Pregnancy and Stroke Risk in Women

Jessica Tate; Cheryl Bushnell

Women's Health. 2011;7(3):363-374.

Abstract and Introduction

Abstract

Stroke, the sudden onset of brain dysfunction from a vascular cause, is one of the most common causes of long-term disability. Although rare during childbearing years, stroke is even more devastating when it occurs in a young woman trying to start a family. Pregnancy and the postpartum period are associated with an increased risk of ischemic stroke and intracerebral hemorrhage, although the incidence estimates have varied. There are several causes of stroke that are in fact unique to pregnancy and the postpartum period, such as preeclampsia and eclampsia, amniotic fluid embolus, postpartum angiopathy and postpartum cardiomyopathy. Data regarding these individual entities are scant. Most concerning is the lack of data regarding both prevention and acute management of pregnancy-related stroke. The purpose of this article is to summarize existing data regarding incidence, risk factors and potential etiologies, as well as treatment strategies for stroke in pregnancy.

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Table 1. Summary of the published incidence, mortality and morbidity of pregnancy-related stroke.
Study (year)	Population sampled (years)	Inclusion	Incidence (per 100,000 deliveries)	Mortality/morbidity (%)	Ref.
Cross et al. (1968)	Killearn Hospital, Glasgow, Scotland, UK (1956–1967)	Carotid artery distribution infarcts in pregnancy plus up to 16 days PP	5	Mortality 26	[25]
Wiebers et al. (1985)	Rochester, MN, USA (1955–1979)		3.8		[49]
Simolke et al. (1991)	Parkland Memorial Hospital, Dallas, TX, USA (1984–1990)	Stroke: included CVT ICH: included SAH	Stroke: 10 ICH: 6.7	Overall: morbidity 40, mortality 20	[50]
Sharshar et al. (1995)	Hospitals in region of Ile de France (1989–1992)	Stroke: 'stroke-like deficits', excluded CVT ICH: excluded SAH Pregnancy plus 2 weeks PP	Stroke: 4.3 ICH: 4.6	Stroke: morbidity 33, mortality 0 ICH: morbidity 50, mortality 25	[8]
Kittner et al. (1996)	Hospitals in Baltimore–Washington DC, USA (1988–1991)	Stroke: included CVT ICH: excluded SAH Pregnancy plus 6 weeks PP Women aged 15–44 years	Stroke: 11 ICH: 9		[1]
Lanska and Kryscio (1997)	National Hospital Discharge Survey (1979–1991)	Diagnosis codes 674.0^† or 671.5^‡ from hospitalization of delivery	Stroke: 10.3^† CVT: 8.9	Stroke: mortality 2.2 CVT: mortality 0	[2]
Lanska and Kryscio (1998)	National Hospital Discharge Survey (1979–1991)	Diagnosis codes 674.0 or 671.5, not restricted to hospitalization of delivery Women aged 15–44 years	Stroke: 17.7^† CVT: 11.4	Stroke: mortality 3.3 CVT: mortality 0	[3]
Lanska and Kryscio (2000)	Nationwide Inpatient Sample (1993–1994)	Diagnosis codes 674.0 or 671.5 from hospitalization of delivery Women aged 15–44 years	Stroke: 13.1^† CVT: 11.6	Stroke: mortality^†14.7 CVT: mortality 0 9.3 of those discharged had postacute care needs	[4]
Jaigobin and Silver (2000)	Toronto Hospital, Canada (1980–1997)	Stroke: included CVT ICH: included SAH	Stroke: 18 ICH: 8	Stroke: mortality 0 ICH: mortality 23	[11]
James et al. (2005)	Nationwide Inpatient Sample (2000–2001)	Included hemorrhage, arterial stroke, CVT or diagnosis code 674.0	34.2	Mortality 4.1 22 discharged to facility other than home	[5]
Bateman et al. (2006)	Nationwide Inpatient Sample (1993–2002)	ICH: diagnosis code 431 Women aged 15–44 years	ICH: 6.1	Mortality 20.3	[7]
Liang et al. (2006)	Chang Gung Memorial Hospital, Taiwan (1992–2004)	Stroke: included CVT ICH: included SAH	Stroke: 13.5 ICH: 25.4		[12]

^†The ninth edition of the International Classification of Diseases (ICD-9) 674.0 includes the following ICD-9 codes, occurring during pregnancy, childbirth or the puerperium: 430 SAH; 431 ICH; 432 other and unspecified intracranial hemorrhage; 433 occlusion and stenosis of precerebral arteries; 434 occlusion of cerebral arteries; 436 acute, but ill-defined cerebrovascular disease (which includes apoplectic apoplexy and cerebral seizure); 437 other and ill-defined cerebrovascular disease (which includes cerebral atherosclerosis, hypertensive encephalopathy, cerebral aneurysm unruptured, cerebral arteritis, Moyamoya disease, nonpyogenic thrombosis of the intracranial venous sinus and transient global amnesia).
^‡ICD-9 671.5: CVT.
CVT: Cerebral venous thrombosis; ICH: Intracerebral hemorrhage; PP: Postpartum; SAH: Subarachnoid hemorrhage.

