DOI: 10.1161/CIRCULATIONAHA.116.

021594

Pregnancy and the Risk of Aortic Dissection or Rupture:

A Cohort-Crossover Analysis

Running title: Kamel et al; Pregnancy and Aortic Dissection or Rupture

Hooman Kamel, MD1,2; Mary J. Roman, MD3; Alex Pitcher, MD, DPhil4;

Richard B. Devereux, MD3

1
Department of Neurology, 2Feil Family Brain and Mind Research Institute, and 3Division of

Cardiology,
Card
Ca rdiology
rd gy,, We
gy rk, NY; 4Radcli
Weill Cornell Medicine, New York
York, Radcliffe
ifffe De
Dep
Department
partment of Medicine,

Divisi
Division
ion of
of Cardiovascular
Card
rdiovascula
rd lar Medicine,
Mediccin
ne,, University
Uniiveers
rsit
ityy of Oxford,
it Oxforrd, Oxford,
Oxford, UK
UK

Address for Correspondence:

Hooman Kamel, MD
Weill Cornell Medicine
407 East 61st St
New York, NY 10065 USA
Phone: 212-746-0225; fax: 212-746-5509
hok9010@med.cornell.edu

Journal Subject Terms: Pregnancy; Aortic Dissection

1
 DOI: 10.1161/CIRCULATIONAHA.116.021594

Abstract

Background—Case series have described aortic dissection and rupture in pregnancy. Few
population-based data exist to support an association.
Methods—We performed a cohort-crossover study using data on all emergency department
visits and acute care hospitalizations at nonfederal healthcare facilities in California, Florida, and
New York. We included women t12 years of age with labor and delivery or abortive pregnancy
outcome between 2005 and 2013. Our outcome was a composite of aortic dissection or rupture.
Based on the timing of reported aortic complications during pregnancy, we defined the period of
risk as 6 months before delivery until 3 months after delivery. We compared each patient’s
likelihood of aortic complications during this period to an equivalent 270-day period exactly 1
year later. Incidence rates and incidence rate ratios were computed using conditional Poisson
egression with robust standard errors.
regression
Results—Among
— 6,566,826 pregnancies in 4,933,697 women, we identified 36 cases off aortic
aortiic
dissection or rupture during the pregnancy or postpartum period and 9 cases during the control
periodd 1 year
yea
earr later.
l ter.
la r. The rate of aortic complications
complicationns was 5.5 (95%
% confi
fide
d nce interval [CI], 4.0-
confidence
7.8)) pper
er million
onn pat
atie
at i nt
ntss du
patients duri
ring
ng ppregnancy
during regn
re g an
gn anccy andd the
t e postpartum
th post
stpa
st part
pa rtum
rt um pperiod,
e io
eriod,
d coomp
mpar
ared
ar ed w
compared ith 1.
with 1.44 (9
(95%
5%
CI, 00.7-2.9)
.7-2.9) per
er million
il on dur
million rin
ing the equiv
during iv
valent pe
equivalent period 1 yyear
earr llater.
ea atter. P regnnancy was aassociated
Pregnancy ssocciated wi
ss with
a sign
gnnif
ific
ican
icantl
antlyy iincreased
tl
significantly ncrreassedd riskk ooff ao
aort
rtiic
rt ic ddissection
aortic isse
isseccti
se tion
on oorr ru
upt
ptur
uree (incidence
ur
rupture (inc
(i ncid
nc den
ence
c rate
raatee ratio,
rat
atio
io,, 4.
io 4.00; 995%
4.0; 5% CI
I,
CI,
2 0 8 2) compared to the control period 1 year later
2.0-8.2) later.
Conclusions—The risk of aortic dissection or rupture is elevated during pregnancy and the
postpartum period.

Key words: aorta; aneurysm; pregnancy and postpartum

2
 DOI: 10.1161/CIRCULATIONAHA.116.021594

Clinical Perspective

What Is New?
x Case series suggest that pregnancy may trigger aortic dissection or rupture, but few
population-based data exist to support an association between pregnancy and aortic
complications.
x Using administrative data from a large population, we compared the risk of aortic
complications during pregnancy and the postpartum period with a control period 1 year
later.
x The incidence of aortic complications was 5.5 per million patients during pregnancy and
the postpartum period versus 1.4 per million during the control period (incidence rate
ratio, 4.0; 95% CI, 2.0-8.2).
x The availability of a control period in this study supports an association between
bet
etwe
et ween
we en
n
pregnancy and aortic complications.

