Role of pregnancy and female sex steroids on aneurysm ... · for cerebral aneurysm formation, growth, and rup-ture. Female sex has been studied as a significant indepen-dent risk

NEUROSURGICAL FOCUS Neurosurg Focus 47 (1):E8, 2019

Physiological changes that occur during a woman’s lifetime may predispose her to different levels of risk for cerebral aneurysm formation, growth, and rup-ture. Female sex has been studied as a significant indepen-dent risk factor for intracranial aneurysm formation and

growth,10 and the International Study of Unruptured Intra-cranial Aneurysms evaluated 4060 patients and found that 75% were women.32 Two instances during which women are believed to have a unique risk for the development or rupture of cerebral aneurysms due to hormonal and hemo-

ABBREVIATIONS aSAH = aneurysmal SAH; AVM = arteriovenous malformation; CCA = common carotid artery; CI = confidence interval; C-section = caesarean section; GDC = Guglielmi detachable coil; HBMEC = human brain microvascular endothelial cell; HRT = hormone replacement therapy; OR = odds ratio; SAH = subarachnoid hem-orrhage.SUBMITTED March 1, 2019. ACCEPTED April 12, 2019.INCLUDE WHEN CITING DOI: 10.3171/2019.4.FOCUS19228.

Role of pregnancy and female sex steroids on aneurysm formation, growth, and rupture: a systematic review of the literatureMilli Desai, MHS,1 Arvin R. Wali, MD, MAS,2 Harjus S. Birk, MD,2 David R. Santiago-Dieppa, MD,2 and Alexander A. Khalessi, MD, MS2

1School of Medicine and 2Department of Neurological Surgery, University of California, San Diego, California

OBJECTIVE Women have been shown to have a higher risk of cerebral aneurysm formation, growth, and rupture than men. The authors present a review of the recently published neurosurgical literature that studies the role of pregnancy and female sex steroids, to provide a conceptual framework with which to understand the various risk factors associated with cerebral aneurysms in women at different stages in their lives.METHODS The PubMed database was searched for “(“intracranial” OR “cerebral”) AND “aneurysm” AND (“pregnancy” OR “estrogen” OR “progesterone”)” between January 1980 and February 2019. A total of 392 articles were initially identi-fied, and after applying inclusion and exclusion criteria, 20 papers were selected for review and analysis. These papers were then divided into two categories: 1) epidemiological studies about the formation, growth, rupture, and management of cerebral aneurysms in pregnancy; and 2) investigations on female sex steroids and cerebral aneurysms (animal stud-ies and epidemiological studies).RESULTS The 20 articles presented in this study include 7 epidemiological articles on pregnancy and cerebral an-eurysms, 3 articles reporting case series of cerebral aneurysms treated by endovascular therapies in pregnancy, 3 epidemiological articles reporting the relationship between female sex steroids and cerebral aneurysms through retro-spective case-control studies, and 7 experimental studies using animal and/or cell models to understand the relationship between female sex steroids and cerebral aneurysms. The studies in this review report similar risk of aneurysm rupture in pregnant women compared to the general population. Most ruptured aneurysms in pregnancy occur during the 3rd trimester, and most pregnant women who present with cerebral aneurysm have caesarean section deliveries. Endovas-cular treatment of cerebral aneurysms in pregnancy is shown to provide a new and safe form of therapy for these cases. Epidemiological studies of postmenopausal women show that estrogen hormone therapy and later age at menopause are associated with a lower risk of cerebral aneurysm than in matched controls. Experimental studies in animal models corroborate this epidemiological finding; estrogen deficiency causes endothelial dysfunction and inflammation, which may predispose to the formation and rupture of cerebral aneurysms, while exogenous estrogen treatment in this popula-tion may lower this risk.CONCLUSIONS The aim of this work is to equip the neurosurgical and obstetrical/gynecological readership with the tools to better understand, critique, and apply findings from research on sex differences in cerebral aneurysms.https://thejns.org/doi/abs/10.3171/2019.4.FOCUS19228KEYWORDS cerebral aneurysm; pregnancy; female sex steroids; estrogen

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Desai et al.

Neurosurg Focus Volume 47 • July 20192

dynamic changes are during pregnancy and menopause. For example, cardiac output increases by 30%–50% during pregnancy and peaks by the 3rd trimester,16 and estrogen, which is increased in pregnancy, appears to enhance cere-bral blood flow.19 In contrast to pregnancy during which fe-male sex steroids are increased, hormones such as estrogen are decreased in peri- and postmenopause. Studies suggest that this estrogen deficiency leads to endothelial dysfunc-tion and inflammation and explains the increased risk for aneurysmal rupture in women through menopause, but the exact mechanisms remain unspecified.25

Cerebral aneurysms in pregnancy represent a rare but important cause of subarachnoid hemorrhage (SAH), as management and treatment are complicated by consider-ations of both the mother and the fetus. The incidence of unruptured aneurysms in pregnancy is not well established in the literature, and the rate of ruptured aneurysms ranges from 3 to 11 per 100,000 pregnancies.12 Fifty percent of all aneurysm ruptures in women younger than 40 years are reported to be pregnancy related.2 Aneurysm rupture has been shown to have greater mortality risk in pregnant patients than in nonpregnant patients.18 There are limited studies on the relationship of pregnancy and cerebral aneu-rysms: the incidence is rare, and additionally it is not fea-sible to study cohorts of pregnant women through random-ized controlled trials. The risk of aneurysm rupture during pregnancy and subsequent options for treatment and de-livery are controversial. Previous studies have reported an increased risk of aneurysm rupture and subsequent SAH during pregnancy and delivery, with as many as 77% of 154 cases of verified intracranial hemorrhage during preg-nancy caused by aneurysm rupture.5 However, the afore-mentioned study did not include a control group and is therefore limited in interpretation, and more recent studies indicate the risk of aneurysm rupture during pregnancy is similar to that of the general population.11 Treatment mo-dalities for aneurysms have changed since early case re-ports in 1965 showed the options for a ruptured aneurysm in pregnancy were intracranial surgery versus bed rest with imminent death.22 Current treatment modalities in-clude endovascular treatment with a focus on minimizing morbidity from intracranial surgery, as well as minimizing fetal exposure to angiography.17 We rely on epidemiologi-cal data and reviews of cases to identify which trimester of pregnancy patients present with aneurysm rupture, how aneurysms grow during pregnancy, treatment options, and whether vaginal versus caesarean section (C-section) de-liveries are indicated to minimize the risk of aneurysmal SAH (aSAH) during pregnancy.

Women are at highest risk for aneurysm rupture in the perimenopausal and postmenopausal state.4 The relation-ship between postmenopausal estrogen deficiency and aSAH has been studied and described more extensively through experimental studies using animal models.25 Un-derstanding the current literature about experimental mod-els to explain the pathophysiology of cerebral aneurysms in estrogen-deficient states and epidemiological data to understand population health components will shed light on the overall role of female sex steroids and hormones on the development of cerebral aneurysms. These findings can be applied to multiple scenarios of aneurysm formation,

growth, and rupture. Furthermore, these findings point to the development of hormone therapy and targeted therapy to prevent the formation of aneurysms, halt growth, and prevent aneurysm rupture. Understanding the role of fe-male sex steroids such as estrogen will also contribute to an understanding of the underlying sex disparities that ex-ist in presentation of cerebral aneurysms. Here, we review the literature on the role of pregnancy and sex steroids on cerebral aneurysms and summarize salient findings from epidemiological and experimental studies.

