Cerebrovascular

Disorders Complicating
Pregnancy
Steven K. Feske, MD; Aneesh B. Singhal, MD
ABSTRACT
Purpose of Review: This article discusses the physiologic changes of pregnancy and how
they affect riskof ischemic andhemorrhagic strokeandthenreviews epidemiology, diagnosis,
and treatment of ischemic and hemorrhagic stroke in pregnancy and the puerperium.
Recent Findings: This article updates our understanding of the relationship of
preeclampsia/eclampsia to the posterior reversible encephalopathy syndrome and the
reversible cerebral vasoconstriction syndrome, emphasizing their shared pathogenesis. It
reviews the most recent data and offers recommendations concerning the use of
thrombolytic and other revascularization therapies for pregnancy-related strokes.
Summary: Although cerebrovascular complications are uncommon occurrences during
pregnancy and the puerperium, stroke is still the most common seriously disabling
complication of pregnancy. Therefore, stroke and other vascular issues raise questions
about the best evaluation and management that is safe for mother and child.
Continuum (Minneap Minn) 2014;20(1):8099.
PHYSIOLOGY AND
PATHOPHYSIOLOGY OF
PREGNANCY IN RELATION
TO VASCULAR DISEASE
Hemodynamic Changes
Pregnancy is a state of high metabolic
demand. The cardiovascular changes
of pregnancy prepare the maternal
circulation to meet that demand. Es-
trogen and other hormones cause an
increase in renin activity, leading to
retention of sodium and water. This
supports an increase in plasma vol-
ume beginning in the first trimester
around 6 weeks of gestation. Some
studies suggest that this increase in
plasma volume reaches a plateau in
the third trimester. Others suggest a
progressive increase until term.
1
Red
blood cell mass also increases, but
proportionally less, resulting in a mild
physiologic hemodilutional anemia of
pregnancy. Cardiac output, stroke vol-
ume, and heart rate increase 30% to
50% as a result of the increased
demand of the developing fetus and
placenta and maternal hypervolemia.
This begins as early as the fifth
gestational week and reaches a pla-
teau in the late second or third
trimester. Heart rate continues to rise
until term. Increase in prostacyclin
and redistribution of high flow in the
low-resistance uteroplacental circula-
tion and breasts and kidneys cause
systemic vascular resistance (SVR) to
begin to fall around the fifth gesta-
tional week. This drop in SVR is
accompanied by a fall in the systolic
and diastolic blood pressure. It
reaches a nadir in the third or late
second trimester, about 20 to 32
weeks, after which it rises until term
to levels at or slightly above the
normal nonpregnant blood pressure.
There is increased venous capacitance
Address correspondence to
Dr Steven K. Feske, Neurology
Department, Brigham and
Womens Hospital, 75 Francis
Street, Boston, MA 02115,
sfeske@partners.org.
Relationship Disclosure:
Dr Feske has received
royalties from Elsevier for
his role as editor of Office
Practice of Neurology, 2nd
Edition, and receives
research support from the
National Institute of
Neurological Disorders and
Stroke. Dr Singhal has
served as a consultant for
Biogen Idec and as a medical
expert witness in cases of
stroke. Dr Singhals spouse
holds stock or stock options
greater than 5% of the
company or greater than
$10,000 in value in
Biogen Idec and Vertex
Pharmaceuticals Incorporated.
Dr Singhal has received
research support from the
National Institute of
Neurological Disorders and
Stroke, and his institution has
received research support
from Pfizer Inc and
PhotoThera, Inc, for clinical
trial participation.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Drs Feske and Singhal report
no disclosures.
* 2014, American Academy
of Neurology.
80 www.ContinuumJournal.com February 2014
Review Article
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
and reduced blood flow (ie, relative
venous stasis), often accompanied by
orthostatic intolerance. The volume
increase tends to increase preload.
However, preload is heavily depen-
dent upon position, with reduced
preload and orthostasis resulting from
the higher venous capacitance and
from compression on the inferior vena
cava in the supine position.
Vascular and Connective
Tissue Changes
Pregnancy causes remodeling of the
heart and all blood vessels. The walls
of systemic arteries show a reduction
in collagen and elastin content and a
loss of distensibility. Animal models
have shown increased contractile
force, decreased stiffness, and in-
creased relaxation response in the
middle cerebral artery.
2
The roles of
the molecular promoters underlying
these physiologic responses to preg-
nancy and the full effects of these
adaptive changes are complex and
poorly understood. Their relationship
to stroke is not certain; however, one
might expect the hemodynamic
changes near term combined with
these structural changes of blood
vessels to result in a state in which
more vulnerable vascular walls experi-
ence greater hemodynamic stress,
possibly contributing to the risk of
hemorrhage in late pregnancy.
Changes in the
Coagulation System
Both hemodynamic and biochemical
changes make pregnancy a state of
hypercoagulability. Decreased venous
compliance results in venous stasis
and congestion. Compression of the
inferior vena cava, aorta, and blood
supply of the gravid uterus can cause
vascular injury. Levels of procoagulant
factors, coagulation inhibitors, and
other mediators of clot formation
and lysis are altered by pregnancy
resulting in a state of increased
hypercoagulability in late pregnancy.
Levels of procoagulant factors I, VII,
VIII, IX, X, XII, and XIII increase
during pregnancy. There is little
change in levels of factors II, V, and
XI. The levels of some coagulation
inhibitors fall during pregnancy. The
coagulation inhibitor antithrombin III
falls and is at its nadir in the third
trimester. Total and free levels of the
coagulation inhibitor cofactor protein
S are significantly decreased as well.
Although levels of protein C remain
unchanged, almost a third of women
have functional activated protein C resis-
tance during the third trimester. These
changes of venous flow and the molec-
ular mediators of thrombosis are greatest
during the late third trimester and early
puerperium. Along with iron deficiency
and the acute phase responses of the
trauma and hemorrhage of delivery, they
create the greatest hypercoagulability
during the early puerperium.
Preeclampsia/Eclampsia
Preeclampsia is a multisystem disorder
of mid- to late pregnancy traditionally
characterized by pregnancy-induced
hypertension, edema, and proteinuria;
eclampsia is the development of sei-
zures in a patient with preeclampsia.
Preeclampsia and eclampsia can infre-
quently occur after childbirth, usually
within 48 hours (postpartum pre-
eclampsia), or up to 4 to 6 weeks
after childbirth (late postpartum pre-
eclampsia).
3
Postpartum preeclampsia
can manifest de novo postpartum or
result from preeclampsia, preexisting
chronic hypertension, or persistent
gestational hypertension (systolic
blood pressure greater than 140 mm
Hg or diastolic blood pressure greater
than 90 mm Hg without proteinuria).
