DOI: 10.1161/CIRCULATIONAHA.114.010027
Increased Congenital Heart Defects in Children Born to Women with
Systemic Lupus Erythematosus: Results from the Offspring of Systemic
Lupus Erythematosus Mothers Registry Study
Running title: Vinet et al.; Congenital heart defects in SLE offspring
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Évelyne Vinet, MD1,2; Christian A. Pineau, MD2; Susan Scott, MScc1;
12
Ann E. Clarke, MD, MSc1,3; Robert W. Platt, PhD4; Sasha Bernatsky, MD,
MD, PhD
PhD1,2
1
2
Division
Di
viisi
sion
ion off Clin
C
Clinical
li ical Epidemiology, McGilll Un
University Healt
Health
th Ce
Centre,
ent
ntrre,
re Montreal, Canada;
Di
Division
off Rheumatology,
Rhheumaato
olo
logy
gyy, McGill
McGi
Mc
Gill
Gi
l University
Univeerssity Health
Healtth Ce
Centre,
enttre
re, Mont
M
Montreal,
ontrreaal, Ca
Cana
Canada;
nada
da; 3D
da
Division
ivi
visi
sioon ooff
Rhheu
euma
mato
ma
tolo
to
logy
lo
gyy, Un
niv
ver
ersi
sity
si
ty ooff Ca
Calg
lgar
lg
ary,
y, C
alga
al
gary
ga
ry,, Ca
ry
Cana
nada
na
da;; 4De
da
Dept
p of
pt
of Epidemiology,
Epid
Ep
idem
id
em
mio
olo
logy
gy,, Bios
gy
B
Biostatistics
ios
ostaati
tist
stiicss &
st
Rheumatology,
University
Calgary,
Calgary,
Canada;
Occupational
Occu
Oc
cupa
cu
paati
tion
o al H
on
Health,
ealtth, M
ea
McGill
cGil
cG
illl Un
Univ
University,
iverrsi
iv
s ty
ty,, Mo
Mont
Montreal,
n re
real
al,, Ca
al
Cana
Canada
nada
na
daa
Address for Correspondence:
Évelyne Vinet, MD
McGill University Health Center
1650 Cedar Avenue, Room A6 162.2
Montreal (PQ), Canada, H3G 1A4
Tel: 514-934-8037
Fax: 514-934-8570
E-mail: [email protected]
Journal Subject Codes: Etiology:[8] Epidemiology, Cardiovascular (CV) surgery:[41] Pediatric
and congenital heart disease, including cardiovascular surgery
1
DOI: 10.1161/CIRCULATIONAHA.114.010027
Abstract
Background—In a large population-based study, we aimed to determine whether children born
to women with systemic lupus erythematosus (SLE) have an increased risk of congenital heart
defects (CHD) compared to children born to women without SLE.
Methods and Results—The "Offspring of SLE mothers Registry (OSLER)" includes all women
who had •1 hospitalization for delivery after SLE diagnosis, identified through Quebec's
healthcare databases (1989-2009), and a randomly selected control group of women, matched
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
•4:1 for age and year of delivery. We identified children born live to SLE mothers and their
visit
with
matched controls, and ascertained CHD based on •1 hospitalization or physician
n vis
issit w
ithh
it
relevant
elevant diagnostic codes, within the first 12 months of life. We performed multivariable logistic
regression
estimating
method,
egr
gres
essi
es
sion
si
onn analyses,
ana
naly
yse
ses,
s, using the generalized estima
maatinng equation me
eth
t odd, to adjust for relevant
covariates.
Five
women
with
while
matched
co
ovariates.
va
ve hhundred
undr
undr
dred
d aand
nd nnine
inee wome
in
w
ome
men w
itth SLE
LE had
ad 7719
1 cchildren,
19
hiild
ldre
ren,
n w
hile
hi
lee 55824
8244 mat
82
m
atche
tche
hedd
controls
children.
Compared
controls,
women
with
co
ont
n ro
ols
l hhad
ad 88493
4933 ch
49
chil
illdrren
en. Comp
C
omp
mpar
ared
ar
ed
d too co
cont
nttro
rols
lss, cchildren
hiildr
ildr
dren
en bborn
ornn to
or
ow
omen w
omen
ithh SL
it
SLE
E
CHD
(95%CI
versus
experienced mo
more
ree C
HD [[5.2%
5..2% (9
(95%
5%CI
5%
CII 33.7-7.1)
.7-7
.7
-7
7.1
.1)) ve
vers
rsus
rs
u 11.9%
.9%
.9
% ((95%CI
95%C
95
%CII 1.6-2.2),
%C
1.61.
6 2.
62.2)
2),, difference
diff
di
ffer
ff
eren
er
e ce 3.3%
en
(95%CI 1.9-5.2)]. In multivariable analyses, children born to women with SLE had a
substantially increased risk of CHD (OR 2.62, 95%CI 1.77-3.88) compared to controls. In
addition, compared to controls, offspring of SLE mothers had a substantially increased risk of
having a CHD repair procedure (OR 5.82, 95%CI 1.77-19.09).
Conclusions—Compared to children from the general population, children born to women with
SLE have an increased risk of CHD, as well as an increased risk of having a CHD repair
procedure.
Key words: systemic lupus erythematosus, congenital cardiac defect, pregnancy, epidemiology
2
DOI: 10.1161/CIRCULATIONAHA.114.010027
Systemic lupus erythematosus (SLE) predominantly occurs in women of childbearing age, with
prevalence estimates of about 1.5/1000 in females aged 18-44 years1. This disease can cause
considerable morbidity during pregnancy. Pregnant women with SLE and those contemplating
pregnancy often ask if their disease will affect their baby. Although several studies have
evaluated obstetrical outcomes in lupus pregnancy, little is known about the risk of congenital
anomalies.