Table 2. Published causes of ischemic stroke during pregnancy.
Etiologies of ischemic stroke	Preeclampsia/eclampsia (%)	CNS vasculopathy (%)	Arterial dissection (%)	TTP/DIC (%)	Thrombophilia (%)	Amniotic fluid embolism (%)	Cardioembolic (%)	Atherosclerosis (lacune) (%)	Ref.
Kittner et al., n (%) (total n = 17)	4 (24)	3 (18)	1 (6)	1 (6)	–	–	–	–	[1]
Sharshar et al., n (%) (total n = 15)	7 (47)	1 (7)	1 (7)	–	1 (7)	1 (7)	–	–	[8]
Jaigobin et al., n (%) (total n = 21)	6 (29)	–	1 (5)	–	5 (24)	–	4 (19)	–	[11]
Jeng et al., n (%) (total = 27)	1 (4)	–	–	–	10 (37)	–	9 (33)	–	[20]
Liang et al., n (%) (total n = 11)	2 (18)	–	–	–	–	1 (9)	4 (36)	1 (9)	[12]

DIC: Disseminated intravascular coagulation; TTP: Thrombotic thrombocytopenic purpura.

Table 3. Published causes of pregnancy-related intracerebral hemorrhage.
Etiologies of ICH	Preeclampsia/eclampsia (%)	Vascular anomaly (%)	Cocaine (%)	CNS vasculopathy (%)	DIC/coagulopathy (%)	Ref.
Kittner et al., n (%) (total n = 14)	2 (14)	3 (21)	2 (14)	2 (14)	–	[1]
Bateman et al., n (%) (total n = 423)	129 (31)	30 (7)	–	–	36 (9)	[7]
Sharshar et al., n (%) (total n = 16)	7 (44)	6 (38)	–	–	–	[8]
Jaigobin et al., n (%) (total n = 13)	1 (8)	8 (62)	–	–	2 (15)	[11]
Jeng et al., n (%) (total = 22)	7 (32)	8 (36)	–	–	1 (5)	[20]
Liang et al., n (%) (total n = 21)	5 (24)	6 (29)	–	–	4 (19)	[12]

DIC: Disseminated intravascular coagulation; ICH: Intracerebral hemorrhage.

Table 4. Summary of cases of recombinant tissue plasminogen activator for pregnant women with acute ischemic stroke.
Study (year)	Patient age, gestation, risk factors and presenting symptoms	Thrombolytic	Maternal outcome	Fetal outcome	Ref.
Murugappan et al. (2006)	37 years of age AA, known pregnancy at 12 weeks Mechanical valve, off anticoagulation L hemiparesis, NIHSS 19	IV rtPA	NIHSS eventually improved to 4 Small intrauterine hematoma	Elective termination	[44]
Murugappan et al. (2006)	31 years of age, unknown pregnancy at approximately 4 weeks R hemiparesis, expressive aphasia	IV rtPA	NIHSS eventually improved to 4	Elective termination	[44]
Murugappan et al. (2006)	29 years of age, unknown pregnancy AVR, off anticoagulation L hemiplegia, NIHSS 13	IV rtPA	No improvement, died during subsequent angioplasty owing to arterial dissection	Maternal demise	[44]
Murugappan et al. (2006)	43 years of age, known pregnancy at 37 weeks AT-III and functional protein C deficiency R hemiparesis, global aphasia, NIHSS 25	IV rtPA	Improved to NIHSS 11; 90 days after event had no residual deficits	Healthy infant delivered at term via spontaneous vaginal delivery	[44]
Murugappan et al. (2006)	28 years of age, known pregnancy in first trimester Protein C and S deficiencies, PFO, L iliac DVT Vertigo, nausea/vomiting and eventually coma due to basilar occlusion	IA UK	Improved Buttock hematoma	Healthy infant delivered at term	[44]
Murugappan et al. (2006)	25 years of age, known pregnancy in first trimester MVR with endocarditis R hemiparesis, expressive aphasia	IA UK	Improved; 4 months later no residual deficits Asymptomatic ICH	Spontaneous abortion	[44]
Murugappan et al. (2006)	40 years of age, known pregnancy at 6 weeks Polycythemia vera, essential thrombocytosis Nausea/vomiting, papilledema, CN VI palsy due to CVT	Local UK	Improved; residual visual field deficit	Spontaneous abortion (lethal chromosomal abnormalities)	[44]
Murugappan et al. (2006)	21 years of age, known pregnancy at 8 weeks Antiphospholipid antibody syndrome HA, nausea/vomiting, altered mental status, seizures, R hemiparesis due to CVT	Local UK	Improved; residual short-term memory deficit Asymptomatic ICH at ventriculostomy site	Elective termination	[44]
Wiese et al. (2006)	33 years of age, known pregnancy at 13 weeks Mechanical valve, transitioned from warfarin to subcutaneous heparin due to pregnancy R hemiparesis, expressive aphasia, NIHSS 13	IV rtPA	NIHSS eventually improved to 4	Healthy infant delivered at term via cesarean section	[46]
Dapprich (2002)	First trimester	IV rtPA	Improved	Healthy infant delivered at term	[47]
Elford et al. (2002)	28 years of age s/p in vitro fertilization, with ovarian hyperstimulation syndrome L hemiplegia, NIHSS 11 (angiogram showed R M1 occlusion)	IA rtPA	Improved to NIHSS 3, then worsened and found to have R basal ganglia hemorrhage, ultimately improved	Healthy infant delivered at term via SVD	[45]
Johnson et al. (2005)	39 years of age with known pregnancy at 37 weeks L hemiplegia, NIHSS 20 (angiogram showed R M1 occlusion)	IA rtPA	Improved to NIHSS 7; ultimately no residual deficits	Healthy infant delivered at term via SVD	[43]