The criteria for diagnosis depend on
the definition of the clinical syndrome.
KEY POINTS
h Pregnancy results in
increased metabolic
demand, sodium and
water retention, and
decrease in systemic
vascular resistance,
leading to expansion of
plasma volume; mild
anemia; increased
stroke volume, heart
rate, and cardiac
output; and decreased
systolic and diastolic
blood pressures.
h Changes in vascular
structure and the
coagulation system,
although adaptive,
also lead to a relative
vulnerability to
hemorrhage and
ischemic stroke,
especially during the
postpartum period.
81 Continuum (Minneap Minn) 2014;20(1):8099 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Modern consensus definitions all en-
dorse pregnancy-induced hypertension
beginning after the 20th week with
proteinuria as preeclampsia, and gener-
ally accept the inclusion of women with
pregnancy-induced hypertension with-
out proteinuria but with other common
manifestations, including (1) cerebral
symptoms, (2) epigastric or right upper
quadrant pain with nausea or vomiting,
or (3) thrombocytopenia and abnormal
liver enzymes.
4
It has been claimed that,
although pregnancy-induced hyperten-
sion is the cornerstone of clinical
diagnosis, a significant proportion of
women who develop hemolysis, ele-
vated liver enzymes, and low platelet
count (HELLP) syndrome or eclamptic
seizures do not have hypertension.
5,6
Since the precise diagnosis of pre-
eclampsia is currently limited by the
lack of a specific biomarker, it is often
desirable to entertain a permissively
broad definition for use in clinical
practice. Although much has been
learned about preeclampsia over the
last decade, a clear understanding of
the relationship of the many underlying
risk factors and various features of
abnormal physiology is still lacking.
There is strong evidence that immune
maladaptation is central to its cause.
While abnormal placentation and pla-
cental hypoperfusion play an important
role, hypoperfusion does not seemto be
primary, because markers of preeclamp-
sia are present in the first trimester,
before placental hypoperfusion.
7
Al-
though the triggers for the abnormal
placentation are not clearly understood,
there is strong evidence for dysregula-
tion of angiogenic and vasoactive factors,
such as vascular endothelial growth
factor (VEGF) and placental growth
factor (PlGF) and nitric oxide and,
ultimately, antagonism of these factors
by binding to soluble VEGF receptor-1
(also known as Fms-like tyrosine kinase
1 [sFlt1]). Fundamental to many of the
relevant clinical complications of pre-
eclampsia are endothelial dysfunc-
tion, absence of the normal stimulation
of the renin-angiotensin system despite
hypovolemia, hypersensitivity to angio-
tensin II leading to increased systemic
vascular resistance and hypertension,
augmentation of the normal thrombox-
ane A2/prostacyclin ratio, increased
platelet activation, and increased throm-
bin formation and fibrin generation.
Endothelial dysfunction contributes to
increased capillary permeability that un-
derlies proteinuria, edema, and, most
important among our concerns, brain
edema at relatively modest elevations
of blood pressure.
ISCHEMIC STROKE ASSOCIATED
WITH PREGNANCY
Epidemiology
No long-term prospective studies of
the incidence and types of pregnancy-
associated stroke have yet been done.
Available studies handle spontaneous
and therapeutic abortions and still-
births differently and use different
definitions of the puerperium and
different methods of stroke classifica-
tion. This lack of consistency of data
limits comparisons, but we can esti-
mate the impact of stroke from these
studies. Table 4-1
8
summarizes nine
maj or st udi es publ i shed si nce
1985.
9Y17
From the three population-
based studies, we can estimate the
incidence of stroke. In these three
studies, the incidence of all types of
stroke ranges from four to seven cases
per 100,000 pregnancies. However,
data from the National Inpatient
Sample of the Healthcare Cost and
Utilization Project suggest that the
incidence of pregnancy-associated
stroke has risen since the 1990s. These
data estimate the incidence of all types
of pregnancy-associated stroke, in-
cluding ischemic and hemorrhagic
strokes, subarachnoid hemorrhage,
KEY POINT
h Preeclampsia/eclampsia
is a state of
hypertension,
endothelial and
platelet dysfunction,
and enhanced
coagulability with
many pathologic
consequences.
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Cerebrovascular Disorders Complicating Pregnancy
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
and cerebral venous sinus thrombosis,
to be 25 to 34 per 100,000 deliveries.
This analysis compares data from 1994
and 1995 to data from 2006 and 2007.
Between these intervals, antenatal hos-
pitalizations increased by 47% (from
0.15 to 0.22 per 1000 deliveries), and
postpartum hospitalizations by 83%
(from 0.12 to 0.22 per 1000 deliveries),
with the increases largely explained by
concurrent hypertensive disorders or
heart disease.
18
In comparison, the
incidence of stroke in nonpregnant
women in the 15- to 45-year age group
is 11 per 100,000.
19
Kittner found
no increased risk of ischemic stroke
TABLE 4-1
Studies of Stroke in Pregnancy
a
Study Location Methods
Time
Interval
Number of
Pregnancies
Number of Strokes
Ischemic Hemorrhagic
Feske et al,
2009
Boston
hospital
Retrospective 1996Y2005 101,570 17 36
Postpartum
period
(PP) = 3 months
Liang et al,
2006
Taiwan
hospital
Retrospective 1992Y2004 66,781 11 21
PP = 6 weeks
Jeng et al,
2004
Taiwan
hospital
Retrospective 1984Y2002 Data not
reported
27 22
15Y40-year-olds
PP = 6 weeks
Jaigobin et al,
2000
Toronto
hospital
Retrospective 1980Y1997 50,711 21 13
PP = 6 weeks
Witlin et al,
1997
Memphis
hospital
Retrospective 1985Y1995 79,301 14 6
PP = not
reported
Kittner et al,
1996
Maryland and
Washington DC
(46 hospitals)
Retrospective 1988Y1991 234,023 17 14
Population-
based
PP = 6 weeks
Sharshar et al,
1995
Ile de France
(63 hospitals)
Retrospective 1989Y1991 348,295 15 16
Population-
based
PP = 2 weeks
Awada et al,
1995
Saudi Arabia
hospital
Retrospective 1983Y1993 Data not
reported
9 3
pp = 15 days
Wiebers et al,
1985
Rochester, MN
hospitals
Retrospective 1955Y1979 26,099
(live births)
1 0
Population-
based
PP not included
a
Modified with permission from Feske SK, Semin Neurol.
8
B 2007, Thieme Medical Publishers. www.thieme-connect.com/DOI/
DOI?10.1055/s-2007-991126.