Congenital heart defects (CHD) are the most frequent type of birth defects, accounting
for approximately a third of all congenital anomalies2; they are associated with substantial child
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
morbidity3. In utero exposures, such as maternal illnesses and medications, are thought to play an
important
mportant role in the yet to be fully elucidated etiology of CHD4. In particular, a rrecent
eccen
entt st
stud
study
udyy
ud
suggests
uggests a 3-fold increased risk of CHD in children born to mothers with various systemic
connective
co
onn
nnec
ecti
ec
tive
ti
vee ttissue
issuue disorders,
is
di
including SLE5. However,
Hoowever, the investigators
investi
tiga
g tor
orrs did
did not specifically
assess
asseess
s the SLE
E effect
efffec
ectt estimate
esti
es
tima
ti
m te for
ma
forr the
the
he risk
rissk of
of CHD
CHD
D and
andd did
did not
noot control
contro
ntroll for
fo
or medication
medica
med
dicaati
t on
on eexposures.
xppos
osur
ures
ur
e.
Certain
drugs
SLE
manifestations,
such
methotrexate
mycophenolate
mofetil,
Cert
Ce
r ai
rt
ainn dr
drug
ugss us
ug
used
ed
d tto
o ttreat
reeat
eat SL
LE ma
mani
nife
feesttat
atio
ions
io
nss, su
uch aass me
meth
thot
otre
ot
reexaate aand
ndd m
ycop
yc
ophe
op
hennola
he
laatee m
ofeetil
of
et
are known teratogens,
teera
rato
toge
to
gens
ge
n , and
ns
a d affected
an
affe
af
f ct
cted
e women
ed
wom
men might
mig
ight
htt be
be inadvertently
inaadv
dver
erte
er
teent
ntly
l exposed
ly
exp
xpos
osed
os
ed to these
the
hese
se agents
age
g nts durin
during
ng
pregnancy, potentially increasing the risk of CHD6.
Only very few uncontrolled observational studies have assessed CHD in offspring of
mothers with SLE. Notably, in a study of fetal echocardiography in a small number of SLE
pregnancies7, 7.5% of fetuses had a CHD, which is more than 5-fold what is usually observed
among live births from the general population (0.6-1.3%), although that is clearly not an
equivalent comparison group8. Investigators have also observed CHD in 16-42% of children with
congenital heart block born to mothers with anti-Ro/SSA antibodies, after excluding cases with
CHD that could have caused congenital heart block9-13. Although the prevalence of CHD was
3
DOI: 10.1161/CIRCULATIONAHA.114.010027
lower in children born to mothers with anti-Ro/SSA antibodies who did not develop congenital
heart block (2.8%), the frequency was still substantially higher than in the general population9. In
such studies, the most frequently observed CHD were atrial septal defects (ASD), ventricular
septal defects (VSD), and valve anomalies9-13.
Given the paucity of existing literature, we aimed, in a large population-based study, to
determine whether children born to women with SLE have an increased risk of CHD compared
to children born to women without SLE. In addition, we aimed to determine if offspring of SLE
mothers have an increased risk of particular CHD subtypes, including ASD, VSD, and valve
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
anomalies, compared to offspring born to unaffected mothers.
Methods
St
tud
udyy Design
Desi
De
sign
si
gn and
and Subjects
Subjects
Study
T
The
hee "Offspring
ng ooff SL
SLE
LE mo
moth
mothers
ther
th
errs Re
Reg
Registry
gistry
gis
y (O
(OSLER)"
OSL
LER
R)" iss a po
population-based
opuula
lattio
tion-b
baseed ccohort
ohor
oh
ortt of 7719
19 cchildren
hild
hi
ldrren
ld
born
wee
bo
orn to
to mothers
mo
oth
ther
erss with
wiith SLE,
SLE,
LE, matched
matc
matc
tche
hedd to 8493
he
849
4933 control
co
ont
n roll children.
ch
hilldr
dreen.
en To create
cre
reat
atee this
th
his llarge
arrge ccohort,
ohoort,
or , w
identified
dentified alll w
women
omen
om
en w
with
i h SL
it
SLE
E wh
whoo ha
had
ad •
•11 hospitalization
hosp
ho
spit
sp
i al
it
a iz
i attio
ionn fo
forr a de
deli
delivery
live
li
very
ve
ry rresulting
e ullti
es
ting
ng iin
n a stillbirth
or live birth, between January 1989 and December 2009, using data from the Quebec MEDECHO (“Maintenance et Exploitation des Données pour l'Étude de la Clientèle HOspitalière”)
hospitalization and “Régie de l’Assurance Maladie du Québec (RAMQ)” physician billing
databases.
MED-ECHO is the administrative database collecting information on all hospitalizations
in Quebec since 1987, and provides, for each hospitalization, a primary discharge diagnosis and
up to 15 non-primary diagnoses, captured as International Classification of Diseases (ICD)-9
codes, and since 2006, ICD-10 codes. RAMQ billing database records one physician-assigned
4
DOI: 10.1161/CIRCULATIONAHA.114.010027
diagnosis, based on ICD-9 codes, for each physician encounter.
Exposure of Interest
Women were identified as SLE cases, based on a validated definition14, using ICD-9 code 710.0
or ICD-10 code M32, if they had any of the following: 1) •1 hospitalization with a diagnosis of
SLE, either primary or non-primary, prior to the delivery, 2) a diagnosis of SLE, either primary
or non-primary, recorded at the time of their hospitalization for delivery, or 3) •2 physician visits
with a diagnosis of SLE, occurring 2 months to 2 years apart, prior to the delivery. From these
databases, a general population control group was composed of women individually-matched
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
•4:1 for age and year of delivery, who did not have a diagnosis of SLE prior to or at the time of
delivery.
Mother-child linkage was done using the encrypted mother's number, which is present in
ev
ver
eryy ch
chil
ild’
il
d’s filee iin
d’
n the RAMQ and MED-ECHO
O ddatabases,
atabases, and wh
w
erre it
it remains through
every
child’s
where
ch
hilldhood, lea
adi
ding
ng too ve
ery
ry ffew
ew llinkage
in
nka
kage
gee ffailures
ailu
ure
res (<
< 22%).
%).
).. T
ho
osee cchildren
hilldre
renn bborn
orn
n llive
ive we
ive
were
r tthe
re
hee bbasis
asiis
childhood,
leading
very
Those
off the
the OSLER
OSL
LER cohort
coh
ohor
ortt for
for outcome
outc
tcom
tc
om
me ascertainment,
asceerttai
asce
ainm
nmen
nm
entt, one
en
on
ne being
beein
ingg the
th
he exposed
expo
ex
pose
po
seed group
g ou
gr
oupp consisting
co
ons
nsistting
g ooff
wom
omen
en with
wit
ithh SLE,
SL
LE,
E and
and
d the
the other
oth
theer being
bein
be
ingg th
in
thee co
cont
ntro
nt
rol gr
ro
grou
oupp co
ou
cons
nsis
isti
is
ting
ti
ng ooff children
children bornn to women
control
group
consisting
born to women without SLE. Stillbirths were not included since a substantial proportion of
stillbirths in Quebec result from pregnancy termination, for which no information for our
outcome of interest is recorded neither for SLE mothers, nor controls (see Online Data
Supplements)15.