What
hat Are thee C
Wh Clinical
liini
n ca Implications?
al Im
mpl
plic
icat
ic atio
at ions??
io
x These findings
ngss can
finddin can be
be used to
to counsel
ounsel patients
co nts aatt hi
p tiien
pa high baseline
seline riskk ooff aort
gh bas aortic
tic
complications
comp
mpli
mp ns about
liccatiion
li aboutt the
the risks
skss off pregnancy.
risk
sk pregn
gnan
gn y. Inn our
ancy
an our study,
stu dy, absolute
tudy
dy bsollute risks
ab risk were
isks wer particularly
eree pa
particular
arly
ar
elevated
elevat
l d iin
ed n those
h with
wi h a ddocumented
ith diagnosis
ocumentedd di is off hhypertension
diagnosi i or a connective
ypertension i tissue
connective tiissue
disease.
x Furthermore, our findings suggest that clinicians should have a lower threshold for
initiating diagnostic testing for symptoms of a possible aortic dissection or rupture in
pregnant or postpartum patients—especially those with connective tissue disorders or
hypertension—than in nonpregnant women of similar age.

3
 DOI: 10.1161/CIRCULATIONAHA.116.021594

Pregnancy significantly increases the risk of vascular events. Pregnant women face a several-fold

higher risk of venous thromboembolism,1 myocardial infarction,2 and stroke3 compared with

nonpregnant women of childbearing age. These risks extend for several months into the

postpartum period.4

Besides these relatively common vascular disorders, pregnancy may also increase the risk

of rarer vascular events. Aortic dissection and aortic rupture are uncommon but potentially life-

threatening conditions that often result in death without prompt treatment. Aortic complications

are particularly common in those with connective tissue disorders and in those with a family

history, but may also occur in the absence of these risk factors. A number of case reports and

case series over several decades suggest that pregnancy may trigger aortic dissect
tio uptu
up re.5
ionn or rrupture.
dissection ture
ture

Aortic complications in pregnancy have been described in Marfan syndrome,6, 7 Loeys-Dietz

yndrome,,8 the vascular type (Type 4) of Ehlers-Danlos syndrome,9 Turner syndrome,10 and
syndrome,

congenital
cong
ngeenital aor
ng aortic
rti
ticc ma
m
malformations
lffor
orma
mati
ma t on
onss su
such
c aass a bicu
ch bicuspid
usp
s id
d aor
aortic
rti
ticc va lve..111 H
valv
valve.
lv However,
owev
ow e err, ao
aort
aortic
rtic
rt ic com
complications
mpl
plic
icat
ic atio
at ions
io

have
hav
ve also been
ve n rreported
ep
porteed in ppregnant
re
regnant wo
women
omen w
without
ithou
out an
anyy ot
othe
other
herr kn
he known
now
wn rrisk
isk a tors.12-
skk ffactors.
ac 12-14
4

Besides
Besi
Beside
dess th
thes
these
esee su
sugg
suggestive
gges
esti
tive
ve ccase
asee st
as stud
studies,
udie
iess, ffew
ew po
popu
population-based
pula
lati
tion
on-b
-bas
ased
ed ddata
ataa ex
at exis
exist
istt to ssupport
uppo
up port
rt aan
n

association between pregnancy and aortic complications. Of note, three prospective

observational studies involving a total of 145 pregnancies in 78 patients with Marfan syndrome

failed to find an obviously elevated risk of aortic complications during pregnancy in the absence

of significant aortic enlargement.15-17 In the absence of an appropriate control group, it remains

uncertain whether pregnancy is actually associated with aortic complications or whether

publication bias has resulted in more frequent reporting of complications during pregnancy.18 To

better assess the relationship between pregnancy and aortic complications, we performed a

cohort-crossover analysis in a large population-based sample of patients.