83 Continuum (Minneap Minn) 2014;20(1):8099 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
during pregnancy (relative risk 0.7) but
a large relative increase during the
6-week postpartum period (relative
risk 8.7). Figure 4-1 shows a similar
preponderance of events in the post-
partumperiod in the authors study. The
higher proportions of strokes in the
other studies are probably due to referral
bias, since these represent series from
single large referral hospitals. Despite its
low overall incidence, stroke contributes
a major proportion of the long-term
disability resulting from pregnancy.
Mechanisms
Although differences and limitations
in methods of case assessment com-
promise interpretations, the ischemic
strokes can be broken down by types
to assess the mechanisms and con-
tributing causes of pregnancy-related
strokes (Table 4-2
8
). Here, the au-
thors have classified venous sinus throm-
bosis with ischemic-thrombotic stroke,
although many will have components of
hemorrhage. When mechanisms of ische-
mic stroke are identified, the major ones
are cardioembolism and venous sinus
thrombosis. Preeclampsia/eclampsia ap-
pears to be a major contributor to stroke
risk. In studies in which preeclampsia/
eclampsia is reported, it is present in
11% to 47% of cases of stroke. The
contribution of preeclampsia/eclampsia
to the cause of strokes is presumed to
be complex and related to the various
vasculopathic and prothrombotic ef-
fects discussed above. Other well-
established causes of stroke in young
patients, such as arterial dissection
and moyamoya syndrome, can present
during pregnancy and should be consid-
ered (Case 4-1). Other pregnancy-
specific causes, such as peripartum
cardiomyopathy, choriocarcinoma,
and embolization of amniotic fluid
or air, are very rare and should be
considered based on the clinical pre-
sentations. Amniotic fluid embolism
should be considered when evidence of
diffuse or multifocal brain ischemia is
present and accompanied by features of
pulmonary embolism.
Evaluation
Stroke is suspected clinically based on
the sudden onset of a neurologic
deficit suggestive of a focal lesion
and without an alternative cause.
KEY POINTS
h The risk of ischemic
stroke is increased
during the postpartum
period.
h Although
pregnancy-associated
ischemic stroke is rare, it
is a major contributor to
long-term disability
resulting from
pregnancy.
h Cardioembolism,
preeclampsia/eclampsia,
and cerebral venous
sinus thrombosis
account for most
pregnancy-related
ischemic stroke.
FIGURE 4-1
Timing of events during pregnancy and the puerperium. Each dot represents
the time during pregnancy (in weeks) or the puerperium (in days) of a single
event as color-coded.
Reprinted with permission from Feske SK, et al, International Stroke Conference.
17
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Cerebrovascular Disorders Complicating Pregnancy
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Properly timed neuroimaging will con-
firm the great majority of ischemic
strokes. Concerns arise when planning
neuroimaging during pregnancy.
These are discussed in detail in the
article Neuroradiology in Women of
Childbearing Age by Drs Riley Bove
and Joshua Klein in this issue of
. In general, with prop-
er precautions, CT and MRI should be
used as with nonpregnant patients to
identify areas of infarction and to
investigate the cerebral vasculature.
Cerebral vessel imaging with magnetic
resonance (MR) angiography, CT
angiography, or transfemoral catheter
angiography is indicated to assess
for cerebral arterial dissection, revers-
ible cerebral vasoconstriction syn-
drome, moyamoya disease, or other
arteriopathies. Cardiac ultrasound should
be performed in patients with embolic
infarctions, and should include agitated
saline injection (bubble study) to investi-
gate for a right-to-left shunt froma patent
foramen ovale, the presence of which
may suggest paradoxical embolism and
warrant further testing for lower extrem-
ity or pelvic deep vein thrombus.
22
As
with any patient with stroke, blood tests
such as lipid panel, hemoglobin A1C,
erythrocyte sedimentation rate, C-
reactive protein, and others should be
routinely performed, with additional tests
such as hemoglobin electrophoresis for
sickle cell disease or antiphospholipid
antibody panel performed on a case by
case basis. Genetic testing for throm-
bophilia (prothrombin G20210A muta-
tion, factor V Leiden mutation,
methylenetetrahydrofolate reductase
mutation) can be performed during
pregnancy, but testing for other hyper-
coagulable states (protein C, protein S,
TABLE 4-2
Causes of Ischemic Strokes in Pregnancy (% of All Ischemic Strokes)
a,b,c
Study Cardioembolism
Preeclampsia/
Eclampsia
Angiopathy
Venous Sinus
Thrombosis Unknown Other
Feske et al,
2009
35 30 39 I 22
Liang et al,
2006
36 18 27 I I
Jeng et al,
2004
44 I 22 22 I
Jaigobin et al,
2000
20 20 40 20 15
Witlin et al,
1997
I I 64 I I
Kittner et al,
1996
I 38
d
6 38 19
Sharshar et al,
1995
I 54
d
I 27 20
Awada et al,
1995
33 11 I 44 11
a
Modified with permission from Feske SK, Semin Neurol.
8
B 2007, Thieme Medical Publishers. www.thieme-connect.com/DOI/
DOI?10.1055/s-2007-991126.
b
Totals of the rows may exceed 100% because multiple contributing causes may be counted.
c
Ellipses indicate that data was not reported.
d
These authors reported preeclampsia/eclampsia-associated and CNS angiopathy separately (see text).
85 Continuum (Minneap Minn) 2014;20(1):8099 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
and antithrombin III deficiency) should
be performed at least 6 weeks after
delivery when physiologic changes due
to pregnancy will have normalized.
Therapies and Outcomes
IV recombinant tissue plasminogen
activator (tPA) is a US Food and Drug
Admi ni strati on (FDA)Yapproved
thrombolytic drug that remains the
only proven efficacious therapy for
acute ischemic stroke.
23,24
Many large
stroke centers offer intra-arterial throm-
bolysis as a salvage therapy in severe
stroke cases. Intra-arterial thromboly-
sis typically involves mechanical clot
Case 4-1
A 20-year-old woman developed right hemichorea during the second
trimester of her first pregnancy. Brain imaging showed subcortical infarctions
predominantly in the left hemisphere and severe stenosis of the right and left
middle cerebral arteries (Figure 4-2). No headache or fever or segmental arterial
narrowing or other evidence of cerebral arteritis or infection was present.
Hemoglobin electrophoresis was normal, ruling out sickle cell anemia.
Comment. This patient was diagnosed with moyamoya disease,
an idiopathic noninflammatory cerebral arteriopathy. The choreiform
movements resolved after a short course of steroids. The patient declined
the option of surgical intervention with the encephaloduroarteriosynangiosis
procedure, which has been shown to reduce the risk for future stroke.
20,21
She was treated with aspirin 325 mg/d for stroke prevention. She went on to
have three vaginal deliveries without further neurologic symptoms such as
headache, chorea, or weakness. Follow-up brain imaging studies showed no
evidence for new stroke.