Outcome Assessment
The cohort of children described above was linked to the MED-ECHO and RAMQ databases to
determine hospitalizations and all diagnoses occurring throughout the study interval of these
offspring. This study interval spanned from birth to the first of the following: end of eligibility
5
DOI: 10.1161/CIRCULATIONAHA.114.010027
for RAMQ coverage (i.e. migration from Quebec), event of interest (e.g. CHD), age 1, death, or
end of study (i.e. December 31st 2009).
Our ascertainment of CHD in live-born babies was based on the presence, at birth or
within the first 12 months of life, of •1 ICD-9 code 745, 746, and 7471-7474 and/or ICD-10
code Q20-26, using the methodology developed by the "European Surveillance of Congenital
Anomalies (EUROCAT)" network16. Use of ICD-9/10 codes for identification of CHD has been
previously validated in Quebec's administrative databases17. We further excluded subjects with
ICD-9/10 codes referring to congenital heart block and/or patent ductus arteriosus, as the only
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
CHD. However, subjects with a diagnosis of congenital heart block and/or patent ductus
arteriosus and any other CHD were included as cases. ASD, VSD, and valve anom
om
mal
a iees we
were
re
anomalies
defined based on •1 relevant diagnostic code (see Online Data Supplement). We included
eco
ord
rdss of C
H ddiagnosed
HD
iagnosed within the first 12 m
iag
ontths of life, to ccapture
on
a ture
ap
ree eevents
v nts with delayed
ve
records
CHD
months
de ection or reg
dete
egis
i trrattio
is
ion.
n..
detection
registration.
Asse
As
sess
se
ssin
ss
ingg Re
Rele
levvan
nt C
nt
ov
var
a ia
ate
tess
Assessing
Relevant
Covariates
For all mothers
moth
herrs inn our
our
u study,
stu
t dy
dy,, we reviewed
rev
evie
i we
ie
wedd the
th
he MED-ECHO
MEDME
D EC
DCHO and
and RAMQ
RAM
AMQ
Q data
data
t to
to identify
iden
id
enti
en
t fy specific
ti
pre-existing and current co-morbidities (i.e. hypertension, pregestational diabetes, asthma)
recorded in the two years prior to the time of delivery, as well as obstetrical complications, such
as gestational diabetes, at the time of the hospitalization for delivery. The diagnosis of specific
co-morbidities listed above was based on ICD-9/10 codes indicating •1 hospitalization or •2
physician visits, at least 8 weeks apart, for the diagnosis of interest, as per previously validated
methodology18-19.
Available through the "Institut de la Statistique du Québec" were data on the
demographics of the parents at the time of delivery, including maternal education, as well as
6
DOI: 10.1161/CIRCULATIONAHA.114.010027
maternal and paternal birthplace, maternal language, and language spoken at home, which were
used to establish the race/ethnicity of the offspring (see Online Data Supplement). These
demographic data were used in our analyses as covariates.
Comprehensive and valid data on drug exposures is available from the RAMQ
prescription (RAMQ-Rx) database, but only for beneficiaries of the public drug plan20. The
RAMQ-Rx plan covers recipients of social assistance, and workers and their families who do not
have access to private drug insurance. In our cohort, 22% of exposed children and 21% of
controls were born to a mother with RAMQ-Rx plan coverage throughout pregnancy.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
In this subgroup, we obtained all information on the prescription of certain types of
antid
depre
epr sssants
an
nts
ts,, an
and
medications, including corticosteroids, antimalarials, immunosuppressives, antidepressants,
anticonvulsants. Of note, there is no information recorded on intravenous cyclophosphamide
ex
xpo
posu
sure
su
re in
in the
th RAMQ-Rx
RAMQ
RA
M -Rx database, as this medication
medi
dicaation is administered
di
admini
nist
s ered
ed
d in
in hospital. We used
exposure
gesttat
a ional ag
ge rrecorded
ecord
rded
rd
ed
d aatt bbirth
irtth
ir
th tto
o cal
ccalculate
alculatee bback
ack
k too th
he es
est
timat
ateed
ed sta
tart
rtt ooff th
he ge
gest
stat
st
attio
ionnal
nal pe
peri
r od,
gestational
age
the
estimated
start
the
gestational
period,
hen determined
det
e er
ermi
minned
mi
ned whether
whet
wh
ethe
herr a medication
medi
medi
dica
cati
ca
tion
ti
on exposure
exp
xpoosur
osur
uree of
of interest
intter
eres
estt ever
es
ev
ver
e occurred
occ
ccur
u red during
ur
duuri
r ng pregnancy
pre
regn
gnnan
ncy bbased
ased
e
then
rip
ipti
tion
ti
on
n ffilled
i leed att aany
il
n ti
ny
time
me dduring
urin
ur
in
ng gestation.
gest
ge
stat
st
atio
at
io
on.
n
on •1 prescr
prescription
Statistical Analysis
We calculated the prevalence and computed the odds ratios (OR) for all types and specific
subtypes of CHD in the group of children born to mothers with SLE versus the control group,
performing both univariable and multivariable regression analyses estimated with generalized
estimating equations21. Missing data on education and race/ethnicity covariates, occurring in
<6% of subjects, were handled by using multiple imputation (see Online Data Supplement).
In these analyses, we matched SLE exposed and unexposed children for maternal age
group and calendar year of delivery, but we also further adjusted for maternal age and calendar
7
DOI: 10.1161/CIRCULATIONAHA.114.010027
year to control for potential confounding by these variables (see Online Data Supplement). In
addition, we adjusted for relevant demographic factors and maternal co-morbidities, including
the following: sex of child, birth order, maternal education, race/ethnicity, pregestational and
gestational diabetes, maternal hypertension, and asthma. In the subsample with RAMQ-Rx plan
coverage, we also adjusted for in utero maternal medication exposures, including corticosteroids
(i.e. oral or intravenous corticosteroids), antimalarials (i.e. hydroxychloroquine or chloroquine),
immunosuppressives (i.e. azathioprine, mycophenolate mofetil, mycophenolate sodium, and
methotrexate), and any types of antidepressants. Of note, we excluded exposure to
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
anticonvulsants from the subsample multivariable model because no CHD case was recorded for
this
his covariate.