4
 DOI: 10.1161/CIRCULATIONAHA.116.021594

Methods

Design

Using administrative claims data on all emergency department (ED) visits and acute care

hospitalizations at nonfederal healthcare facilities in California, Florida, and New York from

2005 through 2013, we performed a cohort-crossover analysis in which the risk of aortic

dissection or rupture for each pregnant woman was compared with her risk during the equivalent

period 1 year later. Since each patient served as her own control, this design reduced the risk of

residual confounding compared with traditional case-control or cohort studies.19 We chose these

three states because they are demographically heterogeneous, comprise three of the four most

populated U.S. states and approximately 25% off the U.S. population, and
and providee deidentified
dei
eide
dent
de ntif
nt ifie
if iedd
ie

administrative claims data that permit tracking off individual patients across visits over multiple

years. All patients

patients are included regardless of insurance status. Trained analysts at each healthcare

facility
faci
ili
litty use automated
auttomat
omat
ated
d oonline
nlin
nl inee reporting
in repo
re port
po rtin
rt i g software
s ftwaare too provide
so prov
ovid
ovidee these
id thesse da
th data
ta iin
n a st
standardized
tan
anda
dard
da rdized
rd ed fformat
orma
or matt to
ma

the
he respective
re state
state health
ta e he department,
eallth de
dep which
partment, w hich th n pperforms
then errfo
form
rmss a mu
rm multistep quality
ulttistepp qu assurance
uality assu
sura
su check
raance chec
eck
ec

too identify
ide
dent
ntif
ifyy in
inva
invalid
vali
lidd or inconsistent
inc
ncon
onsi
sist
sten
entt records.
reco
re cord
rdss. We
We obtained
obta
ob tain
ined
ed these
the
hese
se data
dat
ataa in a deidentified
dei
eide
dent
ntif
ifie
iedd format
form
fo rmat
at from
fro
romm

the Healthcare Cost and Utilization Project.20 Our institutional review board approved our

analysis of these deidentified and publicly available data.

Patients

Following standard methods, we identified pregnant women t12 years of age by noting all

encounters with an International Classification of Diseases, 9th Revision, Clinical Modification

(ICD-9-CM) discharge code for labor or an abortive outcome.4, 21 When multiple labor-related

hospitalizations occurred during a single 40-week period, we defined delivery as the latest

hospitalization during that time so as to exclude visits for false labor.4 Since we did not have

5
 DOI: 10.1161/CIRCULATIONAHA.116.021594

precise data on when each pregnancy began, we assumed that labor or an abortive outcome

occurred at 40 weeks of gestation; this was a conservative approach because it overestimated the

duration of exposure to pregnancy and therefore underestimated the risk of aortic complications

during pregnancy versus nonpregnant periods. In our primary analysis, we included all recorded

pregnancies for each patient; in a sensitivity analysis, we focused on the first-recorded pregnancy

because women who have already completed a first pregnancy without an aortic complication

may be at a lower risk of subsequent aortic complications than the general population of women

of child-bearing age.22

Measurements

Our outcome was a composite of aortic dissection or rupture, defined by ICD-9-CM

CM
M ccodes
odes
od es

441.0x (dissection of aorta), 441.1 (ruptured thoracic aortic aneurysm), 441.3 (ruptured

abdominal aortic aneurysm), 441.5 (ruptured aortic aneurysm of unspecified site), and 441.6

(ruptured
rupptu
tured thoracoabdominal
thorac
acoaabd
ac b om
omin
inal
in a aneurysm).
ane
neur
urys
ur ysm)
ys m)). Only events
eve
v nt
nts resulting
res
esul
esulti
ulting
ting in
in hospitalization
hoosp
hosp
s it
ital
a izaati
tion
on were
were in
incl
included
clud
cl uded
ud ed in

ourr outcome.
ou To
T ffocus
o fo incident
ocuss on inc
ncident outc
nc outcomes,
comes, we excluded
w ex
excl
lud ed aany
uded diagnoses
iagnosses ooff aorticc ddissection
ny dia
ia n oorr
issseection

rupture
upt
ptur
uree recorded
reco
re cord
rded
ed after
aft
fter
er an
an index
ind
ndex
ex diagnosis.
dia
iagn
gnos
osis
is. In our
our primary
pri
rima
mary
ry analyses,
anal
alys
yses
es, we used
use
sedd both
both principal
pri
rinc
ncip
ipal
al and
and

secondary diagnosis codes to define outcomes, but in sensitivity analyses, we limited our

outcomes to only principal diagnoses of an aortic complication or only aortic complications

accompanied by a concomitant procedure code for surgical (ICD-9-CM procedure codes 38.44 or

38.45) or endovascular (39.71 or 39.73) aortic repair.