AA: African–American; AT-III: Antithrombin III; AVR: Aortic valve replacement; CN: Cranial nerve; CVT: Cerebral venous thrombosis; DVT: Deep venous thrombosis; HA: Headache; IA: Intra-arterial; ICH: Intracerebral hemorrhage; IV: Intravenous; L: Left; MVR: Mitral-valve replacement; NIHSS: NIH Stroke Scale; PFO: Patent foramen ovale; R: Right; rtPA: Recombinant tissue plasminogen activator; s/p: Status post; UK: Urokinase.

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Executive Summary

Epidemiology of stroke in pregnancy

The incidence of stroke during pregnancy ranges from approximately 9 to 34 per 100,000 deliveries worldwide.
Of all stroke types, intracerebral hemorrhage during pregnancy and the puerperium carries the highest morbidity and mortality, with an in-hospital mortality of 20%.
Although infrequently reported, the morbidity following pregnancy-related stroke is lower than for typical stroke patients, and the risk for recurrent stroke in subsequent pregnancies is very low.
Causes of pregnancy-related stroke include those that are unique to pregnancy (preeclampsia/eclampsia, postpartum angiopathy, amniotic fluid embolism and postpartum cardiomyopathy) and causes seen in nonpregnant women, including hypertension, diabetes, vasculitis, arteriovenous malformations or aneurysms.

Risk factors for pregnancy-related stroke & cerebral venous thrombosis

The women who are at the highest risk for pregnancy-related stroke are those who are over the age of 35 years; those who are of African–American race-ethnicity; and those with preeclampsia/eclampsia/gestational hypertension, thrombophilias, migraine headaches, diabetes, prepregnancy hypertension, hyperemesis gravidarum, anemia, thrombocytopenia, postpartum hemorrhage, transfusion, fluid, electrolyte and acid-base disorders and infection.

Diagnosis of pregnancy-related stroke & cerebral venous thrombosis

Brain imaging is essential in order to determine whether a pregnant woman has suffered an intracerebral hemorrhage. Brain MRI and magnetic resonance venogram are generally considered the gold standard for the diagnosis of ischemic stroke and cerebral venous thrombosis, respectively.
The timing of scans may depend on the stage of pregnancy and the risk–benefit ratio of performing these scans. The risk from MRI is generally considered lower after the first trimester, and the risks with administration of gadolinium is still under debate.

Stroke prevention during pregnancy

Strategies to prevent stroke during pregnancy in high-risk women mimic those used for thromboprophylaxis, which include either unfractionated or low-molecular-weight heparin to 13 weeks' gestation, followed by warfarin until the middle of the third trimester, then heparin until delivery and warfarin for 6 weeks postpartum.
There are no randomized controlled trials of acute stroke treatment with thrombolysis or mechanical thrombectomy to guide decision-making in the pregnant population.

Treatment of acute pregnancy-related stroke

Treatment of acute stroke in pregnant women is still controversial, but not strictly contraindicated. Several case reports have documented successful reperfusion, in addition to satisfactory maternal and fetal outcomes.
However, there are no trials of anticoagulation or antiplatelet therapies for stroke prevention in pregnancy.

Future perspective

There are many gaps in our knowledge about pregnancy-related stroke, including detailed knowledge about mechanism outcomes posthospital discharge, due to the lack of patient-level detail.
In order to better understand pregnancy-related stroke causes and outcomes, the development of multisite, multidisciplinary registries are needed.
In the next 5–10 years, it is most likely that an increasing number of pregnant women with acute ischemic stroke will be treated with recombinant tissue plasminogen activator as neurologists and interventional radiologists develop new or improved imaging strategies (e.g., MRI perfusion) to identify women who would clearly benefit from reperfusion while minimizing the risk to the fetus.
In the next couple of years, new anticoagulants, such as direct thrombin inhibitors (dabigatran), may be used in pregnancy, especially for women who cannot receive heparin or warfarin. Dabigatran is currently US FDA category C for pregnant women, but more testing in humans will be required in order to determine the number of adverse pregnancy outcomes and the risk–benefit ratio for preventing stroke and cerebral venous thrombosis during pregnancy.

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Pregnancy and Stroke Risk in Women

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