Moreover, we performed a sensitivity analysis to account for the possibility of detection
bias.
Indeed,
undergo
fetal
biiass. In
Inde
deed
de
ed, of
ed
ooffspring
fssprin
pri g of SLE mothers are moree llikely
ikkely to underg
go feta
taal echocardiography
ec
as part
screening
detect
heart
block
utero
maternal
antioff rroutine
o tine scree
ou
eeni
n ng tto
o de
dete
tect
te
ct ccongenital
onge
on
gennittall hea
ge
artt blo
ockk in
n tthose
hosse eexposed
ho
xpposed
d iin
n ut
uter
eroo to m
er
aterrnaal an
ater
ntiiSSA/Ro
women
with
SLE
SS
SA/
A/Ro
R and/or
Ro
and
nd/o
/orr anti-SSB/La
anti-S
ant
ti-SSB
SB
B/L
/La antibodies,
a ti
an
tibo
bodi
bo
dies
ess, which
whiichh are
wh
are pre
ppresent
resen
esen
entt in
in uup
p to 440%
0%
% ooff wome
w
ome
m nw
ith
th
hS
LE
E222.
Dm
ight
ig
ht bbee mo
m
re eeasily
assil
i y de
ddetected
teect
cted
ed iin
n cchildren
h ld
hi
ldre
r n bo
re
born
rn too wo
w
menn wi
me
with
th S
LE tthan
hann in
ha
Hence, CHD
might
more
women
SLE
controls, leading to an overestimation of the association. Thus, to account for this possibility, we
re-ran the analysis excluding children who had •1 fetal echocardiography.
In addition, to investigate the clinical impact of a potentially increased risk of CHD in
SLE offspring versus controls, we further assessed the risk of CHD repair procedures (see Online
Data Supplement), adjusting for the potential confounders mentioned above, except medication,
due to the small number of procedure events in the subsample with public drug coverage.
The study was approved by the "Commission d'Accès à l'Information du Québec" and the
McGill University Research Ethics Board. Informed consent is not required for administrative
8
DOI: 10.1161/CIRCULATIONAHA.114.010027
database research in Quebec. The first author takes full responsibility for the accuracy and
completeness of the data.
Results
Five hundred and nine women with SLE had 719 children, while 5824 matched controls had
8493 children. Mean maternal age in the overall sample of mothers and mean SLE disease
duration were respectively 30.3 (standard deviation, SD, 5.0) and 3.7 (SD 4.0) years (Table 1).
Mothers with SLE had similar demographic characteristics compared to control mothers, except
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
for race/ethnicity since they were less likely to be Caucasians (as expected, because black and
Asian race/ethnicity may predispose to SLE)1. In addition, mothers with SLE ha
had
ad mo
m
more
ree ccooomorbidities and experienced substantially more obstetrical complications, such as preterm births
an
and
nd pre-eclampsia/eclampsia,
pree-ec
pr
e-eccla
lam
mpsi
siia/
a/ec
e lampsia, compared to control
contrrol mothers.
mothers. In ut
utero
ter
e o dr
drug
rug exposures were more
ffrequent
req
que
u nt in SLE
SL
LE offspring
offfssprin
ng compared
comp
co
mpar
arred too controls,
conttro
rols, with
with exposures
wit
expos
xpossures too corticosteroids
cor
orti
t costterroi
oids
dss aand
nd
antimalarials
an
nti
tima
mala
ma
lari
rial
alss being
al
beiing the
be
the most
mo t common
com
mmo
monn drugs
drug
dr
ugss prescribed
ug
prres
e criibed
d during
dur
urin
ingg SLE
SL
LE pregnancies.
p egn
pr
egnanc
nanc
ncie
iees. Among
Among
mong the
thee 11
11
children withh in uutero
tero
te
r iimmunosupressive
ro
mmun
mm
unos
un
osup
upre
up
reess
s iv
ve exposures,
expo
ex
posu
po
s re
su
res,
s, all
alll were
wer
e e exposed
expo
ex
p se
po
sedd to azathioprine,
aza
zath
th
hio
iopr
prin
pr
ine,
in
e with 7/11
e,
having •3 records of the drug dispensed, and one child was additionally exposed to
mycophenolate mofetil, albeit with only one record of the drug dispensed early in gestation.
Compared to controls, children born to women with SLE experienced more CHD [5.1%
(95% CI 3.7, 7.1) versus 1.9% (95% CI 1.6, 2.2), difference 3.2% (95% CI 1.9-5.2)], including
more ASD, VSD, and valve anomalies (Table 2). In offspring with maternal drug coverage
throughout pregnancy (n=1925), we observed 5 cases of CHD (4 born to SLE mothers and 1 to a
control mother) among the 46 children exposed to corticosteroids, and one case of CHD in the 11
children exposed to immunosuppressives, all born to SLE mothers.
9
DOI: 10.1161/CIRCULATIONAHA.114.010027
In multivariable analyses including all children (n=9212), children born to women with
SLE had a substantially increased risk of CHD (OR 2.62, 95%CI 1.77-3.88) compared to
controls (Table 3). Specifically, offspring of SLE mothers had substantially increased odds of
ASD (OR 3.32, 95%CI 1.97-5.77), VSD (OR 2.50, 95%CI 1.31-4.75), and valve anomalies (OR
2.95, 95%CI 1.23-7.07) compared to controls. Other predictors of CHD included pregestational
diabetes and asthma (Table 3).