To perform analyses stratified by the baseline risk of aortic complications, we noted

comorbidities that were definable by ICD-9-CM codes and have been reported in association

with aortic complications during pregnancy: Marfan syndrome (ICD-9-CM code 759.82),6

Ehlers-Danlos syndrome (756.83),7 Turner syndrome (758.6),10 and hypertension (401-405) or

6
 DOI: 10.1161/CIRCULATIONAHA.116.021594

pre-eclampsia or eclampsia (642).13

Statistical Analyses

Based on the temporal pattern of reported cases of aortic complications during pregnancy, we

defined the period of risk to extend from 6 months prior to delivery or abortive outcome through

the postpartum period.23, 24 Following the approach of prior studies, we defined the postpartum

period as the 12 weeks after delivery (rather than the traditional 6 weeks) to ensure

comprehensive capture of any events that could be related to a preceding pregnancy.1, 4 We then

compared each patient’s likelihood of aortic dissection during this period to the equivalent 270-

day period exactly 1 year later. We performed exploratory analyses limited to outcomes in the

antepartum or the postpartum period; in cases where both dissection and laborr or ab
abor
orti
ortive
tive
abortive

outcome were documented during the same hospitalization, we used previously validated

present-on-admission codes to determine the relative timing of events.25 We performed subgroup

analyses
anal
alyyses stratified
al stratif
iffie
iedd by
b the
the presence
pre
r se
senc
ncee or
nc o absence
abs
b ence of
o a documented
doccum
umen
ente
ented connective
te conn
connec
nn ecti
ective
tiv tissue
tis
issu
suee disorder,
su d sord
di rder
rd er,, th
er thee

presence
pres
sence absence
en or absencce ooff docum
bse documented hypertension,
umented hy
um p rtensiion, aand
hype cesarean
ndd ce
cesa
sare
sa reean vversus
errsus vvaginal
agi
gina
gi delivery.
n l deli
ivery
ry. In a
ry

sensitivity
ens
nsit
itiv
ivit
ityy an
anal
analysis,
alys
ysis
is, we llimited
imit
imited
ed oour
ur ssample
ampl
amplee to ppatients
atie
at ient
ntss wi
with
th aatt le
leas
least
astt on
onee ED vvisit
isit
is it oorr hospitalization
hosp
hospit
ital
aliz
izat
atio
ionn

after the end of their crossover period, thus ensuring that they were alive and resident within the

state throughout follow-up. Since women who have an aortic complication before a pregnancy

may be less likely to become pregnant in the future, falsely reducing the control-time risk

estimates in a cohort of only women who were pregnant, we also performed a sensitivity analysis

using a case-crossover design in which the odds of pregnancy prior to an aortic complication

were compared to the odds of pregnancy in the corresponding 270-day period 1 year earlier.

Incidence rates and incidence rate ratios (IRR) were calculated using conditional Poisson

regression for matched data and robust standard errors to account for clustering among patients

7
 DOI: 10.1161/CIRCULATIONAHA.116.021594

with multiple pregnancies. In a confirmatory analysis, we combined data on hospitalizations with

demographic data from the U.S. Census Bureau26 to compare age-standardized rates of aortic

complications in pregnant patients versus nonpregnant controls. All analyses were performed

using Stata/MP version 13 (College Station, TX).