MethodsA systematic review to analyze the role of pregnancy and

sex steroids in cerebral aneurysms was performed through the PubMed registry with articles dating from January 1, 1980, to February 1, 2019. Search terms were “(“intracrani-al” OR “cerebral”) AND “aneurysm” AND (“pregnancy” OR “estrogen” OR “progesterone”).” This search yielded a total of 392 results from the PubMed database. Articles were included within this review if they presented primary human or animal data or investigated the epidemiology of pregnancy, sex steroids (i.e., estrogen and/or progesterone), and cerebral aneurysms. Case-series analyses were includ-ed. Articles were excluded if aneurysms were not differen-tiated from other intracranial vascular abnormalities (i.e., arteriovenous malformations [AVMs]). Single case reports were excluded from our review because multiple articles have already synthesized the published single case reports as case series.

The extracted articles were then divided into two cat-egories: 1) epidemiological studies about the formation, growth, rupture, and management of cerebral aneurysms in pregnancy; and 2) investigations on female sex steroids and cerebral aneurysms (animal studies and epidemio-logical studies). Epidemiological studies were reviewed for study design, sample size of population studied, age and gestational age if applicable, and outcomes of cerebral an-eurysm formation, growth, rupture, treatment, and man-agement. Animal studies were evaluated for study design (in vivo vs in vitro), subject type, injury model, number of animals included in experimental and control groups, and outcomes of cerebral aneurysm formation, growth, rup-ture, treatment, and management.

ResultsThree hundred ninety-two articles were initially identi-

fied from the PubMed database. After applying inclusion and exclusion criteria, 20 papers were selected for review and analysis. Using the search criteria, no prospective or randomized controlled trials in pregnancy were identified. The 20 articles presented here include 7 epidemiological articles on pregnancy and cerebral aneurysms, 3 articles reporting case series of cerebral aneurysms treated by en-dovascular therapies in pregnancy, 3 epidemiological arti-cles reporting the relationship between female sex steroids and cerebral aneurysms through retrospective case-control studies, and 7 experimental studies using animal and/or cell models to understand the relationship between female sex steroids and cerebral aneurysms. Figure 1 is a flow-chart describing the paper selection process.


Desai et al.

Neurosurg Focus Volume 47 • July 2019 3

Epidemiological Studies of Cerebral Aneurysms in Pregnancy

Seven epidemiological articles reporting cerebral aneu-rysms in pregnancy were included. A full description of results from these investigations can be found in Table 1. Within the 7 articles, we include 1 case crossover study, 1 retrospective cohort study, 2 retrospective reviews, 1 ret-rospective review and literature review of cases, 1 case-series report, and 1 literature review of cases. Among 89 cases from single case reports that have been summarized in 2 studies, 72 (approximately 80%) represented cases of ruptured aneurysms in the 3rd trimester of pregnancy.1,23 This finding is consistent with previous studies and case-series reports that have found that aneurysms are most likely to rupture in the 3rd trimester of pregnancy and up to 6 weeks postpartum.12,24 Studies that summarized case reports also indicated aneurysm occlusion through surgi-cal clipping in 53.8% of cases and with an endovascular procedure in 36.5% of cases,23 and coil embolization being associated with a lower complication rate than clipping in patients with ruptured aneurysms (9.5% vs 23.1%).1 One study in our analysis reported that 19.8% (22 of 111 cases) of hemorrhagic stroke in pregnancy was due to aneurysm rupture.33 In 2 longitudinal studies in our analysis with a combined sample size of 1130 patients, the relative risk of rupture during pregnancy and deliveries was compa-rable to the annual rupture risk in the general population (1.4%, 95% confidence interval [CI] 1.35%–1.57%) during pregnancy and 0.05% (95% CI 0.0468%–0.0634%) during delivery; and in the second study, 0.4% (95% CI 0.2%–0.9%) during pregnancy, delivery, or the puerperium.11,30 In

a study of 5 aneurysms in pregnancy with monitoring of aneurysm growth, the aneurysms in 4 pregnancies did not change in size, remaining 2–5 mm, while in 1 pregnancy, the aneurysm increased from 6 to 7 mm during the 3rd trimester, but returned to its original size in the postpar-tum period.28 Of the 5 studies we include that compared C-section and vaginal delivery rates in pregnant women with cerebral aneurysms, all reported increased rates of C-sections as the method of delivery, regardless of aneurysm rupture or nonrupture.1,11,23,24,28 A C-section followed by an-eurysm treatment was reported in 1 study as the accepted delivery method for ruptured aneurysms,24 whereas in 2 other studies the widespread use of C-sections in unrup-tured aneurysms was reported to be unnecessary.11,30

Endovascular Treatment of Cerebral Aneurysms in Pregnancy

Three articles reporting case series of cerebral aneu-rysms treated by endovascular therapies in pregnancy were identified. A full description of results from these investi-gations can be found in Table 2. Summaries of case reports that we have included report that in 89 cases of cerebral aneurysms in pregnancy, occlusion of the aneurysm was achieved through surgical clip placement in 53.8% of cas-es.23 Surgical clipping of aneurysms is still used and re-ported in the literature, but the most recent neurosurgical literature has discussed endovascular coil embolization of aneurysms as a treatment option. In the combined 8 cases of aneurysms treated endovascularly in pregnancy that we include in this review, all were treated successfully with Guglielmi detachable coils (GDCs) and without the need

FIG. 1. Flow diagram demonstrating the search algorithm to identify literature from the PubMed database. A total of 392 articles were initially identified using our search criteria, of which 20 met the inclusion and exclusion criteria and were included within this review.


Desai et al.


TABL

E 1.

Seve

n ep

idem

iolo

gica

l stu

dies

on

preg

nanc

y and

cere

bral

aneu

rysm

s

Auth

ors &

Ye

arSt

udy T

ype

Title

Yrs

Samp

le Si

zeM

atern

al Ag

e &

Gesta

tiona

l Age

Relat

ive R

iskVa

ginal

Birth

vs C

-Sec

tion

Conc

lusion

s

Tiel

Groe

ne-

stege

et

al., 2

009

Case

cros

s-ov

er st

udy

The r

isk of

aneu

rys-

mal s

ubar

achn

oid

hemo

rrhag

e du

ring p

regn

ancy

, de

liver

y, an

d the

pu

erpe

rium

in th

e Ut

rech

t pop

ulatio

n

1987

–200

624

418

–42 y

rsRe

lative

risk

of aS

AH du

ring

preg

, deli

v, or

puer

pe-

rium

was 0

.4% (9

5% C

I 0.

2–0.9

%); b

ased

on no

. of

wome

n age

d 18–

42 yr

s w/

in ca

tchme

nt ar

ea &

no. o

f pr

egs w

/in st

udy p

eriod

, ex

pecte

d no.

of pts

w/ a

SAH

durin

g pre

g, de

liv, o

r pue

r-pe

rium

was 1

2, re

sultin

g in

stand

ardiz

ed in

ciden

ce ra

tio

of 0.6

% (9

5% C

I 0.2

–1.1%

)

NAaS

AH ri

sk is

not in

cr du

ring

preg

, labo

r, or p

uerp

e-riu

m; no

need

to ad

vise

again

st pr

eg in

wom

en

w/ an

incr

risk o

f SAH

&

no ev

idenc

e to a

dvise

ag

ainst

vagin

al de

liv in

su

ch w

omen

Kim

et al.

, 20

13Re

tro co

hort

study

Ce

rebr

al an

eury

sms

in pr

egna

ncy a

nd

deliv

ery:

preg

nanc

y an

d deli

very

do no

t inc

reas

e the

risk

of

aneu

rysm

ruptu

re

1988

–200

971

4 RAs

in pr

eg,

172 R

As in

de

liv

NARu

pture

risk

s dur

ing pr

eg &

de

livs w

ere 1

.4% (9

5%

CI 1.