There was an imbalance between the 2 groups in terms of fetal echocardiography, with
16.3% of SLE offspring having •1 fetal echocardiography compared to 2.5% of control children.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
When accounting for the possibility of detection bias by excluding children with •1 fetal
echocardiography (n=331) from the multivariable analyses, adjusted effect estima
estimates
were
maatees we
w
re
similar
4).
imilar to the primary multivariable analysis results for CHD and all subtypes of CHD (Table 4)
subsample
medications
IIn
n th
thee su
ubs
bsaample
am analysis controlling forr ma
maternal medicat
attio
i ns ((Table
Table 5), though the
effect
ef
ffeect
c estimates
es for
for the
the
h association
asssoc
ocia
iati
ia
tion
on
n of
of ASD
A D (OR
AS
(O 2.05,
2.005, 95%CI
95%C
95
%C
CI 0.66-6.37)
0.666-6.
6 37
37) with
with maternal
mat
ater
errna
n l SLE
SLE
remained
ema
main
ined
in
ed similar
sim
imil
ilar
arr to
to the
th
he primary
p im
pr
imar
a y multivariable
ar
mulltiv
mu
ltiv
varria
iabble
ble analysis
a alyysis
an
ys s result,
res
esuult,
ul , the
thee 95%CI
95%
5%CI
CI was
was
as wide
wid
de and
andd included
in
ncl
cluude
uded
ed
the
SLE
he null value
ue due
due to
to reduced
reedu
d ce
cedd sample
saamp
m le size
siz
izee (155
iz
(1555 SL
LE of
ooffspring
fsspr
prin
ingg an
in
andd 17
1770
70 ccontrols).
ontr
on
trol
ols)
ol
s).. In aaddition,
s)
ddition,
after adjusting for maternal medication exposures, results were inconclusive for the risk of CHD
and specifically VSD in SLE offspring compared to controls. However, we observed an effect of
corticosteroid exposure on the likelihood of CHD (OR 5.65, 95%CI 1.65-19.34), after adjusting
for both pregestational and gestational diabetes. Of note, we could not perform a multivariable
analysis adjusting for medication exposure for the outcome of valve anomaly, as no case was
observed in SLE offspring in the subsample with provincial drug coverage.
Among children with CHD, those born to SLE mothers had more CHD repair procedures
compared to controls [10.5% (95%CI 2.9-24.8) versus 3.7% (95%CI 1.4-7.9)] (Table 6). In
10
DOI: 10.1161/CIRCULATIONAHA.114.010027
addition, compared to controls, offspring of SLE mothers had a substantially increased likelihood
of having a repair procedure for any type of CHD (OR 5.82, 95%CI 1.77-19.09), and specifically
having a cardiac septal defect repair procedure (OR 4.95, 95%CI 1.22-20.07), after adjusting for
relevant covariates.
Discussion
Compared to children from the general population, children born to women with SLE have an
increased risk of CHD, including a specifically increased risk of ASD, VSD, and valve
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
anomalies. In addition, offspring of SLE mothers have substantially increased odds of CHD
repair
SLE
epair procedures compared to children from the general population. The effect ooff SL
S
E on aall
ll
ll
types
ypes of CHD does not seem to be explained by detection bias and might be independent of
medication
medi
me
dica
di
cati
ca
tion
ti
on exposures.
expos
ossure
ures. Because of the limited power
pow
oweer afforded by the
ow
t e sample
th
saample
mp of subjects who had
provincial
drug
analyses
inconclusive,
prov
vincial dru
ug cove
ccoverage,
overa
raagee, th
thee find
ffindings
ind
din
ings
gs ooff an
nal
alyysess llimited
imiite
ited
ed tto
o th
this
iss ssubgroup
ubgr
ub
grrouup are
are in
inc
connclu
nclu
lusi
siive
ve,,
though
increased
CHD,
regardless
medication
hou
ough
gh sstill
till
ti
lll ppointing
oinntin
oi
ng tto
o aan
n in
ncr
c eaase
sedd ri
risk
sk ooff C
HD,, re
HD
egaard
dle
lesss ooff me
medi
dica
di
caatiion
o eexposure.
xpos
xp
osur
uree.
ur
We found
foun
fo
undd an association
un
ass
ssoccia
iati
tion
ti
on
n between
bettwe
ween
en in
in utero
uter
ut
e o exposure
er
expo
ex
p su
po
sure
re to
to corticosteroids
cort
co
r ic
icos
oste
os
tero
te
roid
ro
idss and
id
and CHD,
CHD althoughh
the confidence interval was wide. Several studies have investigated the potential association
between in utero corticosteroid exposure and congenital anomalies, but despite a potential and
still controversial increased likelihood of oral cleft defects, no excess risk has been seen for other
types of congenital anomalies, in particular cardiac23. The effect of corticosteroid exposure on
CHD observed in our study might be in part explained by confounding by disease severity.
Indeed, if SLE itself has a causal effect on CHD (e.g. mediated through inflammation and/or
autoantibodies), and women with more severe SLE are more likely to have active disease during
pregnancy and require corticosteroids for disease control, then confounding by disease severity is
11
DOI: 10.1161/CIRCULATIONAHA.114.010027
likely to have occurred and account for some of the apparent effect of corticosteroid exposure.
We observed that pregestational diabetes was a potentially important predictor of CHD
and all subtypes investigated. It is well recognized that, in the conception period and the first
trimester of pregnancy, maternal hyperglycemia can cause diabetic embryopathy resulting in
major congenital anomalies24. The most frequent type of major congenital anomalies seen in
women with pregestational and gestational diabetes is CHD24. Prior studies have shown that the
likelihood of CHD was highest in women with pregestational diabetes compared to those with
gestational diabetes (respectively 3-fold and 1.5-fold increased risk relative to healthy women)25Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
26
. We observed similar effect estimates, suggesting that our findings are consistent with
published literature on diabetic embryopathy.