Results

Among 6,566,826 pregnancies in 4,933,697 women (Table 1), we identified 36 cases of aortic

dissection or rupture during the pregnancy or postpartum period and 9 cases during the control

period 1 year later. The incidence of dissection or rupture was 5.5 (95% confidence interval [CI],

4.0-7.8) per million patients during pregnancy and the postpartum period, compare
redd wi
re
compared with
th 11.4
.4

95% CI, 0.7-2.9) per million during the equivalent period 1 year later (IRR, 4.0; 95% CI, 2.0-
(95%

8.2). The rate of 5.5 aortic complications per million pregnancies was also significantly higher

han
n tthe
than h rate of 11.7
he .77 (95
5% CI
(95% C
CI,, 11.5-1.9)
.5-
5-1.
5- 1.9)
1. 9 aaortic
9) o tic co
or omp
m li
licati
tiion
onss pe
complications perr mi
mill
lio
ion du
million dduring
ring
ng aan
n eq
equiva
vale
va lent
le
equivalentnt 2270-
7 -
70

dayy period
pe amo
mong
mo ng nonpregnant
among nonnpregna
nant controls
na controlls (IRR,, 3.2;
3.22; 95%
955% CI,
CI 2.4-4.3).
2.4-44.33).
2.

Al
Alll 36 pregnancy-related
pre
regn
gnan
ancy
cy-r
-rel
elat
ated
ed complications
com
ompl
plic
icat
atio
ions
ns occurred
occ
ccur
urrred during
dur
urin
ingg the
the first-
firs
fi rst-
t- or
or second-recorded
seco
se cond
nd-r
-rec
ecor
orde
ded
d

pregnancy. The incidence during a first-recorded pregnancy (5.1 [95% CI, 3.5-7.7] per million)

did not differ appreciably from the rate during a second-recorded pregnancy (8.2 [95% CI, 4.6-

15.9] per million). There was no obvious difference in risk when considering events only in the

antepartum period (IRR, 4.0; 95% CI, 1.6-10.2) or considering events only in the 3-month

postpartum period (IRR, 3.5; 95% CI, 1.2-10.6) as compared to the equivalent nonpregnant

period 1 year later.

The absolute increase in the risk of aortic dissection or rupture was much higher in

patients with a documented connective tissue disorder (4,960.6 [95% CI, 1,870.1-17,746.3] per

8
 DOI: 10.1161/CIRCULATIONAHA.116.021594

million) compared to the remaining patients (4.9 [95% CI, 3.5-7.0] per million) (P <0.001 for

interaction). However, even in patients without documented connective tissue disease, the risk

was higher during pregnancy than outside of pregnancy (IRR, 3.6; 95% CI, 1.7-7.3). Although

the relative increase in the risk of aortic complications during pregnancy was similar for patients

with and without pre-existing hypertension (P = 0.54 for interaction), both the baseline risk and

the absolute risk increase associated with pregnancy appeared higher in those with hypertension:

106.2 (95% CI, 44.9-317.1) per million during pregnancy versus 42.6 (95% CI, 9.2-428.3)

during the crossover period. Both the estimates for connective tissue disease and hypertension

were based on small numbers of patients (Table 1). We found no interaction between pregnancy

P = 0.76 for
and the mode of delivery in relation to the risk of aortic complications ((P interaction),
for in
inte
tera
te ract
ra ctio
ction)
io n,

nor an interaction between pregnancy and the presence or absence of pre-eclampsia/eclampsia

(P=0.45).
P=0.45)).

findings
Our find
ndin
nd ngs
g wwere
eree si
er ssimilar
mila
mi larr in sen
la sensitivity
nsi
s tivity analyses
y an es llimited
nallyses imit
imited
it d tto
o ea
each patient’s
h patie
ient
ie nt’s
nt ’s ffirst-recorded
i st-r
ir -rec
-r ecor
ec orde
or dedd
de

pregnancy
gnancy (IRR,
preg RR, 3.1;
(IRR
RR 3.1; 95%
955% CI,
CI, 1.4-6.9), limitedd to patients
pati
tieent
ti ntss with
w th att least
wi leastt one after
fteer the
onne visit af he endd of
th of

their
hei crossover
eirr cr
cros
osso
sove period
verr pe
peri od ((IRR,
riod IRR
IR R, 33.4;
.4;
4; 95
95% CI, 11.5-8.0),
% CI .5-
5-88.0) limited
0), li
limi tedd to ooutcomes
mite utco
ut come defined
mess de
defi nedd by pprincipal
fine rinc
ri ncip
ipal
al

diagnosis codes (IRR, 2.9; 95% CI, 1.4-5.8), or limited to outcomes accompanied by a procedure

code for aortic repair (IRR, 2.8; 95% CI, 1.1-7.2).