35–1

.57%

) & 0.

05%

(9

5% C

I 0.0

468–

0.063

4%),

resp

ectiv

ely

Of 21

8 deli

vs pe

rform

ed w

/ UA

, 153

wer

e C-s

ectio

n de

livs (

70.18

%, 9

5% C

I 64

.06–

76.3

0%),

sugg

est-

ing th

e rate

of C

-sec

tion

deliv

s in p

ts w/

UAs

is

signifi

cantl

y high

er th

an

in ge

nera

l pop

ulatio

n (p

5

mm

but w

/o ble

bs,

irreg

ular s

hape

, high

-risk

loc

ation

, or in

cr as

pect

ratio

are a

lso at

low

risk

of ru

pture

& ar

e not

likely

to

chan

ge du

ring p

reg

CONT

INUE

D ON

PAG

E 5

»


Desai et al.


TABL

E 1.

Seve

n ep

idem

iolo

gica

l stu

dies

on

preg

nanc

y and

cere

bral

aneu

rysm

s

Auth

ors &

Ye

arSt

udy T

ype

Title

Yrs

Samp

le Si

zeM

atern

al Ag

e &

Gesta

tiona

l Age

Relat

ive R

iskVa

ginal

Birth

vs C

-Sec

tion

Conc

lusion

s

Yosh

ida et

al.

, 201

7Re

tro re

view

Stro

kes a

ssoc

iated

wi

th pr

egna

ncy

and p

uerp

erium

: a

natio

nwide

stud

y by

the J

apan

Stro

ke

Socie

ty

2012

–201

315

1 pre

g-as

soci-

ated s

troke

sNA

Caus

es &

freq

uenc

ies of

111

hemo

rrhag

ic str

okes

wer

e an

eury

sm, 2

2 (19

.8%);

AVM,

19 (1

7.1%)

; PIH

, 13

(11.7%

); HE

LLP

synd

rome

, 9

(8.1%

); ca

vern

ous a

ngiom

a, 8 (

7.2%)

; RCV

S, 5

(4.5%

); mo

yamo

ya di

seas

e, 2

(1.8%

), oth

er C

VDs,

8 (7.

2%);

other

obste

tric

comp

licati

ons,

7 (6.

3%);

& un

deter

mine

d, 18

(16.

2%)

NAM

ay be

diffe

renc

es in

pro-

porti

on of

hemo

rrhag

ic str

oke a

mong

preg

nant

Japa

nese

wom

en vs

wo

men i

n Wes

tern

coun

tries

Robb

a et a

l., 20

16Re

tro re

view

& lit

revie

w of

case

s

Aneu

rysm

al su

bara

ch-

noid

hemo

rrhag

e in

preg

nanc

y—ca

se

serie

s, re

view,

an

d poo

led da

ta

analy

sis

1995

–200

552

(7 fr

om re

tro

analy

sis of

int

erna

l dat

a &

45 fr

om lit

da

ta ex

trac-

tion)

31.5

± 5.

8 yrs

(ra

nge 2

0–42

; me

dian 3

1);

73.1%

(n =

38)

in

3rd t

rimes

ter,

19.2

% (n

=

10) in

2nd

seme

ster, &

7.7

% (n

= 4)

in

1st tr

imes

ter;

mean

gest

was

29.0

± 8.1

0 wks

(ra

nge 9

–39

wks,

media

n 32

wks)

Mea

n H&H

scor

e (8 c

ases

NA

) 2.7

± 0.9

(ran

ge 2–

5; me

dian 2

); Fis

her s

core

was

de

scrib

ed fo

r 67.3

% (n

= 3

5)

pts; o

f thes

e, 65

.7% (n

= 23

) ha

d Fish

er sc

ore I

V &

34.3%

(n

= 12

) had

Fish

er sc

ore

btwn

I & II

I; dist

ribut

ion of

an

eury

sms w

as in

76.9

%

of pts

in an

terior

circ

ulatio

n (n

= 15

ICA,

n =

9 MCA

, n =

6 AC

omA,

n =

2 ACA

, n =

7 PC

omA)

& 23

.0% in

ps

t circ

ulatio

n (n =

8 VA

, BA

, or P

ICA,

& n

= 4 P

CA);

aneu

rysm

occlu

sion w

as

achie

ved b

y sur

gical

clipp

ing

in 53

.8% of

case

s (n =

28) &

w/

endo

proc

edur

e in 3

6.5%

(n

= 19

)

Data

on m

ode o

f deli

v we

re av

ailab

le fo

r 49/

52

wome

n; 3 (

6.4%)

did n

ot de

liver

at al

l (1 ab

ortio

n &

2 dea

ths i

n uter

o); of

re

maini

ng 4

6 pts,

72.3%

(n

= 3

4) ha

d C-s

ectio

n, of

which

mor

e tha

n 70%

we

re em

erge

ncy p

roce

-du

res;

rema

ining

25.5%

(n

= 12

) had

vagin

al de

liv

RAs i

n pre

gnan

t pts

w/

aSAH

may

be sa

fely

se-

cure

d in t

imely

man

ner;

diagn

ostic

& Tx

stra

tegy

fo

r eac

h of th

ese p

ts sh

ould

cons

ider p

eculi

ar

mater

nal &

obste

tric

factor

s & re

quire

s mu

ltidisc

iplina

ry as

sess

-me

nt inv

olving

obste

t-ric

s, ne

uros

urge

ons,

& int

ensiv

ists

» CON

TINU

ED F

ROM

PAGE

4

CONT

INUE

D ON

PAG

E 6

»


Desai et al.


TABL

E 1.

Seve

n ep

idem

iolo

gica

l stu

dies

on

preg

nanc

y and

cere

bral

aneu

rysm

s

Auth

ors &

Ye

arSt

udy T

ype

Title

Yrs

Samp

le Si

zeM

atern

al Ag

e &

Gesta

tiona

l Age

Relat

ive R

iskVa

ginal

Birth

vs C

-Sec

tion

Conc

lusion

s

Roma

n et

al., 2

004

Case

serie

sSu

bara

chno

id he

morrh

age d

ue to

ce

rebr

al an

eury

s-ma

l rup

ture d

uring

pr

egna

ncy

1992

–200

08

31.5

± 4.

8 yrs;

6 p

ts we

re in

3r

d ges

tatio

nal

trime

ster, 1

in

2nd t

rimes

ter,

& 1 i

n 1st

trime

ster

Aneu

rysm

was

resp

onsib

le fo

r SAH

in 6

case

s & fo

r cr

anial

nerv

e pals

y by

aneu

rysm

al co

mpre

ssion

in

2 cas

es; s

urgic

al cli

pping

wa

s per

form

ed in

4 ca

ses;

2 pts

admi

tted w

/ gra

de II

I &

IV st

atus,

resp

ectiv

ely,

were

trea

ted 3

days

after

C-

secti

on w

hen s

tatus

had

impr

oved

; 1 pt

had s

urgic

al cli

pping

at 12

wks

’ ges

t; 1

pt ha

d ane

urys

mal s

urge

ry

befo

re de

liv, a

t 34 w

ks’ g

est,

but a

few

hrs l

ater C

-sec

tion

was p

erfo

rmed

; IVE

was

pe

rform

ed on

2 pts

Emer

genc

y C-s

ectio

n was

pe

rform

ed on

5 pts

w/

3rd t

rimes

ter ge

st &

it pr

eced

ed an

eury

sm Tx

in

4 cas

es; v

agina

l deli

v wa

s per

form

ed on

1 pt

who h

ad co

mplet

e an-

eury

smal

clipp

ing du

ring

1st tr

imes

ter &

in 1

pt w/

2n

d trim

ester

unde

tected

SA

H; th

ere w

as no

deliv

fo

r pt 7

due t

o dea

th of

fetus

, follo

wed a

few

hrs

later

by de

ath of

pt

If ges

tatio

nal a

ge al

lows i

t, im

media

te de

liv sh

ould

be pe

rform

ed w

hene

ver

poss

ible;

other

wise

, feta

l mo

nitor

ing sh

ould

be

perfo

rmed

syste

matic

al-ly;