The strength of our study resides in the use of Quebec's administrative databases, which
collect
co
olllec
ectt info
iinformation
nfo
form
rmattio
rm
on on all deliveries performed in the
th
he province, al
allo
allowing
l wiing uuss to create OSLER, the
lo
largest
Quebec's
arg
ges
e t cohortt of
of children
ch
hilldre
renn born
born to
to mothers
moth
mo
th
hers with
with
h SLE
LE ever
evver
ver assembled.
assseemb
bleed.
d In
In addition,
addi
addi
diti
tion
ti
on,, Qu
Queb
ebecc's
eb
administrative
source
for
conduct
with
ad
dmi
mini
nist
ni
stra
rati
tive
ti
ve ddatabases
ataabas
abassess aare
r a vvalid
re
alid
al
id ddata
ata so
ata
sou
urce
ce fo
or th
thee co
con
nduc
nduc
uctt of
o oobservational
b ervvati
bs
vatiion
onal
a sstudies,
al
tu
udiees,, wi
wit
th
th
definition
prior work from
fro
om our
our group
grou
gr
o p showing
ou
show
sh
ow
win
ingg that
t at our
th
our SLE
SLE ccase
asse de
defi
fini
fi
niti
ni
tion
on hhas
as a vvery
eryy hi
er
high
gh sspecificity
peci
pe
c ficity
ci
(0.99)14. Of note, 16% of SLE children were exposed in utero to antimalarial drugs, which are
used to prevent SLE flare. This is comparable to exposure in SLE pregnancies observed over a
similar time period and from a well-established tertiary care lupus cohort, where 22% were
exposed to antimalarials beyond the first trimester27. Furthermore, a recent study assessed the
validity of pregnancy-related variables recorded in the RAMQ, MED-ECHO, and ISQ databases,
such as gestational age and live births, and showed very high sensitivity (0.97-0.99) and
specificity (0.92-0.98) for all the variables examined, concluding that these administrative
databases are a valid data source for pregnancy-related variables28.
12
DOI: 10.1161/CIRCULATIONAHA.114.010027
We used a widely accepted definition of CHD based on ICD-10/9 diagnostic codes
established by the EUROCAT network16. In addition, a recent study assessed the validity of
ICD-10/9 diagnostic codes for major congenital anomalies, including CHD, recorded in Quebec's
administrative databases17. Those investigators used medical chart as the gold standard and
evaluated the performance of relevant diagnostic codes recorded during the first year of life in
children born to asthmatic women compared to children born to non-asthmatic women. Results
were similar between both groups; in particular, both the positive predictive value of CHD and
the negative predictive value for any type of congenital anomalies were high (both more than
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
94%)17. As asthma is one of the most frequent chronic diseases encountered during pregnancy,
with potential for disease exacerbation, similar to SLE in pregnancy, it is of inte
interest
ere
rest
stt tto
o no
note
te tthat
hat
ha
there
here was no differential ascertainment of congenital anomalies in offspring of affected women
compared
co
omp
mpar
ared
ar
ed to
to controls.
cont
ntro
nt
rols
ro
l . We would hope, though we cannot
cannot be sure
sure,
e, that
at tthere
he would similarly be
here
nnoo differential
dif
i ferentiall ascertainment
assceerttai
a nm
men
entt of
of congenital
con
onge
geni
nittal anomalies
anomaaliies in
ano
in offspring
offfsprin
of
prin
ng of women
wom
men
n affected
aff
ffec
eccteed by
b SLE,
SLE
LE,,
compared
controls.
co
omp
mpar
ared
ar
ed tto
o co
con
ntro
ntro
ols
ls..
wee ac
accounted
the
possibility
more
Still,, w
cco
coun
u te
un
t d fo
forr th
he po
poss
sib
ibil
ilit
il
itty of ddetection
e ec
et
e ti
tion
on bbias
iaas du
due to m
oree fr
or
ffrequent
eque
eq
uent
ue
nt uuse
se of fetal
echocardiography in SLE pregnancies, which is a considerable strength of our study. After
excluding children who had •1 fetal echocardiography, the effect estimates for all types and
subtypes of CHD were similar compared to the overall analysis results. However, this sensitivity
analysis did not account for subtle forms of detection bias that might have occurred after
delivery. Indeed, mothers with SLE might be more concerned that their child develops a health
problem than control mothers, and might seek more frequently medical attention for their
offspring. If this were the case, it would increase the number of CHD cases diagnosed in children
born to SLE mothers, particularly minor and/or asymptomatic cases. To strengthen our case, we
13
DOI: 10.1161/CIRCULATIONAHA.114.010027
found a substantially increased risk of CHD repair procedures in offspring of SLE mothers
compared to controls, which does not suggest that detection bias occurring after the pregnancy
solely explained the observed association between CHD and maternal SLE.
Our study has some potential limitations. As mentioned previously, the subsample
analysis accounting for relevant medication exposures did not allow us to precisely estimate the
association between maternal SLE and CHD in offspring due to the limited power given by the
reduced sample of subjects with provincial drug coverage. Regardless, this is the largest study to
date assessing the risk of CHD in SLE offspring.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Another potential limitation is that medication exposures were defined based on filled
prescriptions, which might not have reflected actual intake. However, it is likely
y tthat
haat mo
most
st
women who filled a prescription for a specific medication took at least one dose because, within
the
their
medication
he RA
RAMQ
MQ pprescription
resc
sccri
ripption plan, beneficiaries need
d tto
o ccover
over part of th
heirr me
medi
d cation cost29.
In addi
addition,
diti
tiion
on, in all
lll oobservational
bser
bs
errva
vati
tioona
ti
onal sstudies,
tudi
diiess, un
unmeasured
nmeaasu
asured
ured
d or
or poorly
pooorl
rlyy me
m
measured
asur
as
ured
ur
ed cconfounding
onfo
on
f un
fo
undi
dinng
ng
represents
epr
pres
essen
e ts a major
maj
ajor
or concern.
connceern
rn. We have
hav
avee considered
cons
cons
nsid
iderred
id
e this
this
thi
is and
and
d used
use
sedd well-defined
well
ll-d
ll
-deefin
-d
ned
d proxies
pro
roxi
xiies for
orr certain
cer
erta
taain
n
variables (e.g.
(e.g
.g
g. socio-economic
soci
so
cioci
o eccon
oo om
omic
i status,
ic
stat
a us
us, race/ethnicity).
race
ra
ce/e
ce
/eeth
hni
n ci
c ty
ty).
). S
Still,
till
ti
ll,, ad
ll
admi
administrative
mini
mi
n st
stra
rati
ra
tive
ti
ve ddatabases
atab
at
abas
ab
ases
as
es ddo
o not
contain information on, for example, smoking, obesity, or alcohol use, which have all been
associated with an increased risk of having a child with CHD in exposed pregnant women.
However, prior data from Quebec suggest that smoking practices, obesity prevalence, and
alcohol use in SLE patients are comparable to the general population30. Therefore, the lack of
information on these variables is unlikely to have introduced substantial bias.
