlled trials demonstrating that direct mechanical thrombectomy improves functional outcomes at a similar rate to bridging therapy (in which intravenous thrombolysis is utilized before thrombectomy) (211). There may be reason to believe that some risk could be mitigated in the future by proceeding directly to mechanical thrombectomy (in centers where thrombectomy is available), which would then avoid the risk associated with intravenous thrombolysis.

Data from the Get with the Guidelines-Stroke Registry reveal that pregnancy-related stroke treated with intravenous tPA or endovascular thrombectomy had similarly favorable outcomes as stroke treated in nonpregnant women (117).

Cerebral venous sinus thrombosis (CVST). CVST, even when associated with hemorrhage, benefits from intravenous heparin followed by 3 to 6 months of anticoagulation. During the postpartum state, low molecular weight heparin or a vitamin K antagonist with an INR goal of 2 to 3 can be utilized (128). In cases with a persistent prothrombotic state, long-term treatment is warranted. A small systematic review of 26 patients treated with systemic thrombolysis showed that 88% of patients regained their independence, but two died from intracerebral hemorrhage (204). Patients with severe edema and herniation, including comatose with bilaterally dilated pupils, may benefit from decompressive surgery. Comatose patients were less likely to become independent (64). Isolated cortical vein thrombosis is usually treated with anticoagulation (42).

Posterior reversible encephalopathy syndrome (PRES). PRES and eclampsia are treated with intravenous magnesium sulfate that promotes vasodilation, protects the blood-brain barrier, prevents edema formation, as well as acts as a potential anticonvulsant (61). Gradual treatment of elevated blood pressure with labetalol or nicardipine is advised to avoid placental hypoperfusion. The target levels are 140 to 155 mmHg systolic and 90 to 105 mmHg diastolic (41). The cytotoxic medications causing PRES should be stopped or the dosage reduced. Seizures should be treated with an appropriate antiepileptic unless eclampsia is present, which is generally treated with magnesium sulfate.

Reversible cerebral vasoconstriction syndrome (RCVS). RCVS management was not tested in randomized trials. It is important to differentiate it from CNS vasculitis. The general recommendations are bed rest, avoidance of sexual activity, Valsalva maneuvers, vasoactive medications, or other potentially offending drugs. Headache responds to analgesics and seizures to antiepileptic drugs. Intravenous hydration and vasodilator drugs like nimodipine, verapamil, or magnesium sulfate for 4 to 12 weeks have been tried. Although nimodipine improves headache, some patients still develop new hemorrhages, transient ischemic attack, or ischemic stroke several days after the inception of therapy. Glucocorticoids should be avoided. In severe cases, angioplasty or intraarterial nimodipine was attempted with variable success (150). In case reports RCVS resolved soon after cesarean delivery (102; 48). Upshaw-Schulman syndrome is RCVS associated with anemia and thrombotic thrombocytopenic purpura and responds to plasmapheresis (201).

Cerebral vasculitis. Cerebral vasculitis treatment was not studied in randomized trials. The response to corticosteroids with or without cyclophosphamide is good in most cases (172). One patient with intracerebral hemorrhage and focal cerebral angiitis required the addition of cyclophosphamide to steroids for an adequate clinical response (215). Another woman with idiopathic granulomatous angiitis of the nervous system during pregnancy had a good outcome with an expectant approach (18). A careful assessment of the risks and benefits as well as the optimal timing of therapy is essential in pregnant women.

HELLP syndrome responds to delivery. The urgency depends on the degree of maternal or fetal distress and gestational age (05).

Amniotic fluid embolism requires hemodynamic stabilization and correction of any metabolic derangements or coagulopathy. Air embolism is treated with hyperbaric oxygen and supportive care (153).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Elizabeth Anderson MD

Dr. Anderson of NYC Health and Hospitals/Kings County has no relevant financial relationships to disclose.
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Editor

Steven R Levine MD

Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.
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Former Authors

Steven J Kittner MD MPH
Ann Helms MD MS
Rima M Dafer MD
Adrian Marchidann MD

Patient Profile

Age range of presentation: 13 to 64 years
Sex preponderance: female>male>2:1
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Cerebrovascular disorders in the puerperium: 674.0

Cerebrovascular disorders with delivery, with or without mention of antepartum condition: 674.01

Cerebrovascular disorders, with delivery, with mention of postpartum complication: 674.02

Antepartum cerebrovascular disorders: 674.03

Postpartum cerebrovascular disorders: 674.04
ICD-10: Complication of the puerperium, unspecified: O90.9

Delayed delivery after spontaneous or unspecified rupture of membranes: O75.6

Gestational [pregnancy-induced] hypertension without significant proteinuria: O13

Other complications of the puerperium, not elsewhere classified: O90.8

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Pregnancy and stroke

Associated Disorders

Air embolism
Amniotic fluid embolism
Cerebral venous thrombosis
Choriocarcinoma
Intracerebral hemorrhage
- Ischemic stroke
- Moyamoya disease
- Subarachnoid hemorrhage

Differential Diagnosis

metabolic disorders
seizures
migraine
psychogenic disorders
eclampsia
- posterior reversible encephalopathy syndrome
- reversible cerebral vasoconstriction syndrome
- cerebral vasculitis
- HELLP syndrome

Also Relevant

Basilar artery stroke
Cerebral embolism
Hormonal contraception and stroke
Hypercoagulable states and cerebrovascular disease
Ischemic stroke
- Pregnancy: CNS complications
- Pregnancy and epilepsy
- Seizures associated with eclampsia
- Stroke in young adults
- Stroke therapy

Clinical Categories

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Web References

Guidelines

Testing

MTHFR Thermolabile Variant

Pregnancy and stroke …

Pregnancy and stroke

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Upadacitinib

Dextromethorphan hydrobromide and quinidine sulfate

DNA- and RNA-directed gene therapies

Amblyopia

Coma due to supratentorial and cerebellar lesions

Third nerve palsy

Nystagmus

Myofascial pain syndrome

Pregnancy and stroke

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Upadacitinib

Dextromethorphan hydrobromide and quinidine sulfate

DNA- and RNA-directed gene therapies

Amblyopia

Coma due to supratentorial and cerebellar lesions

Third nerve palsy

Nystagmus

Myofascial pain syndrome

This is an article preview.
Start a Free Account
to access the full version.