C-s

ectio

n foll

owed

by

aneu

rysm

al Tx

appe

ars

to be

a wi

dely

acce

pted

strate

gy; o

utcom

e of p

ts w/

good

clini

cal s

tatus

is

as fa

vora

ble as

that

of no

npre

gnan

t ser

ies

Barb

arite

et

al., 2

016

Lit re

view

of ca

ses

The m

anag

emen

t of

intra

cran

ial

aneu

rysm

s dur

ing

preg

nanc

y: a s

ys-

temati

c rev

iew

1991

–201

544

NARu

pture

was

confi

rmed

on

imag

ing in

36 a

neur

ysms

(7

2%),

& mo

st an

eury

sms

ruptu

red d

uring

3rd

trim

ester

(7

7.8%)

; coil

embo

lizati

on

was a

ssoc

iated

w/ lo

wer

comp

licati

on ra

te th

an cl

ip-pin

g in p

ts w/

RAs

(9.5%

vs

23.1%

); fo

r pts

w/ U

As,

surg

ical m

anag

emen

t was

as

socia

ted w

/ 31.9

% fe

wer

comp

licati

ons v

s no T

x

Mos

t pts

unde

rwen

t C-

secti

on de

liv (8

4%),

& a

comb

ined n

euro

surg

ical

obste

trica

l pro

cedu

re

was u

sed f

or 8

pts w

/ RA

s nea

r ter

m

Tx of

intra

cran

ial an

eury

sms

durin

g pre

g is s

afe &

ef

fectiv

e; fu

rther

more

, en

do co

iling w

as su

g-ge

sted a

s 1st-

line T

x ove

r su

rgica

l clip

ping

ACA

= an

terio

r cer

ebra

l arte

ry; A

Com

A =

ante

rior c

ommu

nicat

ing ar

tery

; BA

= ba

silar

arte

ry; C

VD =

card

iovas

cular

dise

ase;

deliv

= de

liver

y; en

do =

endo

vasc

ular;

gest

= ge

statio

n; HE

LLP

= he

moly

sis, e

levate

d live

r en-

zyme

s, low

plat

elet c

ount;

H&H

= H

unt a

nd H

ess;

ICA

= int

erna

l car

otid

arte

ry; in

cr =

incr

ease

(d);

IVE

= int

rava

scula

r emb

oliza

tion;

lit =

litera

ture

; MCA

= m

iddle

cere

bral

arte

ry; N

A =

not a

vaila

ble; P

CA =

pos

terio

r cer

ebra

l ar

tery

; PCo

mA

= po

sterio

r com

munic

ating

arte

ry; P

ICA

= po

sterio

r infe

rior c

ereb

ellar

arte

ry; P

IH =

preg

nanc

y-ind

uced

hype

rtens

ion; p

reg =

preg

nanc

y; ps

t = p

oste

rior;

pt =

patie

nt; R

A =

rupt

ured

aneu

rysm

; RCV

S =

reve

rs-

ible c

ereb

ral v

asoc

onstr

iction

synd

rome

; ret

ro =

retro

spec

tive;

Tx =

trea

tmen

t; UA

= un

rupt

ured

aneu

rysm

; VA

= ve

rtebr

al ar

tery.

» CON

TINU

ED F

ROM

PAGE

5


Desai et al.


TABL

E 2.

Thr

ee ca

se se

ries o

n ce

rebr

al an

eury

sm ru

ptur

e and

trea

tmen

t/man

agem

ent i

n pr

egna

ncy

Auth

ors &

Ye

arTy

pe of

St

udy

Title

No. o

f Ca

ses

Mate

rnal

Age &

Ge

statio

nal A

geCl

inica

l Pre

sent

ation

& Tx

Vagin

al De

liv vs

C-S

ectio

nCo

nclus

ions

Kizil

kilic

et al.

, 200

3Ca

se se

ries

Endo

vasc

ular t

reatm

ent

of ru

pture

d intr

acra

-nia

l ane

urys

ms du

ring

preg

nanc

y: re

port

of th

ree c

ases

325

, 26,

& 39

yrs

at 10

, 18,

& 28

wk

s’ ge

st

Aneu

rysm

s tre

ated i

n pre

g w/ G

DCs:

1) H&

H gr

ade 2

PCo

mA,

10 ×

7 mm

; 2)

H&H

grad

e 2 lt

ICA,

20 ×

12 m

m; 3)

H&

H gr

ade 1

ACo

mA,

2 ×

3 mm

1 pt’s

aneu

rysm

aros

e dur

ing

fetal

perio

d (8t

h wk o

f pr

eg);

electi

ve ab

ortio

n was

pe

rform

ed du

e to p

roba

ble

injur

y to f

etus f

rom

radia

tion

expo

sure

Preg

nant

wome

n can

be su

cces

sfully

tre

ated f

or ru

pture

d intr

acra

nial

aneu

rysm

s w/ e

ndo a

ppro

ach

Pioti

n et a

l., 20

01Ca

se se

ries

Endo

vasc

ular t

reatm

ent

of ac

utely

ruptu

red i

n-tra

cran

ial an

eury

sms

in pr

egna

ncy

228

yrs a

t 32 w

ks’

gest,

31 yr

s at

22 w

ks’ g

est

Aneu

rysm

s tre

ated i

n pre

g w/ G

DCs:

1) 4-

mm an

eury

sm at

bifu

rcati

on of

rt

ICA;

embo

lizati

on pr

oced

ure p

er-

form

ed w

/ sup

erse

lectiv

e cath

eteriz

a-tio

n of a

neur

ysm

unde

r fluo

rosc

opic

contr

ol; 2)

8-m

m an

eury

sm of

rt

supr

aclin

oid ca

rotid

arter

y; w/

pt un

-de

r gen

eral

anes

thes

ia &

w/ sh

ieldin

g of

fetus

, sup

erse

lectiv

e cath

eteriz

a-tio

n of a

neur

ysm

allow

ed an

eury

sm

occlu

sion w

/ plat

inum

GDCs

1) C-

secti

on be

fore

endo

Tx of

an

eury

sm; 2

) vag

inal d

eliv

after

endo

Tx of

aneu

rysm

Succ

essfu

l mate

rnal

& fet

al ou

tcome

s we

re ac

hieve

d in b

oth ca

ses w

/o cr

aniot

omy &

aneu

rysm

al su

rgica

l ex

posu

re

Mey

ers e

t al.