Other limitations include our inability to adjust for folic acid and multivitamin exposures
during pregnancy since these supplements are frequently obtained without a prescription (i.e.
over the counter), and thus not captured in a large proportion of women covered by the RAMQ-
14
DOI: 10.1161/CIRCULATIONAHA.114.010027
Rx plan. Moreover, stillbirths were not included a priori in our analyses because a significant
proportion of stillbirths in Quebec result from pregnancy termination, for which no information
on the outcome of interest is recorded15. Still, in our cohort, we observed few stillbirths resulting
from pregnancy termination, and the effect estimate for CHD did not change when stillbirths
were included in the overall analysis (see Online Data Supplements).
Furthermore, Quebec's administrative databases do not record serological data on any
individual. This would have been of interest particularly in women with SLE to determine if
specific types of maternal autoantibodies, such as anti-Ro//SSA and/or antiphospholipid
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
antibodies, predict CHD in children born to women with SLE. Still, establishing an association
between in utero SLE exposure and CHD shed new light on the potential role off m
a errna
at
nall
maternal
autoantibodies and cytokines in CHD pathogenesis.
IIndeed,
ndee
nd
e d, maternal
ee
mate
aternal SLE-related mechanisms
mechanism
ms that
ms
that could be implicated
imp
m liicaated
te in the
ph
hysiopatholog
ys
ogyy ooff C
HD
D iin
n of
offs
fspr
prrin
ng in
includ
de aut
toantiibo
body
dyy-m
med
dia
iate
tedd da
ddamage
maage aand
ndd ccytokine
y ok
yt
o in
inee
physiopathology
CHD
offspring
include
autoantibody-mediated
imbalance.
mba
bala
lanc
la
nce.
e. Transplacental
Tra
rans
nsspllac
aceenta
enta
t l transfer
trran
a sf
sfer
fer of
of maternal
mate
ma
tern
te
rnal
rn
al IgG
IgG
gG antibodies
antib
ntib
bod
odie
iess begin
beegiin inn the
thhe
he second
sec
econ
o d trim
on
ttrimester,
r messte
ter,
r,
eaching circu
cu
ula
lati
ting
ng llevels
evel
ev
e s in tthe
he nnewborn
ewbo
ew
boorn
n tthat
hatt ex
ha
exce
c ed
ce
e m
ater
at
erna
er
nall le
na
llevels,
vels
ve
lss, du
duee to
t aactive
ctiv
ct
ivee tr
iv
ttransport
ansport
reaching
circulating
exceed
maternal
across the placenta31. Anti-SSA/Ro and anti-SSB/La antibodies, found in approximately 40% of
women with SLE, cross the placenta and are associated with the development of neonatal lupus,
with congenital heart block being the most characteristic cardiac manifestation. Investigators
have demonstrated that maternal anti-SSA/Ro and anti-SSB/La antibodies bind apoptotic fetal
cardiocytes, resulting in the release of pro-inflammatory and pro-fibrosing cytokines, and
ultimately scarring32. This process likely extends beyond the conduction tissue, involving the
myocardium, endocardium and valves. In a recent retrospective analysis of autopsies from 18
cardiac neonatal lupus cases, cardiac histological damage outside of the conduction system was
15
DOI: 10.1161/CIRCULATIONAHA.114.010027
frequently observed12. In particular, one autopsy showed a lympho-histiocytic infiltrate with
inflammatory giant cells in the ventricular septum, while another displayed foci of microscopic
calcification in the atrial septum. Moreover, 40% (6/15) of deaths due to congenital heart block
had pathology findings such as fibrosis and calcification of the valves and/or valve apparatus,
including the tricuspid, mitral, aortic and pulmonary valves12.
Cardiac septation occurs early in embryogenesis and is complete by 6 weeks of
gestation33. Since transplacental passage of maternal autoantibodies only occur as early as the
20th week of gestation, it is unlikely that maternal autoantibodies directly interfere with cardiac
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
septation. However, muscular VSD, which account for approximately 75% of all VSD, are
hought to arise from foci of cellular death that occur during active cardiac remod
oddellin
i g, w
ithi
it
hinn an
hi
thought
remodeling,
within
already formed ventricular septum34. In addition, maternal autoantibodies might prevent closure
car
ardi
diac
di
acc septal
sep
eptall defects
defe
de
f cts that might have closed otherwise,
otherwise, possibly
oth
possibl
blly explaining
ex
xpl
plaaining the excess risk of
off cardiac
cardiac
caard
dia
i c septal ddefects
efects
ts iin
n of
offs
offspring
fspr
fs
prin
pr
ingg off S
SLE
LE m
mothers
ottherss ccompared
om
mpare
pareed to ccontrols.
ontr
trol
o s..
ol
Antiphopholipid
Anttip
ipho
hoppho
pholip
olip
pid antibodies
ant
n ib
boddie
iess (aPL)
(aPL
(aPL
PL)) are
are another
anot
an
otther type
t pe of
ty
of autoantibodies
a toan
au
anti
an
t boddies
ti
diess commonly
com
o mo
monlly found
founnd in
foun
women with
h SLE,
SLE
L , which
w ic
wh
i h also
also cross
cro
ross
s the
ss
thee placenta.
pla
lace
cent
ce
n a. Inn a recent
nt
rec
ecen
ec
entt study
en
sttud
udyy of children
chi
hild
ldre
ld
renn born
re
born to
to women
with antiphospholipid syndrome, 40% of neonates had positive aPL in cord blood35. aPL are
strongly associated with valvular disease (e.g. valvular nodules, regurgitation, and verrucous
endocarditis) in aPL-positive adult patients with and without SLE36. Valvular deposits of aPL in
affected adult subjects are thought to play an important pathogenic role in valvular disease36.
Although prior studies have reported perinatal thrombotic events occurring in children born to
aPL-positive mothers, there is currently no data on the prevalence of congenital valve anomalies
or other types of CHD in these children37. Since aPL are involved in valvular damage in
seropositive adult subjects and cross the placenta, it could be hypothesized that they may play a
16
DOI: 10.1161/CIRCULATIONAHA.114.010027
role in valve anomalies in exposed fetuses.