In a case-crossover design assessing the likelihood of labor during time intervals prior to

an aortic complication, we identified 14,999 cases of aortic dissection or rupture. Of these cases,

62.4% were admitted to the intensive care unit, 30.6% had a documented surgical or

endovascular treatment, and 28.1% died. In a case-crossover analysis limited to women who

were pregnant either around the time of their aortic complication or during the same period 1

year prior to their aortic complication, the association between pregnancy and aortic dissection or

9
 DOI: 10.1161/CIRCULATIONAHA.116.021594

rupture (IRR, 3.5; 95% CI, 2.0-5.9) was similar to the association in our primary analysis above.

Discussion

In a cohort-crossover analysis of a large, population-based sample of patients, we found a strong

association between pregnancy and the risk of aortic dissection or rupture. Relative risks were

increased to a similar extent in both the antepartum and postpartum periods as compared with the

control period 1 year later. We found that pregnancy was associated with an increased risk of

aortic complications among both women with and without documented connective tissue

diseases such as Marfan syndrome, although the risk was significantly greater in those with

connective tissue diseases. Absolute risks were also higher in those with hypertens
hypertension,
nsio
ns ion,
ion, a

potentially modifiable risk ffactor that may be amenable to more intensive risk factor

management during pregnancy among high-risk women.

Our finding
find
ndin
nd ng that
hat pregnancy
th pre
regn
gnan
gn ancy
an cy can
n trigger
can r ggerr aortic
tri aorrtiic ccomplications
ompl
om plic
pl icat
ic a io ns hhas
ions ass iimportant
mpo
mport
po antt implications
rtan
rt an i pl
implic
icat
ic atio
at ions
io ns

pre-pregnancy
for pr
pre-pregna ncyy ccounseling
anc oun
unseling
un ng and pperipartum
erip care.
partum ca
care Women
e. Womeen
om without
en w i ho
it documentation
out doc mentationn of eestablished
ocum stabliishhed

risk
isk factors
fac
acto rs for
tors for aortic
aor ticc complications
orti comp
co mpli
lica
cati onss (such
tion (suc
(s uchh as pre-existing
pre-
pre-ex
exis
isting Marfan
ting Marfann syndrome)
arfa synd
syndrome)) appear
rome app earr to have
ppea avee an
hav

increased relative risk, but the absolute risk remains low. A scarcity of data exists to guide

women with conditions such as Marfan syndrome regarding their risks of serious aortic

complications if they become pregnant.22 The available studies have reported conflicting findings

about whether pregnancy results in an increase in aortic root diameter.15-17, 27 Furthermore, prior

studies appear to have lacked sufficient statistical power to evaluate the association between

pregnancy and the clinical outcome of aortic dissection or rupture.16 In this context, our findings

provide firm support for the current practice of counseling patients at high baseline risk of aortic

complications (such as those with certain connective tissues diseases) that pregnancy is likely to

10
 DOI: 10.1161/CIRCULATIONAHA.116.021594

increase the risk of aortic complications,28, 29 and may provide a more precise estimate of the

magnitude of the increase in relative risk. Furthermore, our findings indirectly support current

guideline recommendations for intensification of monitoring of the aortic root during pregnancy

in patients with connective tissue disorders.28, 29 Lastly, our findings suggest that clinicians

should have a lower threshold for initiating diagnostic testing for symptoms of a possible aortic

dissection or rupture in pregnant or postpartum patients—especially those with connective tissue

disorders or hypertension—than in nonpregnant women of similar age.