, 200

0Ca

se se

ries

Endo

vasc

ular t

reatm

ent

of ce

rebr

al ar

tery

aneu

rysm

s dur

ing

preg

nanc

y: re

port

of th

ree c

ases

334

yrs a

t 33 w

ks’

gest;

36 y

rs,

mid-

3rd t

rimes

-ter

; 36 y

rs, la

te 3r

d trim

ester

(in

labor

)

1) pte

riona

l cra

niotom

y rev

ealed

fusi-

form

aneu

rysm

, whic

h cou

ld no

t be

direc

tly cl

ipped

durin

g 11th

wk,

then

co

iling i

n 33r

d wk f

usifo

rm an

eury

sm

of pr

oxim

al rt

PCA;

2) 7-

mm ba

silar

ter

minu

s ane

urys

m &

1.4-m

m lt

supe

rior c

ereb

ellar

aneu

rysm

, 4

GDC-

10 co

ils de

ploye

d, re

sultin

g in

comp

lete o

cclus

ion of

basil

ar te

rmi-

nus a

neur

ysm;

3) 7-

mm an

eury

sm in

rt

PCom

A, 4

GDC-

10 co

ils, p

rodu

cing

comp

lete o

cclus

ion af

ter C

-sec

tion

deliv

1) va

ginal

deliv

; 2) u

nkno

wn;

3) C

-sec

tion o

f twi

ns be

fore

en

do Tx

of an

eury

sm

Limite

d alte

ratio

ns in

mate

rnal-

fetal

phys

iolog

y, low

relat

ive ri

sk of

sig-

nifica

nt ra

diatio

n exp

osur

e to f

etus

when

appr

opria

te tec

hniqu

es ar

e ob

serv

ed, &

succ

essfu

l outc

omes

su

gges

t end

o app

roac

h to a

neu-

rysm

s dur

ing pr

eg is

war

rante

d &

may b

e les

s inv

asive

to bo

th mo

ther

& fe

tus th

an co

nven

tiona

l ne

uros

urge

ry


Desai et al.


for open craniotomy.13,17,21 Endovascular treatment occurred before vaginal deliveries, as well as after C-section deliver-ies.13,17,21 Time of endovascular treatment ranged from 1st, 2nd, and 3rd trimester of gestation; the only adverse preg-nancy outcome reported was an elective abortion after suc-cessful endovascular treatment of an aneurysm during the 8th week of gestation due to concern for fetal injury from radiation exposure.13

Epidemiological Studies of Female Sex Steroids and Cerebral Aneurysms

Three epidemiological articles reporting the relation-ship between female sex steroids and cerebral aneurysms through retrospective case-control studies were included. A full description of results from these investigations can be found in Table 3. In 76 postmenopausal women with ce-rebral aneurysms compared to matched controls, both later menopause age (odds ratio [OR] 0.79, 95% CI 0.63–0.996, p = 0.046) and ever use of hormone replacement thera-py (HRT; OR 0.23, 95% CI 0.13–0.42, p < 0.0001) were significantly associated with a lower risk of aneurysm in women in the case group.6 Conversely, and showing the same results, in 60 postmenopausal women with intradu-ral aneurysms compared to matched controls, there was a significant association between a lower rate of oral contra-ceptive (OR 2.1, 95% CI 1.17–3.81, p = 0.01) and HRT (OR 3.09, 95% CI 1.54–6.22, p = 0.002) use and the presence of a cerebral aneurysm.3 In a study of 233 women in which 43 had hysterectomies, the women with a history of hyster-ectomy had fewer large aneurysms (8% vs 24%, p = 0.03), and fewer presented with a ruptured aneurysm (28%) than the nonhysterectomy group (51%, p = 0.004).20

Experimental (animal and cell model) Studies Investigating Female Sex Steroids and Cerebral Aneurysms

Seven experimental studies using animal and/or cell models to understand the relationship between female sex steroids and cerebral aneurysms were included. A full de-scription of results from these experimental investigations can be found in Table 4. All 7 studies used in vivo experi-ments, with 1 study using both in vivo and in vitro (human brain microvascular endothelial cell [HBMEC]) experi-ments. Four studies used rat models, 2 studies used mice models, and 1 study used a rabbit model, for a total of 264 animals in the experimental groups, and a total of 98 ani-mals in the control groups. Mechanisms to create cerebral aneurysms in animal models were ligation of a common carotid artery (CCA) and bilateral posterior renal arter-ies,7–9,27 hypertensive diet, and angiotensin II,7 and injec-tion of elastase into the CSF with deoxycorticosterone ac-etate salt hypertension.26 Estrogen deficiency was induced through bilateral oophorectomy7–9,15,26,27 and estrogen E2 receptor blockade.7 Ovariectomized female mice had a sig-nificantly higher incidence of aneurysms than male mice with sham ovariectomy,26 and 3 times higher incidence of cerebral aneurysm formation than females without bilat-eral oophorectomy.8 Estrogen deficiency has been shown to cause endothelial dysfunction, which may lead to changes in vascular wall integrity and contribute to aneurysm for-mation. Aneurysm changes in animal models with oopho-

rectomy and HRT were limited to stage I or II, whereas most changes in animal models with oophorectomy but no HRT were identified as saccular dilation (stage III).9 Estrogen deficiency induced endothelial dysfunction and reactive oxygen species generation in animal models and HBMECs, which triggered endothelial damage that led to cerebral aneurysms.27 Estrogen deficiency may lead to in-flammatory changes that contribute to aneurysm rupture. Estrogen-deficient mice had more aneurysm ruptures than control mice, and were found to upregulate IL-17A, which downregulates E-cadherin, encouraging macrophage in-filtration in the aneurysm vessel wall.7 Hypertension is an additional risk factor for aneurysm development in animal models with estrogen deficiency.9,31 Animal models with estrogen deficiency and induced hypertension had signifi-cantly higher vascular damage scores in multiple regions of the circle of Willis, signifying that hypertension and estro-gen deficiency make the circle of Willis more vulnerable to flow-induced aneurysmal remodeling and tortuosity.31 While estrogen deficiency itself has been reported by the previously mentioned studies to increase risk for cerebral aneurysm complications, exogenous estrogen treatment in an estrogen-deficient state has been shown to be protective from cerebral aneurysm complications in the following 3 studies. Treatment with estradiol,7 a selective estrogen re-ceptor modulator such as bazedoxifene,15 and estrogen26 was shown to decrease the amount of aneurysm ruptures in animal models of estrogen deficiency.

DiscussionSex differences in the care of patients with cerebral

aneurysms provide a unique opportunity for collabora-tion among multiple physician specialties: neurosurgeons, obstetricians/gynecologists, perinatologists, anesthesiolo-gists, radiologists, intensivists, and primary care provid-ers. This systematic review describes the spectrum of risk for women in pregnancy and in estrogen-deficient states (i.e., menopause, surgical oophorectomy, etc.) and provides readers with the information that female sex steroids may impact women and their cerebrovascular anatomy differ-ently at different stages of their life.

Studies included in this review suggest that the rate of aneurysm rupture in pregnancy is not increased compared to the general population. Neurosurgeons can be prepared to manage pregnant women with aneurysms similarly to the general population. As our review indicated, it may not be necessary to advise pregnant women with cerebral an-eurysms against vaginal deliveries, and obstetricians can use these data to collaborate with neurosurgeon colleagues and provide risk stratification to their patients according-ly.11,30 An older study from 1990 reports a fetal case fatality rate of approximately 17% as a result of ruptured intracra-nial aneurysms in pregnancy.5 A more recent retrospective review of case reports describes a fetal case fatality rate of approximately 6.5%.23 In reviewing published papers, stud-ies have not commented extensively on adverse pregnancy outcomes through the natural history of a patient with a ruptured aneurysm or through treatment, perhaps because study design is limited to retrospective and case-series for-mats. We hypothesize that fetal case fatality rates have de-


Desai et al.


TABL

E 3.

Thre

e epi

dem

iolo

gica

l stu

dies

on

fem

ale s

ex st

eroi

ds an

d ce

rebr

al an

eury

sms i

n wo

men

Auth

ors &

Ye

arTy

pe of

St

udy

Title

Yrs

Samp

le Si

zeAg

eRe

lative

Risk

Conc

lusion

s

Niss

on et

al.