FIGURE 4-2
Brain imaging of a 20-year-old primigravida with right hemichorea. Note the
subcortical infarctions predominantly in the left hemisphere (A, fluid-attenuated
inversion recovery [FLAIR] MRI) and severe stenosis of the right and left middle
cerebral arteries (B, head magnetic resonance [MR] angiogram,
three-dimensional time-of-flight image).
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Cerebrovascular Disorders Complicating Pregnancy
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retrieval using FDA-approved devices.
Recent phase III clinical trials showing
no benefit of intra-arterial over IV
t hr ombol ysi s
25
wi l l pr ompt a
reassessment of the role of catheter-
based therapies, but evidence exists
that improved outcomes depend
on early recanalization of occluded
arteries, and FDA-approved devices
will continue to find use as research
proceeds on this issue. Because preg-
nant women were excluded from all
of these trials, there has been no
controlled study of the use of such
agents in pregnancy. Although there
are case reports of successful IV and
intra-arterial thrombolytic use in
pregnant women,
26Y31
questions for
clinicians remain: Should these
therapies be applied in pregnant
women suffering acute ischemic
strokes? Are they safe and effective
for the mother? Are they safe for the
fetus?
IV tPA has a very short serum half-
life of less than 5 minutes. However, it
binds to newly formed fibrin clots,
where its lytic effect lasts for many
hours. It is a large molecule that does
not cross the placenta in animals, and
so it should not be expected to place
the fetus at risk of teratogenicity. The
potential risks of real concern are
maternal hemorrhage, placental hem-
orrhage and abruption, fetal loss, and
preterm delivery. Although there are
theoretical reasons to question com-
parisons to its use in nonpregnant
patients, mainly that pregnancy is a
state of relative hypercoagulability
characterized by decreased intrinsic
tPA and increased plasminogen activa-
tor inhibitor, the ultimate effects of
these changes on the clinical efficacy
of tPA are speculative and unlikely to
be answered by clinical trials. There-
fore, more empirical clinical data must
be used to estimate the risk. The
authors have found reports in the
literature of six women who have
received IV tPA for stroke while preg-
nant, although many more have been
treated as this has become accepted
practice.
26Y31
Of the six women who
received IV tPA, three suffered no
hemorrhagic complications, one had
minor hemorrhagic transformation of
the cerebral infarct, and one had an
intrauterine hematoma. Of these six
cases, no fetal complications occurred
in three, and in two cases the preg-
nancy was terminated allowing no
further analysis. The sixth patient and
fetus died as a result not of a direct
effect of the systemic tPA, but from
arterial dissection complicating angio-
plasty. Of five women treated with
intra-arterial thrombolysis for acute
arterial occlusion (three tPA, two uro-
kinase), none had serious complica-
tions from the procedure; two had
hemorrhagic transformation of the
stroke with good neurologic out-
comes, and one had a minor buttock
hematoma.
26,29,32
Four of the five
women delivered healthy babies; one
pregnancy, in which the stroke
resulted from bacterial endocarditis,
ended in spontaneous abortion. It
should be noted that urokinase, un-
like tPA, does cross the placenta.
Minor hemorrhagic transformation is
common after thrombolysis in gener-
al, and it does not appear to worsen
outcomes. In fact, it has been associ-
ated with better outcomes, possibly
because it is a marker of early recan-
alization. To summarize, of these 11
women who received IV or intra-
arteri al thrombol ysi s and were
reported in the literature, 10 had no
major complications from thromboly-
sis, and the patient who died had a
major complicating illness; of the 11
reported fetal outcomes, seven were
delivered without complications, two
were terminated therapeutically, one
patient with bacterial endocarditis had
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a spontaneous abortion, and one fetus
died along with the mother.
With such limited and uncontrolled
data, it is not possible to draw firm
conclusions; however, it is reasonable
to judge that pregnancy does not
appear to present a decisive added
risk to thrombolytic therapy. There-
fore, thrombolysis should be consid-
ered for all potentially disabling
strokes during pregnancy, and it
should not be excluded based on the
fact of pregnancy alone. As in all
patients, the details of the case should
be carefully weighed, and patients or
proxy decision makers should be well
informed of risks. Obstetric consulta-
tion should be sought from the outset
for careful monitoring and decision
making. Care in facilities with experi-
ence both in advanced stroke care and
high-risk obstetrics is optimal, and the
cause and mechanism of the stroke
should be carefully determined to
the extent possible before therapy is
prescribed. For example, women with
stroke as a result of amniotic fluid
embolism would not benefit from
tPA. Additionally, given the known risk
of cerebral hemorrhage from hyper-
tensive encephalopathy in the setting
of preeclampsia/eclampsia, patients
who have strokes complicating pre-
eclampsia or eclampsia should not
receive tPA.
PREECLAMPSIA/ECLAMPSIA,
HYPERTENSIVE ENCEPHALOPATHY,
AND POSTPARTUM CEREBRAL
ANGIOPATHY
Overview
Preeclampsia/eclampsia contributes to
cerebrovascular events in two major
ways. First, as noted above, preeclampsia/
eclampsia causes many pathophysio-
logic changes in blood vessels and
the thrombotic system and in this way
accounts for a large proportion of is-
chemic strokes in pregnancy. Second,
one direct consequence of preeclampsia/
eclampsia is the posterior reversible
encephalopathy syndrome (PRES), a
form of the syndrome of hypertensive
encephalopathy characterized by re-
versible brain edema, often associated
with elevated blood pressure, seizures,
brain hemorrhage, and ischemic
strokes.
Preeclampsia/Eclampsia
and Posterior Reversible
Encephalopathy Syndrome
Pathophysiologic mechanisms. The
pathophysiology of preeclampsia/
eclampsia is discussed briefly above.
The features of preeclampsia/eclampsia
directly relevant to PRES and probably
also to eclamptic seizures are (1) an
abnormal increase in vascular tone and
(2) dysfunction of endothelial cells.
Patients with preeclampsia/eclampsia
have heightened sensitivity to media-
tors of vasoconstriction, such as angio-
tensin II. This resultant increase in
vascular tone is responsible for system-
ic hypertension and for the vasomotor
instability that underlies vasospasm.
Endothelial dysfunction is in part re-
sponsible for the instability of vascular
tone, and it also results in increased
vascular permeability that underlies the
development of edema and protein-
uria that characterize preeclampsia/
eclampsia. The syndrome commonly
called PRES results from the develop-
ment of cerebral edema. Fluid crosses
from the intravascular to the interstitial
space as a result both of an increase in
capillary filtration pressure caused by
hypertension and of loss of integrity
of the blood-brain barrier caused
by endothelial dysfunction. Animal
models of the blood-brain barriers
response to severe acute hypertension
have shown both increased pinocytosis
and flow across impaired endothelial
gap junctions.