Our findings may reflect prevalent but undiagnosed or undocumented connective tissue

disorders, or they may indicate that the physiological changes of pregnancy can cause aortic

njury even in otherwise healthy women. The mechanisms by which pregnancy may
injury may trigger
trig
tr igge
ig gerr
ge

aortic complications are uncertain. Pregnancy and the postpartum state cause hemodynamic

changes—such as increases in heart rate, stroke volume, cardiac output, and left ventricular

mennsions11—t
dime
me
dimensions —that
—tha
at ma
mayy af
affe
affect
f ct tthe
fe he fforces
o ce
or cess on the
he aor
aortic
orticc wa
wall
wall.
ll. Th
ll This
is m
may
ay bbee ex
exacerbated
xac
acer
erba
er bate
ba t d by

increased
ncrrea
eased outf
outflow
flo
low
w rresistance
esiisttancee iin
n the dist
distal
tal aortaa ddue
uee to ccompression
ompr
ompres
ession
es on by th
tthe
he gr us.30
gravid uuterus.
teru
te ru

Pregnancy
Preg
Pr egna
nanc
ncyy also
also causes
cau
ause
sess hormonal
horm
ho rmon
onal
al and
and biochemical
bio
ioch
chem
emic
ical
al ch
chan
changes
ange
gess th
that
at m
may
ay m
modify
odif
od ifyy tthe
he aability
bili
bi lity
ty ooff th
thee

aorta to withstand the hemodynamic effects placed on it. The importance of dysregulated

signaling (e.g., by TGF-beta) in the genesis of a number of conditions associated with aortic

aneurysms8 suggests one pathway by which the hormonal and biochemical effects of pregnancy

may mediate the risk of aortic complications. Estrogen receptors are present in aortic tissue and

may mediate the effect of pregnancy-induced hormonal changes on the weakening of elastic

fibers.31 These pathways may result in the type of medial degeneration often seen in patients with

aortic disease,31, 32 although in one series only two of six pregnant women with aortic dissection

had clear evidence of medial degeneration on histologic examination of surgical specimens.33

11
 DOI: 10.1161/CIRCULATIONAHA.116.021594

The findings of this study must be interpreted in the context of several limitations. First,

the lack of detailed clinical data precluded an assessment of the risk of aortic complications in

relation to patients’ aortic root diameter prior to pregnancy. Therefore, we cannot comment on

whether pregnancy increases the risk of aortic complications in women with an aortic root

diameter <40 mm or <45 mm, which are the thresholds currently recommended for deciding on

the safety of pregnancy in women with Marfan syndrome or other connective tissue disorders.28,
29, 34
Second, we defined our outcomes using ICD-9-CM codes with unknown sensitivity and

specificity. If these codes have randomly low sensitivity or specificity, the resulting

nondifferential misclassification of outcomes would have falsely attenuated the relationship

between pregnancy and aortic dissection. On the other hand, if providers documen
entt ao
en
document aort
rtic
rt
aorticic

complications more reliably in young pregnant women than in young nonpregnant women, or

ystematically miscode other pregnancy-related complications using these codes, then the
systematically

esuult
ltin
i g differential
resulting differrenti
tiial
a m iscl
is clas
cl a si
sifi
fica
fi cati
ca
misclassification tion
ti o w ould hhave
would avee upwardly
upw
war
ardl
dlyy biased
dl b as
bi ased
ed the
the apparent
a pa
appare
rent
re nt association
ass
s occia
iati
tion
tion

betw
wee
e n pregnancy
between pregnnanc
nanc
ncyy and
an
nd aortic
aort
rtiic
rt ic complications.
compl
p icat
attions. We
W thhink
nk such
think such
uch differential
differ
erential
er al misclassiffica
cati
ca tion is
ti
misclassification

unli
un like
kely
unlikelyly bbecause
ecau
ec ause
se w
wee fo
foun
undd a si
found simi
mila
larl
rlyy el
similarly elev
evat
ated
elevateded ri
risk
sk dduring
urin
ur ingg th
thee 3-
3-mo
mont
nthh po
3-month post
stpa
part
rtum
postpartumum pperiod
erio
er iodd as

during pregnancy itself. Furthermore, diagnosis codes for major illnesses have been validated to

have good sensitivity and specificity in these administrative claims data.35 Also, the outcomes of

patients with diagnoses of aortic complications in our study are consistent with modern series

based on detailed clinical data,36 further supporting the validity of the diagnosis codes used in

our study, and our findings were similar in an analysis limited to patients with a documented

aortic repair procedure. Third, our subgroup analyses should be interpreted with caution, because

it is possible that only more severe cases of hypertension or connective tissue disease were

documented, thereby inflating the apparent risks of aortic complications in these groups. Fourth,