, 201

8Re

tro ca

se-

contr

olCe

rebr

al an

eury

sms

differ

in pa

tients

wi

th hy

stere

cto-

mies

2010

–201

323

3: his

tory p

ositiv

e for

hy

stere

ctomy

was

pres

-en

t in 18

.5% (4

3/23

3) of

stu

dy po

pulat

ion, n

one

had o

opho

recto

mies

re

cord

ed; o

nly fe

male

pts &

pts e

qual

or ol

der

in ag

e to y

oung

est p

t in

hyste

recto

my gr

oup w

ere

includ

ed in

contr

ol gr

oup

NAPt

s in h

yster

ectom

y gro

up m

ore o

ften

pres

ented

in go

od ne

urolo

gical

cond

ition b

efore

surg

ery (

88%

vs

74%

, p =

0.04

) & ha

d few

er la

rge

aneu

rysm

s (8%

vs 24

%, p

= 0.

03);

fewer

pres

ented

w/ R

A (2

8%) t

han

nonh

yster

ectom

y gro

up (5

1%, p

=

0.004

); 7.7

% (3

/39)

of hy

stere

c-tom

y pts

had l

arge

aneu

rysm

s vs

23.7%

(40/1

69) in

nonh

yster

ec-

tomy g

roup

Fema

le pts

w/ s

urgic

al his

tory o

f hy

stere

ctomy

have

lowe

r rate

s of

large

aneu

rysm

s, pr

esen

t in be

tter

neur

ologic

al co

nditio

n, &

are

less l

ikely

to pr

esen

t w/ R

A th

an

female

s w/o

hyste

recto

my

Ding

et al

., 20

13Re

tro ca

se-

contr

olYo

unge

r age

of

meno

paus

e in

wome

n with

cere

-br

al an

eury

sms

2007

– 201

176

postm

enop

ausa

l wom

en

w/ ce

rebr

al an

eury

sms

(und

er ca

re of

sing

le ph

y-sic

ian);

case

grou

p dat

a we

re m

atche

d w/ th

ose o

f co

ntrol

grou

p for

age (

in ca

tego

ries o

f <45

, 45–

54,

& >5

4 yrs)

& ed

ucati

on

level

(≤12

th gr

ade,

>12t

h gr

ade)

Age a

t men

opau

se w

as

subd

ivide

d into

prem

a-tur

e men

opau

se (<

40

yrs),

early

men

opau

se

(41–4

4 yrs)

, nor

mal

meno

paus

e (45

–55

yrs),

& la

te me

nopa

use

(>56

yrs)

Both

later

men

opau

se ag

e (OR

0.79

, 95

% C

I 0.6

3–0.9

96, p

= 0.

046)

&

ever

use o

f HRT

(OR

0.23

, 95%

CI

0.13

–0.42

, p <

0.000

1) we

re si

g-nifi

cantl

y ass

ociat

ed w

/ lowe

r risk

of

aneu

rysm

in w

omen

in th

e cas

e gr

oup;

for e

ach c

atego

rical

incr in

me

nopa

use a

ge, r

isk of

cere

bral

aneu

rysm

decr

by 21

%

Tren

d sho

wing

that

earlie

r age

at

meno

paus

e is a

ssoc

iated

w/

pres

ence

of ce

rebr

al an

eury

sm;

this

sugg

ests

that

loss o

f estr

ogen

ea

rlier in

a wo

man’s

life m

ay co

n-tri

bute

to pa

thog

enes

is of

cere

bral

aneu

rysm

; thes

e dat

a may

iden

tify

a risk

facto

r for

cere

bral

aneu

rysm

pa

thog

enes

is &

also a

poten

tial

targ

et fo

r futu

re th

erap

iesCh

en et

al.,

2011

Retro

case

-co

ntrol

Oral

contr

acep

tive

and h

ormo

ne

repla

ceme

nt th

erap

y in w

omen

wi

th ce

rebr

al an

eury

sms

2008

–201

060

wom

en w

/ intra

dura

l ce

rebr

al an

eury

sms

NAM

ultiva

riate

logist

ic re

gres

sion

show

ed si

gnific

ant a

ssoc

iation

bt

wn lo

wer r

ate of

oral

contr

a-ce

ptive

use (

OR 2.

1, 95

% C

I 1.1

7–3.

81, p

= 0.

01) &

HRT

(OR

3.09

, 95%

CI 1

.54–

6.22

, p =

0.0

02) &

pres

ence

of ce

rebr

al an

eury

sm

Thes

e dat

a sug

gest

that

expo

sure

to

exog

enou

s estr

ogen

agen

ts in

wome

n is a

ssoc

iated

w/ lo

wer

frequ

ency

of ce

rebr

al an

eury

sms

decr

= de

crea

se(d

).


Desai et al.


TABL

E 4.

Seve

n ex

perim

enta

l stu

dies

usin

g an

imal

and/

or ce

ll mod

els t

o un

ders

tand

the r

elat

ions

hip

betw

een

fem

ale s

ex st

eroi

ds an

d ce

rebr

al an

eury

sms

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

elEx

perim

enta

l Gro

upCo

ntrol

Grou

pFin

dings

Conc

lusion

s

Hoh e

t al.,

2018

Estro

gen d

eficie

ncy

prom

otes c

ereb

ral

aneu

rysm

ruptu

re

by up

regu

lation

of

Th17

cells

and

inter

leukin

-17A

which

down

regu

-lat

es E

-cad

herin

In viv

oMi

ceCe

rebr

al an

eury

sm

(lt CC

A &

rt re

nal

arter

y wer

e liga

t-ed

, hyp

erten

sive

diet, a

ngiot

ensin

II)

; estr

ogen

de

ficien

cy (O

VE

or by

estro

gen

E2 re

cepto

r blo

ckad

e)

1819

Estro

gen d

eficie

ncy u

preg

ulates

Th1

7 ce

lls &

IL-17

A &

prom

otes a

neu-

rysm

ruptu

re; e

strog

en-d

eficie

nt mi

ce ha

d mor

e rup

tures

than

co

ntrols

(47%

vs 7%

, p =

0.04

); es

tradio

l sup

pleme

ntati

on or

IL-17

A inh

ibitio

n dec

r the

no. o

f rup

tures

in

estro

gen-

defic

ient m

ice (e

strad

iol

6% vs

37%

, p =

0.04

; IL-1

7A in

hibi-

tion 1

8% vs

47%

, p =

0.01

8)

Estro

gen d

eficie

ncy p

ro-

motes

cere

bral

aneu

rysm

ru

pture

by up

regu

lating

IL-

17A,

whic

h dow

nreg

ulates

E-

cadh

erin,

enco

urag

ing

macr

opha

ge in

filtra

tion i

n an

eury

sm ve

ssel

wall

Mae

kawa

et

al., 2

017

Baze

doxif

ene,

a se

lectiv

e estr

ogen

re

cepto

r mod

ulator

, re

duce

s cer

ebra

l an

eury

sm ru

pture

in

ovar

iectom

ized

rats

In viv

oRa

tCe

rebr

al an

eury

sm

& es

troge

n de

ficien

cy (O

VE,

hemo

dyna

mic

chan

ges,

& HT

N)

n = 8

4; 28

vehic

le,

28 0.

3 mg/

kg/da

y BZ

A, 28

1.0 m

g/kg

/day B

ZA

28Du

ring 1

2-wk

obse

rvati

on, in

ciden

ce

of an

eury

sm ru

pture

was

52%

in

ovar

iectom

ized r

ats; w

/ no e

ffect

on bl

ood p

ress

ure,

Tx w

/ 0.3

or 1.