33
KEY POINT
h Although data on the
use of thrombolytic
therapies during
pregnancy are scarce,
limited experience
suggests that these
agents can be given
with safety comparable
to that in nonpregnant
patients.
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Cerebrovascular Disorders Complicating Pregnancy
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Postpartum Cerebral
Angiopathy
Postpartumangiopathy is one of several
conditions included in the spectrum of
the reversible cerebral vasoconstriction
syndromes (RCVS).
34
Postpartum an-
giopathy is characterized by severe
headaches and reversible narrowing of
intracerebral arteries, often com-
plicated by seizures, reversible brain
edema, lobar hemorrhage, convexity
(nonaneurysmal) subarachnoid hemor-
rhage, and ischemic strokes. In the
past, patients with this syndrome were
often misinterpreted as having inflam-
matory cerebral vasculitis because the
latter can also manifest with headache,
stroke, and cerebral angiographic ab-
normalities; however, postpartum
angiopathy is a noninflammatory, vaso-
constrictive condition. Approximately
one-third of patients with postpartum
angiopathy are noted to have revers-
ible cerebral edema and clinical fea-
tures (headaches, seizures) which are
very similar to patients with PRES, and
more than half the patients with PRES
show evidence of cerebral artery nar-
rowing on vascular imaging.
35
Hence,
postpartum angiopathy and PRES are
considered overlapping conditions.
36
Case 4-2 illustrates this overlap in a
single patient. The pathophysiologic
mechanisms whereby preeclampsia/
eclampsia is related to PRES are prob-
ably also applicable to postpartum
angiopathy.
Evaluation
The syndromes mentioned aboveV
variously called eclampsia, hyperten-
sive encephalopathy, PRES, RCVS, and
postpartum angiopathyVcan then be
considered as various presentations of
a similar fundamental underlying path-
ophysiology. This clinical lumping is
not meant to oversimplify the com-
plex pathophysiology of preeclampsia/
eclampsia, nor to make the claim that
our understanding of this disorder is
well developed. For example, there
may be important pathophysiologic
differences in classic preeclampsia/
eclampsia and postpartum syndromes
that lack proteinuria or even hyper-
tension.
4
Nonetheless, it has been
recognized in recent years that the
basic preeclampsia/eclampsia patho-
physiology may account for these late
pregnancy and postpartum syn-
dromes when they do not fit the
traditional definition of preeclampsia/
eclampsia with proteinuria and when
they develop up to many weeks after
delivery.
4,38
Eclamptic hypertensive encepha-
lopathy (ie, PRES) typically presents
with headache, visual symptoms refer-
able to the occipital lobes, and sei-
zures. Eclamptic RCVS presents with
thunderclap headache, seizures, and
focal neurologic deficits. Imaging typ-
ically shows posterior white and often
gray matter change consistent with
vasogenic cerebral edema (hypodense
on CT and hyperintense on T2-
weighted MRI), the findings typical of
PRES, or segmental narrowing and
dilation of large and medium-sized
cerebral arteries, the findings typical
of RCVS. Both or either of these
imaging patterns may be seen, and
these imaging findings have limited
sensitivity, so imaging may be un-
revealing in otherwise clinically con-
vincing cases. Although most lesions
are limited to edema and are there-
fore reversible, hemorrhages and focal
ischemic strokes may also occur.
Therapies and Outcomes
The goals of therapy are to control
elevated blood pressure, control sei-
zures, and minimize vasospasmand risk
of secondary infarct and hemorrhage.
Because the authors interpret these
syndromes in association with preg-
nancy as manifestation of eclampsia,
KEY POINTS
h Preeclampsia/eclampsia
can lead to several
cerebrovascular
syndromes, including
posterior reversible
encephalopathy
syndrome, reversible
cerebral vasoconstriction
syndrome, and ischemic
and hemorrhagic
strokes.
h The major CNS
complications of
preeclampsia/eclampsia
are a form of
hypertensive
encephalopathy.
They should be treated
aggressively with
rapid control of blood
pressure and IV
magnesium sulfate.
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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Case 4-2
A 36-year-old woman developed severe headaches associated with new-onset hypertension 10 days
after delivery of twins by cesarean delivery. The initial brain MRI and CT examinations were normal.
Headaches persisted despite antihypertensive medications. A seizure and an episode of aphasia and
hemiparesis occurred. Repeat MRI on day 18 (Figure 4-3A
37
) showed hyperintense regions in both
parietalYoccipital lobes with elevated diffusionVfindings consistent with vasogenic edema. These
clinical-imaging features are consistent with the posterior reversible encephalopathy syndrome (PRES).
Magnetic resonance (MR) angiography of the circle of Willis showed multifocal stenoses in the
FIGURE 4-3
Brain imaging of a 36-year-old woman with severe headaches associated with postpartum hypertension.
A, fluid-attenuated inversion recovery (FLAIR) image shows hyperintense regions in both parietal and occipital
lobes (arrows) with elevated diffusion (not shown), findings that are consistent with vasogenic edema.
B, Magnetic resonance (MR) angiography of the circle of Willis shows multifocal stenoses in the proximal anterior, middle, and
posterior cerebral arteries. This finding is consistent with postpartum angiopathy. C and D show hyperintense lesions (arrows)
on FLAIR and diffusion-weighted images, respectively, from MRI performed 1 day later, a finding consistent with ischemic
stroke. E, a follow-up MR angiogram shows worsening of the multifocal cerebral arterial stenosis. F, FLAIR shows bilateral
cerebral infarction with edema and hemorrhage.
Reprinted with permission fromSinghal AB et al, NEngl J Med.
37
Copyright B 2009, Massachusetts Medical Society. www.nejm.org/doi/full/10.1056/NEJMcpc0809063.
Continued on page 91
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Cerebrovascular Disorders Complicating Pregnancy
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
treatment with IV magnesium sulfate
along with other therapies directed at
bl ood pressure and sei zures i s
recommended. Several studies have
shown the superiority of magnesium
sulfate over commonly used anticon-
vulsants for prevention and treatment
of eclamptic seizures.
39Y41
The authors
give a loading dose of 4 g to 6 g of
magnesium sulfate over 20 to 30
minutes followed by continuous infu-
sion at 2 g per hour with an additional
2 g bolus if seizures occur during this
therapy. Patients should be monitored
cl osel y and magnesi um sul fate
stopped if deep tendon reflexes are
lost, if respirations are depressed, or if
urine output falls below 100 mL in 4
hours. Calcium gluconate 1 g slow IV
push can be given to reverse severe
toxicity. In addition, patients with
eclamptic syndromes should be treated
urgently with IV antihypertensive
agents and with additional antiepileptic
agents if needed for seizure control.