12
 DOI: 10.1161/CIRCULATIONAHA.116.021594

we did not have precise data about the timing of gestation. We addressed this by taking a

conservative approach that likely overestimated the duration of pregnancy. Similarly, aortic

complications resulting in death early in pregnancy may have been missed. These limitations

would be expected to attenuate our estimates of risk during pregnancy, suggesting that the true

risk of aortic complications during pregnancy may be somewhat higher than what we found.

Conclusions

We found that the absolute increase in the risk of aortic dissection or rupture attributable to

pregnancy was approximately 4 per million pregnancies. This may be helpful when counseling

patients about the risks of pregnancy, when formulating multidisciplinary plans of care
car
aree fo high-
forr hi
high
g -
gh

risk
isk patients, and when evaluating symptoms concerning for aortic dissection or rupture in

pregnant or postpartum patients.

Funding
nding Sources:
Fund
nd Sourrce Hooman
ces: Ho
ooman
nKKamel acknowledges
amel ack dgess ffunding
knowled und
ndin
nd support
ingg su
in upportt from
mNNIH/NINDS
NDS ((grants
IH/NIN grantss
K23NS082367
K23N
K2 3NS0
NS0
S082
8236
82 3677 and
36 nd R01NS097443)
an R001NS0
R01N S097
097
9744
443)
44 3) and
d the
and the Michaele Goldberg
Micchaael Gold
Go ldbe
ldberrg
be rg Research
Res rcch Fund.
eseaarch nd. Alex
Fuund
Fund Pitcher
Alex Pittch
cher
er
acknowledges funding support from the Marfan Foundation; the Gibson fund; the NIHR
Biomedical Research Centre, Oxford; the British Heart Foundation Centre of Research
Excellence (grant code RE/13/1/30181), and the Academy of Medical Sciences Clinical Lecturer
Starter Grant scheme. No funding organization had a role in the design and conduct of the study;
collection, management, analysis, and interpretation of the data; and preparation, review, or
approval of the manuscript.

Conflict of Interest Disclosures: None.

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Table 1. Baseline Characteristics of Patients At Time of First Pregnancy, Stratified

Stratifieed by the
the
Occurrence of Aortic Complications During Pregnancy

Aortic No Aortic
Complication Complication
Char aracteristic*
Characteristic
C (N
N = 36) (N = 4,933,661) P Value
Age,e, mean (SD),
(SD)
D), y
D) 29.22 ((7.0)
29 7.0)
7. 0) 227.3
7 3 (6
7. (6.8
(6.8)
.8))
.8 00.11
0. 11
Age
Ag
ge <35 years 27 (75.0)
(75
75.0
.0))
.0 44,027,057
4, 0227,05
0577 (81.6)
05 6) 0.311
White
Wh itee race†
hit 11 ((30.6)
30.6) 2,121,171
2 12
2, 21,1717
71 (43.0) 0) 0.13 3
Private
Priv
Pr ivat
atee insura
insurance
ranc
ra ncee 155 ((41.7)
4 .7))
41 2,
2,732,249
,73
732,2,24
2499 (5
((55.4)
5.4)
5. 4) 00.10
.10
10
Vascular l risk
i k factors
f
Absence of pre-existing hypertension 31 (86.1) 4,895,363 (99.2) <0.001
Absence of pre-eclampsia 21 (58.3) 4,505,942 (91.3) <0.001
Absence of eclampsia 36 (100.0) 4,929,694 (99.9) 0.87
Absence of connective tissue disorder§ 32 (88.9) 4,933,033 (99.9) <0.001
Abbreviations: SD, standard deviation.
*
Data are presented as number (%) of participants unless otherwise specified. Comparisons were made using the chi-
square test or t-test.
†
Self-reported by patients or their surrogates.
§
Marfan, Turner, or Ehler-Danlos Syndromes.

16