0 mg

/kg/da

y BZA

lowe

red t

his ra

te to

11%

& 17

%, a

lmos

t the s

ame a

s in

HTN

rats

(17%)

BZA

decr

the i

ncide

nce

of an

eury

sm ru

pture

in

ovar

iectom

ized r

ats

Tutin

o et a

l., 20

15Hy

perte

nsion

and

estro

gen d

eficie

ncy

augm

ent a

neur

ys-

mal re

mode

ling i

n th

e rab

bit ci

rcle

of W

illis i

n res

pons

e to

caro

tid lig

ation

In viv

oRa

bbit

Intra

cran

ial an

eu-

rysm

& es

troge

n de

ficien

cy (H

TN

& es

troge

n defi

-cie

ncy,

then

bilat

CC

A lig

ation

)

83,

ligati

on on

ly Co

mpar

ed to

ligati

on-o

nly ra

b-bit

s, lig

ation

+ H

TN &

estro

gen

defic

iency

grou

p had

sign

ifican

tly

highe

r vas

cular

dama

ge sc

ore i

n 3 r

egion

s: BA

(16.

8 ± 2.

9 vs 7

.8 ±

1.8

, p =

0.02

5), S

CA or

igin (

10.6

± 1.6

vs 5.

6 ± 1.

2, p =

0.02

5), &

PC

omA

origi

n (11

.1 ±

1.5 vs

6.6 ±

1.2

, p =

0.03

1)

HTN

& es

troge

n defi

cienc

y ma

ke ci

rcle

of W

illis m

ore

vulne

rable

to flo

w-ind

uced

an

eury

smal

remo

delin

g &

tortu

osity

; we p

ropo

se

they

do so

by lo

werin

g to

leran

ce of

vasc

ular

tissu

e to h

emod

ynam

ic fo

rces

caus

ed by

CCA

lig

ation

, thus

lowe

ring t

he

thre

shold

nece

ssar

y to

incite

vasc

ular d

amag

eTa

da et

al.,

2014

Roles

of es

troge

n in

the f

orma

tion

of int

racr

anial

aneu

-ry

sms i

n ova

riecto

-mi

zed f

emale

mice

In viv

oMi

ceInt

racr

anial

aneu

-ry

sms (

single

inj

ectio

n of e

las-

tase

into

CSF

w/

deox

ycor

ticos

te-

rone

acet

ate sa

lt HT

N)

3 fem

ale m

ice w

/ bil

at OV

E (su

rgica

l me

nopa

use),

4 ov

ariec

tomize

d fem

ale m

ice w

/ es

troge

n Tx (

surg

i-ca

l men

opau

se +

es

troge

n rep

lace-

ment)

1 male

mou

se

w/ sh

am O

VE

(lapa

rotom

y),

2 fem

ale m

ice

w/ sh

am O

VE

Ovar

iectom

ized f

emale

mice

had

signifi

cantl

y high

er in

ciden

ce of

an-

eury

sms t

han m

ale m

ice w

/ sha

m OV

E (5

9% vs

15%

, p <

0.01);

ther

e wa

s also

a tre

nd fo

r estr

ogen

Tx to

re

duce

incid

ence

of an

eury

sms i

n ov

ariec

tomize

d fem

ale m

ice (3

8%

vs 59

%, p

= 0.

06)

Resu

lts ar

e con

sisten

t w/

epide

miolo

gical

studie

s th

at sh

owed

fema

le pr

e-po

nder

ance

of an

eury

sms

after

perim

enop

ausa

l age

CONT

INUE

D ON

PAG

E 11

»


Desai et al.


TABL

E 4.

Seve

n ex

perim

enta

l stu

dies

usin

g an

imal

and/

or ce

ll mod

els t

o un

ders

tand

the r

elat

ions

hip

betw

een

fem

ale s

ex st

eroi

ds an

d ce

rebr

al an

eury

sms

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

elEx

perim

enta

l Gro

upCo

ntrol

Grou

pFin

dings

Conc

lusion

s

Jamo

us et

al.

, 200

59Ro

le of

estro

gen

defic

iency

in th

e fo

rmati

on an

d pro

-gr

essio

n of c

ereb

ral

aneu

rysm

s. Pa

rt I: e

xper

imen

tal

study

of th

e effe

ct of

ooph

orec

tomy

in ra

ts

In viv

oRa

tCe

rebr

al an

eury

sm

(ligati

on of

rt C

CA

& bil

at ps

t ren

al ar

teries

, OVX

)

30 ra

ts in

grou

ps II

& III

unde

rwen

t lig

ation

of rt

CCA

&

bilat

pst r

enal

ar-

teries

; 1 m

o afte

r lig

ation

proc

edur

e, gr

oup I

I rats

un

derw

ent O

VX

15; g

roup

I con

-sis

ted of

inta

ct fem

ales

Incid

ence

of ce

rebr

al an

eury

sm

form

ation

in gr

oup I

I (60

%) w

as 3×

hig

her t

han t

hat in

grou

p III (

20%)

, &

mean

aneu

rysm

size

in gr

oup I

I (m

ean 7

6 ± 27

μm) w

as la

rger

than

th

at in

grou

p III (

28 ±

4.6 μ

m; p

Desai et al.


TABL

E 4.

Seve

n ex

perim

enta

l stu

dies

usin

g an

imal

and/

or ce

ll mod

els t

o un

ders

tand

the r

elat

ions

hip

betw

een

fem

ale s

ex st

eroi

ds an

d ce

rebr

al an

eury

sms

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

elEx

perim

enta

l Gro

upCo

ntrol

Grou

pFin

dings

Conc

lusion

sTa

mura

et

al., 2

009

Endo

theli

al da

mage

du

e to i

mpair

ed

nitric

oxide

bioa

vail-

abilit

y trig

gers

ce

rebr

al an

eury

sm

form

ation

in fe

male

rats

In viv

o &

in vit

ro

Rat, HB

MEC

sCe

rebr

al an

eury

sm

(ligati

on of

rt C

CA

& bil

at ps

t ren

al ar

teries

, OVX

)

Hype

rtens

ive ra

ts (n

= 20

), OV

X (n

=

18),

ooph

orec

-tom

ized h

yper

-ten

sive (

n = 18

), oo

phor

ectom

ized

hype

rtens

ive w

/ HR

T (n

= 15

), oo

phor

ectom

ized

hype

rtens

ive ra

ts w/

ARB

(n =

16)

15 sh

amIn

ciden

ce of

aneu

rysm

al ch

ange

s (h

igher

than

stag

e I) w

as hi

gher

in

OVX

& oo

phor

ectom

ized h

yper

-ten

sive t

han i

n hyp

erten

sive r

ats

(p <

0.05 v

s HTN

), su

gges

ting t

hat

OVX

marke

dly ex

acer

bated

endo

-th

elial

dama

ge; 1

/2 of

ooph

orec

to-

mize

d hyp

erten

sive r

ats de

velop

ed

sacc

ular a

neur

ysms

(sta

ge II

I); th

is wa

s tru

e for

10%

of hy

perte

nsive

ra

ts &

17%

of O

VX ra

ts (p

<0.0

5);

signifi

cantl

y few

er oo

phor

ectom

ized

hype

rtens

ive ra

ts re

ceivi

ng H

RT

than

untre

ated o

opho

recto

mize

d hy

perte

nsive

rats

exhib

ited c

ereb

ral

aneu

rysm

al ch

ange

s (p <

0.05)