Most women with preeclampsia/
eclampsia are volume contracted and
will benefit from volume replacement
and maintenance. Although many prac-
titioners have used calcium channel
blockers and glucocorticoids in these
patients, this use is not supported by
clinical data. No evidence has proven
that calcium channel blockers are more
effective than other antihypertensive
agents. In a study of 139 patients with
RCVS, of which 12 were postpartum,
corticosteroids were associated with a
trend toward poorer outcomes.
34
This
series is weighted toward the RCVS
presentation, so it is not representative
of eclampsia in general. A third of the
patients in this series presented with
seizures, and a third suffered ischemic
strokes. Ninety percent had good out-
comes (Modified Rankin Scale 0 to
3).
34
Most patients with pregnancy-
associated PRES and RCVS have a self-
limited clinical course with benign
outcome and resolution of brain and
vascular imaging abnormalities within
days to weeks; however, 5% to 12%
can have a fulminant course with prog-
ressive vasoconstriction, brain edema,
and strokes, culminating in persistent
severe neurologic deficits or death.
37,42
proximal anterior, middle, and posterior cerebral arteries. This finding is consistent with
postpartum angiopathy. MRI performed on postpartum day 19 showed hyperintense lesions on FLAIR
and diffusion-weighted images, a finding consistent with ischemic stroke. Despite multiple attempts to
dilate the cerebral arteries with intracerebral vasodilator injections, the patient showed clinical and
angiographic progression over the course of 1 week. A follow-up MR angiogram showed worsening of
the multifocal cerebral arterial stenosis, and FLAIR showed bilateral cerebral infarction with edema and
hemorrhage. The patient eventually died. On autopsy, the cerebral arteries were normal, with no
evidence of inflammation.
Comment. This is a classic example of postpartum eclampsia with postpartum angiopathy and
features of posterior reversible encephalopathy and reversible cerebral vasoconstriction syndromes,
illustrating that these causes of postnatal ischemic and hemorrhagic stroke are interrelated
conditions. These syndromes are difficult to predict or prevent. Considering these as manifestations
of preeclampsia/eclampsia, the authors treat with magnesium sulfate, based on the clinical trials
discussed in the text. It is also important to control blood pressure when elevated, as with other forms
of hypertensive encephalopathy. No treatment has proven efficacy for the cerebral artery narrowing
of postpartum angiopathy. Calcium channel blockers are a reasonable, if untested, choice. While
90% of patients have a self-limited course and recover within days to weeks, some patients
(as in this example) may have a progressive course and even a fatal outcome.
Continued from page 90
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CEREBRAL VENOUS SINUS
THROMBOSIS
Epidemiology
This review includes the cases of
cerebral venous thrombosis among
those of arterial ischemic infarction
above in discussing the rate of ische-
mic stroke in pregnancy because it is
often not clearly distinguished from
arterial stroke in large series of preg-
nancy and stroke. However, cerebral
venous sinus thrombosis is a disorder
very different from arterial occlusion
with different pathophysiology, ther-
apy, and outcomes. Cerebral venous
thrombosis accounts for 6% to 64% of
all pregnancy-associated strokes in
large reported series and 17% in the
authors series.
16
Venous thrombosis
may present with imaging findings of
thrombus within a cerebral vein or
venous sinus without parenchymal
changes or with evidence of cerebral
edema, apparent ischemic stroke, or
hemorrhage, and as a result, this
disorder is classified differently by
different authors.
Mechanisms
Thrombosis in the venous circulation,
including the cerebral venous sinuses
and veins, is presumed to be the
outcome of the underlying hyper-
coagulable state of pregnancy, promoted
by the various pathophysiologic
changes of pregnancy described above.
These effects reach their peak during
the early postpartum period, the time
when most cases of cerebral venous
thrombosis present. Figure 4-1 shows
the time during pregnancy of the
diagnosis of cerebral venous thrombo-
sis in the authors patients.
17
In addi-
tion to the known alterations in
platelet function and prothrombotic
and antithrombotic proteins, iron defi-
ciency anemia and the adaptive re-
sponse to the acute trauma and
hemorrhage of labor and delivery may
contribute to the propensity for abnor-
mal thrombosis. This timing of risk is
comparable to lower extremity deep
venous thrombosis in pregnancy.
43
Although often called venous infarc-
tion, with large collecting sinus
thrombosis, the brain lesions typically
begin as areas of brain edema without
infarction as a result of impaired venous
drainage and increased venous pres-
sures. Ultimately, stasis of flow may
cause these lesions to progress to in-
clude areas of infarction and hemor-
rhage. In addition, hemorrhage may
extend to other compartments, includ-
ing the subarachnoid, subdural, and
intraventricular spaces. Because the pri-
mary process is edema, much of the
visualized lesion (hypodensity on CT or
hyperintensity on T2-weighted MR) is
reversible with treatment, and outcomes
are typically very good, much better than
for comparable-sized arterial strokes.
Evaluation
Women with cerebral venous throm-
bosis may present with headaches,
focal neurologic deficits, depressed
level of consciousness, or seizures,
and the pregnant state should greatly
heighten the index of suspicion for
this diagnosis. Cerebral venous sinus
thrombosis can be detected on
noncontrast CT as hyperdensity in
the region of thrombosis or as paren-
chymal hypodensity from edema or
infarction or hyperdensity from hem-
orrhage. Contrast CT may show a
filling defect within the thrombosed
sinus surrounded by the enhancing
dura of the sinus wall (empty delta
sign). Contrast CT venography may
show the thrombosis as a filling defect
in the region of the affected sinus. On
MRI, venous sinus thrombosis can be
seen directly as thrombus with signal
characteristics appropriate to the
time since onset (T1-isodense and
KEY POINT
h Cerebral venous
thrombosis, especially
postpartum, is one
of the most common
cerebrovascular
complications of
pregnancy.
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Cerebrovascular Disorders Complicating Pregnancy
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T2-hypodense when acute, with T1
turning hyperintense followed by T2
turning hyperintense so that the
thrombus is bright on both T1- and
T2-weighted images when in the late
subacute phase). Since cerebral venous
thrombosis may have been present for
some time before symptoms lead to
diagnosis, it is common to see later-
phase characteristics upon initial diag-
nosis. MR venography can also show
the thrombosis as a filling defect. This
can be done without contrast, an advan-
tage during pregnancy and nursing. As
with arterial stroke, with proper pre-
cautions, it is possible to obtain good
imaging confirmation safely during
pregnancy. Cerebral cortical vein throm-
bosis without venous sinus thrombosis
can be more difficult to confirm but is
commonly visible as an expanded tubu-
lar vein on the cortical surface, often
with T2-weighted signal hyperintensity
in the adjacent parenchyma.