; th

ere w

as no

stati

stica

l diffe

renc

e bt

wn un

treate

d & A

RB-tr

eated

oo

phor

ectom

ized h

yper

tensiv

e rats

; inc

idenc

e of s

accu

lar an

eury

sms

was s

ignific

antly

lowe

r in oo

phor

ec-

tomize

d hyp

erten

sive r

ats re

ceivi

ng

HRT

or A

RB th

an in

ooph

orec

to-

mize

d hyp

erten

sive r

ats re

ceivi

ng

no Tx

(p <

0.05)

Resu

lts su

gges

t that

estro

-ge

n defi

cienc

y ind

uces

en

doth

elial

dysfu

nctio

n &

reac

tive O

2 spe

cies

gene

ratio

n, tri

gger

ing

endo

theli

al da

mage

that

leads

to ce

rebr

al an

eu-

rysm

s, &

that

HTN

is ad

-dit

ional

risk f

actor

; ther

apy

targ

eted a

t end

otheli

um

& ma

nage

ment

of HT

N ma

y help

prev

ent c

ereb

ral

aneu

rysm

s

ARB

= an

giote

nsin

II rec

epto

r bloc

ker;

BZA

= ba

zedo

xifen

e; HT

N =

hype

rtens

ion; O

VE =

ovar

iecto

my; O

VX =

bilat

eral

ooph

orec

tomy

; SCA

= su

perio

r cer

ebell

ar ar

tery.

» CON

TINU

ED F

ROM

PAGE

11


Desai et al.


creased due to advancements in obstetric care, but further research is needed to evaluate this topic.

Based on the data that we present, we have created a diagrammatic algorithm of how to approach a patient who presents with an incidental aneurysm diagnosed during pregnancy (Fig. 2). We conclude that if unruptured intra-cranial aneurysms in pregnancy are stable and asymptom-atic, they may be observed. Symptomatic and/or enlarging unruptured aneurysms may be treated on an individual basis. Ruptured intracranial aneurysms in pregnancy are treated as they would be in nonpregnant patients. Neuro-surgical considerations generally take precedence over obstetric considerations for ruptured, symptomatic, and/or growing intracranial aneurysms. Surgical clipping has historically been accepted as the treatment for ruptured in-tracranial aneurysms during pregnancy, but endovascular coiling is now believed to be a safe treatment and may be preferred to clipping. Because there are no prospective or randomized controlled trials investigating this subject, we rely on retrospective and case report data to inform our clinical decision-making. We have included 2 studies that address this topic. In a retrospective cohort analysis, en-dovascular coiling had lower mortality rates in pregnant women with ruptured aneurysms compared to clipping.11 In a previous literature review, endovascular coiling was found to have lower complication rates than surgical clip-ping in pregnant women with ruptured aneurysms.1 In both studies, surgical management of ruptured intracranial an-eurysms during pregnancy was found to be superior to no treatment. Considerations for endovascular coiling of in-tracranial aneurysms during pregnancy include concern for harmful effects of radiation to the fetus and potential

harmful effects of anticoagulation. Given that the probabil-ity of radiation damage increases with increasing absorbed dose, the radiation dose and stage of fetal development at the time of exposure should be evaluated for endovascu-lar coiling procedures during pregnancy. An International Commission on Radiation Protection report recommended that with optimized abdominal lead shielding, coiling-re-lated fetal radiation can be neglected.29 In the studies we include that used coiling for ruptured aneurysms, radiation exposure was limited through abdominal lead shielding, limited fluoroscopy in proximity to the uterus, and precau-tions to limit radiation exposure to the patient as well as adequate fetal monitoring.11,14,17 Regarding anticoagulation during the endovascular procedure, heparin is not terato-genic and has previously been used for coiling of ruptured intracranial aneurysms during pregnancy, but would need to be discontinued before a C-section.14 Further research is needed to evaluate additional endovascular treatment op-tions such as stent-assisted coiling during pregnancy, and whether aspirin and/or clopidogrel are safe to use in this setting.

This review elucidates the potential with which neuro-surgeons and gynecologists can determine how estrogen deficiency contributes to endothelial dysfunction and in-flammation, which may lead to cerebral aneurysm forma-tion, growth, and rupture as reported by multiple studies in this review. Estrogen HRT is commonly used among postmenopausal women, and this review presents animal data that suggest improvement in aneurysmal outcomes with HRT.3,6 Hormonal therapies and the effect of targeted drugs on cerebral aneurysms should be further studied in human clinical trials.

FIG. 2. Diagrammatic algorithm of how to clinically approach a patient who presents with an incidental aneurysm diagnosed during pregnancy. *Can use MRI to evaluate aneurysm growth during pregnancy. Further research is necessary to elucidate size cutoffs that are clinically meaningful in this population. **Coiling thought to be a safe treatment and may be preferred to clipping in pregnancy. Consider abdominal lead shielding and radiation exposure. ***There is no evidence to suggest that maternal or fetal outcome is improved by C-section delivery in comparison with closely supervised vaginal delivery.


Desai et al.


Our review suggests that estrogen deficiency in ani-mal models contributes to aneurysm formation and rup-ture.7,8,26,27,31 Pregnancy is a high-estrogen state, which might suggest less aneurysm formation and rupture during this time through the findings of estrogen as a protective cerebrovascular factor in animal studies. However, our review of epidemiological data in pregnant women with cerebral aneurysms shows a similar rate of rupture as the general population. In addition to hormonal and hemody-namic factors, there may be additional factors inherent to pregnancy that raise the risk of aneurysm rupture com-pared to that of the general population, despite a high es-trogen state during pregnancy. We hope this review article encourages additional longitudinal research in prospective cohorts to further characterize the underlying causes of pregnancy and sex steroid effects on cerebral aneurysms.

ConclusionsThe mechanisms of cerebral aneurysm formation,

growth, and rupture during pregnancy and in estrogen-de-ficient states are complex. This review article summarizes the current literature of hormonal- and pregnancy-related risks for cerebral aneurysms, and can help guide clinical decision-making for both neurosurgeons and obstetricians and multiple members of the healthcare team about treat-ment and management options for pregnant women with cerebral aneurysms. This article helps readers understand the current research on estrogen deficiency contributing to vascular abnormalities, and the future research of targeted drugs and therapies to prevent aneurysmal growth and rup-ture. Given the sex differences in cerebral aneurysms, this review article allows readers to understand risk prediction for individual patients and populations of women with ce-rebral aneurysms at various stages of their life, from preg-nancy to menopause.

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3. Chen M, Ouyang B, Goldstein-Smith L, Feldman L: Oral contraceptive and hormone replacement therapy in women with cerebral aneurysms. J Neurointerv Surg 3:163–166, 2011

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28. Tanaka H, Katsuragi S, Tanaka K, Iwanaga N, Yoshimatsu J, Takahashi JC, et al: Impact of pregnancy on the size of small cerebral aneurysm. J Matern Fetal Neonatal Med 30:2759–2762, 2017

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DisclosuresThe authors report no conflict of interest concerning the materi-als or methods used in this study or the findings specified in this paper.

Author ContributionsConception and design: Khalessi, Desai, Wali, Santiago-Dieppa. Acquisition of data: Desai, Wali. Analysis and interpretation of data: Desai, Wali, Santiago-Dieppa. Drafting the article: all authors. Critically revising the article: Khalessi, Desai, Wali, Santiago-Dieppa. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Khalessi. Statistical analysis: Desai, Wali. Administrative/technical/material support: Khalessi, Desai, Wali. Study supervision: Khalessi, Desai, Wali.

CorrespondenceAlexander A. Khalessi: University of California, San Diego, CA. [email protected].


Documents

Role of pregnancy and female sex steroids on aneurysm ... · for cerebral aneurysm formation, growth, and rup-ture. Female sex has been studied as a significant indepen-dent risk