Therapy
The best available data support, if
weakly, the use of anticoagulation to
treat cerebral venous thrombosis, in-
cluding in those patients with hemor-
rhagic lesions. Meta-analysis and the
authors experience treating many
such patients are consistent with this
recommendation from the litera-
ture.
44,45
A randomized, controlled
trial by Einha upl was small but seemed
to show a clear benefit.
46
In fact, it was
small because it was terminated early
due to the evidence of benefit in favor
of heparin anticoagulation after only
20 patients had been enrolled. A larger
Dutch study of low-molecular-weight
heparin was negative but showed a
trend in favor of early anticoagula-
tion.
46
This study was limited by the
fact that patients in both groups
received warfarin anticoagulation after
the first 3 weeks of the study treat-
ment, possibly accounting to some
degree for the small difference be-
tween groups. Cerebral hemorrhage
occurs in nearly half of patients with
cerebral venous thrombosis, so the
question of the safety of anticoagula-
tion in this subset is important. In the
Einha upl study, three of 10 patients
treated with heparin had experienced
hemorrhage before treatment. None
of these patients had expansion of
their hemorrhage or new hemor-
rhage, and all recovered fully. This
study also included a retrospective
review of 102 patients with cerebral
venous thrombosis. Among these pa-
tients, 27 of 43 with hemorrhage
received full-dose heparin, while 13
received no heparin after hemor-
rhages were found. Those who re-
ceived heparin had lower mortality
(15% versus 56%). In the Dutch study
as well, no worsening occurred in
those receiving anticoagulation de-
spite the presence of hemorrhage.
The authors recommend full heparin
anticoagulation during the acute
phase of cerebral venous thrombosis
whether hemorrhage is present or
not, and then a period of approxi-
mately 3 to 6 months of ambulatory
anticoagulation. This extended period
of anticoagulation is typically accom-
plished with warfarin postpartum.
During pregnancy, when warfarin is
contraindicated, low-molecular-weight
heparin is given and then held
during the period of labor and deliv-
ery (Case 4-3).
HEMORRHAGIC STROKE AND
VASCULAR MALFORMATIONS
Epidemiology
Hemorrhagic, like ischemic, stroke is
uncommon during pregnancy and the
puerperium. The proportion ranges
from five to 35 per 100,000 in the
reported series (see Table 4-1), and
estimating the incidence from the
three population-based series, it
KEY POINT
h Patients with cerebral
venous sinus
thrombosis benefit
from anticoagulation.
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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
ranges from 0 to 6 per 100,000.
However, despite the low absolute
risk, pregnancy increases the risk for
hemorrhagic much more than for
ischemic stroke. This risk increase is
substantial during pregnancy (relative
risk 2.5) and very great during the
early postpartum period (relative risk
28.5).
9
Despite its rarity, because of the
severe implications of cerebral hemor-
rhage, hemorrhagic stroke is also an
important cause of pregnancy-related
mortality. The major established causes
of pregnancy-related cerebral hemor-
rhage are preeclampsia/eclampsia, fol-
lowed by arteriovenous malformations
KEY POINT
h Pregnancy increases the
risk of hemorrhagic
stroke. This increased
risk is greatest in the
postpartum period.
Case 4-3
A 40-year-old woman developed progressively worsening headaches and nausea in the first trimester
of her third pregnancy. She had a medical history of depression and chronic hypertension; two
previous pregnancies had been uneventful. Her blood pressure was 120/78 mm Hg. The neurologic
and systemic examination findings were unremarkable. On brain imaging (Figure 4-4), MRI showed
hyperintense signal in the region of the right transverse sinus, and magnetic resonance (MR)
venogram showed absence of flow-related signal within the right transverse sinus and decreased
flow-related signal within the right sigmoid sinus and internal jugular veinVresults consistent with
cerebral venous sinus thrombosis. Laboratory tests showed an elevated D-dimer and a low protein S
level. She was treated with low-molecular-weight heparin, and the headaches resolved within 5 days.
A follow-up MR venogram performed after 2 weeks showed complete recanalization of the venous
sinuses. She went on to have an uncomplicated vaginal delivery. Follow-up blood tests showed normal
D-dimer and protein S levels. Six weeks after delivery, low-molecular-weight heparin was discontinued,
and she began treatment with aspirin.
Comment. This case illustrates the association between pregnancy and cerebral venous sinus thrombosis.
Several mechanisms, including low levels of protein S as documented in this patient, contribute to a
transient hypercoagulable state during pregnancy. MR venography was preferred over CT venography to
avoid radiation risks during pregnancy. This patient was treated with low-molecular-weight heparin and
not warfarin because warfarin is teratogenic and can cause bleeding in the fetus.
FIGURE 4-4
Brain imaging of a 40-year-old pregnant woman with progressively worsening headaches and nausea. MRI
revealed hyperintense signal in the region of the right transverse sinus (A, fluid-attenuated inversion recovery
[FLAIR] image), and magnetic resonance (MR) venogram (B) showed absence of flow-related signal within
the right transverse sinus and decreased flow-related signal within the right sigmoid sinus and internal jugular vein. These
imaging results are consistent with cerebral venous sinus thrombosis. A follow-up MR venogram performed after 2 weeks of
treatment with low-molecular-weight heparin showed complete recanalization of the venous sinuses (C).
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Cerebrovascular Disorders Complicating Pregnancy
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and aneurysms. Preeclampsia/eclampsia
probably contributes even a larger por-
tion than is apparent from the series
reported in Table 4-3, since it is likely
that cases that present in late pregnancy
or the puerperium without proteinuria
are often diagnosed and classified as of
unknown cause. Other potential causes,
such as disseminated intravascular co-
agulation, have not been reported com-
monly in these series.
The physiologic changes of pregnancy
reviewed above include expansion of
blood volume, increased stroke volume
and cardiac output, rise of blood pres-
sure from its nadir in the late second or
early third trimester to near or slightly
above normal as term approaches, and
remodeling of vascular tissue with loss
of collagen and elastin content and loss
of distensibility. One might expect
these changes to underlie an increased
risk of hemorrhage near term. The
strain and trauma of labor might be
expected to add to the increased risk.
The risk of aneurysmal rupture
appears to increase severalfold, rising
with gestational age until it peaks at 30
to 34 weeks.
48
Dias and Sakhar
48
reported the mortality of pregnancy-
associated aneurysmal subarachnoid
hemorrhage to be 35%, with a fetal
mortality of 17%. If a ruptured aneu-
rysm is left unsecured surgically, rates
of recurrent hemorrhage and maternal
and fetal mortality are very high. This
mortality may be greatly reduced by
early surgery. In one study, subarach-
noid hemorrhage without early sur-
gery resulted in a maternal mortality
of 63% and fetal mortality of 27%;
these mortalities were lowered to 11%
and 5%, respectively, by early sur-
gery.
48
With evidence that early sur-
gery, open or endovascular, to secure
ruptured aneurysms leads to better
maternal and fetal outcomes, it is rec-
ommended that therapy for women
after aneurysmal rupture proceed as it
does for all patients as dictated by
KEY POINTS
h The major causes of
pregnancy-associated
hemorrhage are
preeclampsia/eclampsia
and cerebral vascular
malformations, such
as aneurysms and
arteriovenous
malformations.
h Aneurysmal subarachnoid
hemorrhage during
pregnancy confers a
high risk of death to
both mother and baby.
h Womenwithsubarachnoid
hemorrhage should be
seen by a neurosurgeon
and undergo vascular
imaging to look for
aneurysm, arteriovenous
malformation, or other
vascular lesions.
TABLE 4-3
Causes of Hemorrhagic Strokes in Pregnancy (% of All Hemorrhagic Strokes)
a,b
Study
Cerebral
Aneurysm
Arteriovenous
Malformation
Cavernous
Malformation
Preeclampsia/
Eclampsia Unknown Other
Feske
et al, 2009
14 14 3 42 22 11
Liang
et al, 2006
10 19 I 24 24 24
Jeng et al,
2004
14 23 I 32 I I
Jaigobin
et al, 2000
23 38 I I 23 15
Witlin
et al, 1997
50
c
I I 50 I
Kittner
et al, 1996
I 23 I 15 31 31
Sharshar
et al, 1995
13 13 13 44 19 I
Awada
et al, 1995
I I I I 100 I
a
Totals of the rows may exceed 100% because multiple contributing causes may be counted.
b
Ellipses indicate that data was not reported.
c
This value combines both cerebral aneurysm and arteriovenous malformation.
95 Continuum (Minneap Minn) 2014;20(1):8099 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
neurosurgical principles. Therefore, if
aneurysmal subarachnoid hemorrhage
occurs during pregnancy, the patient
should proceed to surgery immediately,
if feasible. Endovascular coiling may
be an alternative with proper shielding
to minimize fetal radiation exposure.
49
If urgent obstetric issues (such as ac-
tive labor, eclampsia, or fetal distress)
prevent immediate surgery, then the
woman should undergo urgent cesar-
ean delivery followed by surgical con-
trol of the aneurysm. Because of the
severe morbidity and high mortality
rate of subarachnoid hemorrhage and
the increased risk of rupture near
term, it is recommended that un-
ruptured aneurysms at significant risk
of rupture be secured before preg-
nancy, whenever possible. With the
high rate of screening by MR angiogra-
phy for headaches and other common
disorders, it is not uncommon to find
small, asymptomatic, unruptured aneu-
rysms. In general, the risk of rupture
depends on size and morphology. The
risk is low for small, uncomplicated
aneurysms. Systematically evaluated
clinical experience that would dictate
the best policy for management of such
aneurysms is lacking; however, it is
often considered prudent to deliver
such women by cesarean delivery or
by vaginal methods that interrupt the
second stage of labor. No clear data
have been published to argue against
vaginal delivery for women who have
surgically secured aneurysms, and most
such women can be delivered vaginally
with close monitoring.
Data are conflicting concerning the
influence of pregnancy on arteriove-
nous malformations (AVMs). Hemor-
rhage is the most common presenting
manifestation of AVM, and AVMs that
present with hemorrhage are more
likely to bleed again than those dis-
covered as a result of seizures or focal
neurologic deficits. For many years,
practitioners followed the analysis of
Robinson and colleagues, which
suggested that pregnancy increased
the rate of hemorrhage of AVMs.
50
A
later influential analysis found a back-
ground annual rate of hemorrhage of
3.5% in women with AVM and no prior
hemorrhage and 5.8% in those with
prior hemorrhage, with no increase
conferred by pregnancy.
51
However,
an analysis of the risk of rupture per
day found a severalfold increase in risk
on the day of delivery.
52,53
Also,
although overall hemorrhage rates
appear to be comparable to nonpreg-
nant women, evidence suggests that
when an AVM bleeds during pregnancy,
the rebleeding rate is higher than in
nonpregnant women. In one study of
27 women with intracerebral hemor-
rhage due to AVM during pregnancy
who were not treated with immediate
resection, seven had recurrent hemor-
rhage during or immediately after
pregnancy. This 26% rate of recurrent
hemorrhage in the first year is signifi-
cantly higher than the roughly 6%
rate in nonpregnant women. Well-
controlled data on which to base ther-
apeutic decisions concerning AVMs
discovered during pregnancy are lack-
ing; however, based on the above
considerations, expert recommenda-
tions are that (1) if a woman with
known AVM anticipates pregnancy, the
AVM should be treated before preg-
nancy; (2) if an AVM is discovered
during pregnancy and has not bled
during the pregnancy, conservative
observation is usually recommended,
with plans to proceed to definitive
treatment after delivery; (3) if an AVM
bleeds during pregnancy, consideration
should be given to treatment during the
pregnancy, taking into account the
grade of the lesion and the expected
timing of benefit in lowering risk
(immediate for low-grade lesions ame-
nable to complete surgical excision or
KEY POINT
h Aneurysmal
subarachnoid
hemorrhage should
be treated with early
surgery or endovascular
techniques to secure the
ruptured aneurysm and
minimize the risk of
recurrent hemorrhage.
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Cerebrovascular Disorders Complicating Pregnancy
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embolization but delayed by up to 1 to
3 years for higher-grade lesions requir-
ing radiosurgery and combination ther-
apies).
54
Although no study has shown
an advantage to cesarean delivery,
based on the suggestion of higher
rates of hemorrhage on the day of
delivery, many obstetricians will favor
this approach to minimize risk.
CONCLUSION
Ischemic and hemorrhagic strokes are
uncommon but serious complications
of late pregnancy and the puerperium,
and when they occur, they confer
a major risk of long-term disability
or death. Knowledge of the risks
of pregnancy-associated stroke and
the neurologic manifestations of
preeclampsia/eclampsia will support
and encourage early diagnosis and
optimal management decisions. With
proper precautions to minimize risk to
the fetus, women can generally undergo
diagnostic evaluations and be treated
with aggressive measures appropriate to
the severity of the condition.
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KEY POINT
h Women with
arteriovenous
malformations should
be managed in
consultation with a
neurosurgeon. In most
cases, they can
be treated with
conservative
observation until after
delivery. However,
when hemorrhage
occurs during pregnancy,
patients with low-grade
arteriovenous
malformations may
benefit from early
definitive surgery or
endovascular
embolization.
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