Cytokines, such as transforming growth factor beta (TGF-beta), play an important role in
cardiac embryogenesis. In particular, adequate endocardial cushion formation, which is a critical
step in cardiac septation, requires expression of TGF-beta38. The importance of both maternal
and fetal TGF-beta in cardiac embryogenesis has been well illustrated in animal models38.
Notably, TGF-beta-1-null mice, born to TGF-beta-1-null mothers, demonstrate severe CHD,
while TGF-beta-1-null mice born to wild-type mothers (i.e. with normal expression of TGF-beta1) do not. Because transplacental transfer of circulating TGF-beta can occur from mother to
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
fetus, investigators hypothesized that maternal TGF-beta-1 might rescue any potential heart
defects in the null offspring38. Interestingly, in SLE patients, serum levels of TG
TGF-beta-1
GF-be
F-be
b taa-1 aare
re
substantially
ubstantially lower than in controls, with levels inversely correlating with disease activity39.
Th
hus
us,, maternal
mate
mate
tern
r al T
rn
GF
GF-beta
rescue of fetuses with
h ddefective
effective TGF-b
bet
e a le
eve
vells might not occur in
Thus,
TGF-beta
TGF-beta
levels
w
women
om
men with SLE,
SLE
LE, potentially
po
otent
tent
ntia
iallly
ia
lly accounting
acco
acco
ount
unting forr the
the increased
inccreas
ased
as
ed rrisk
issk of
of C
CHD.
HD.
HD
IInn conclusion,
connclu
co
nclu
usiion
on,, ch
children
hil
ildr
dreen
en bborn
ornn to w
or
women
omen
om
en
nw
with
ith SL
ith
SLE
LE ha
havee aan
n in
increased
ncr
c eased ri
rrisk
sk ooff CHD
C
CHD,
HD,
D,
including
ncluding a sp
spec
specifically
ecif
ec
iffic
ical
a ly iincreased
al
nccre
reas
a ed rrisk
iskk of
is
o A
ASD,
SD,, VS
SD
VSD,
D, and
nd vvalve
alve
al
ve aanomalies,
nooma
mali
lies
li
es,, co
es
comp
compared
mpar
mp
ared
ar
ed to children
n
from the general population. In addition, offspring of SLE mothers have substantially increased
odds of CHD repair procedures compared to children from the general population. Our findings
prompt further research to elucidate the potential role of disease-related factors, such as in utero
drug exposures, maternal autoantibodies and cytokines, which might explain the increased
likelihood of CHD in children born to mothers with SLE.
Funding Sources: This study was funded through a Canadian Institutes of Health Research
operating grant.
17
DOI: 10.1161/CIRCULATIONAHA.114.010027
Conflict of Interest Disclosures: E Vinet reports a Canadian Institutes for Health Research
(CIHR) Fellowship and Fonds de Recherche en Santé du Québec (FRSQ) Fellowship. AE Clarke
is the the Arthritis Society Chair in Rheumatology and Rheumatic Diseases. S Bernatsky
received the FRSQ Career award and CIHR Junior Investigator award. The remaining authors
have no disclosures to report.
References:
1. Chakravarty EF, Bush TM, Manzi S, Clarke AE, Ward MM. Prevalence of adult systemic
lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using
hospitalization data. Arthritis Rheum. 2007;56:2092-2094.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
2. Canfield MA, Honein MA, Yuskiv N, Xing J, Mai CT, Collins JS, Devine O, Petrini J,
Ramadhani TA, Hobbs CA, Kirby RS. National estimates and race/ethnic-specific variation of
elected birth defects in the United States, 1999-2001. Birth Defects Res A Clin Mol
Mol Teratol.
Ter
erat
atol
ol..
selected
2006:747-756.
3. Talner CN. Report of the New England Regional Infant Cardiac Program, by Donald C. Fyler,
MD, Pediatrics, 1980;65:375-461.
19980;65:375-461. Pediatrics. 1998;102:258-259.
199
9 8;102:258-259.
4. Williams
Wil
illi
l ams LJ,
LJ,, Correa
Corr
Co
rrea
eaa A,
A, Rasmussen
R sm
Ra
mus
usse
senn S. Maternal
Mat
ater
erna
nall lifestyle
lifest
styl
ylee factors
yl
f cttor
fa
orss and
and risk
ris for
forr vventricular
e tr
en
tric
icul
ular
ul
a sseptal
ar
epta
ep
t l
defects.
Defects
Res
Mol
Teratol.
2004;70:59-64.
defeect
defe
c s. Birth De
Defe
feectts Re
es A Cl
Clin
in M
ol T
eratol
o . 200
ol
04;70
0:5
599-64
644.
5.. L
Liu
S,, Jo
Joseph
KS,
Lisonkova
S,, Ro
Rouleau
Van
Sauve
R,, Kr
Kramer
MS;
Canadian
iu
uS
ose
seph
ph K
S, L
isson
onko
koovaa S
R
ulea
eauu JJ,, V
ea
an dden
enn Ho
Hoff M, S
au
uve
v R
ram
amer
er M
S; C
anad
anad
diaan
Perinatal
Surveillance
System
(Public
Health
Agency
Canada).
Association
between
maternal
Peri
rina
nata
t l Su
Surv
vei
eillan
ance
ce Sys
ste
t m (P
(Pub
ublic He
Heal
alth
th A
g ncy
ge
y ooff Ca
Cana
nada
d ). A
ssoc
ss
o iat
atio
on be
betw
t ee
een ma
mate
tern
nal
a
chronic conditions
conddittio
ions
nss and
andd congenital
connge
geni
nita
tall heart
ta
hearrt defects:
he
defe
de
fect
fe
cts:
ct
s a population-based
s:
pop
opul
ullat
a io
ionn ba
nbase
s d cohort
coho
co
hort
ho
rt sstudy.
tu
udy
dy.. Circulation.
Circ
Ci
r ulation.
rc
2013;128:583-589.
2013
20
13;1
;128
28:5
:583
83-589
589
6. Østensen M, Förger F. How safe are anti-rheumatic drugs during pregnancy? Curr Opin
Pharmacol. 2013;13:470-475.
7. Krishnan AN, Sable CA, Donofrio MT. Spectrum of fetal echocardiographic findings in
fetuses of women with clinical or serologic evidence of systemic lupus erythematosus. J Matern
Fetal Neonatal Med. 2008;21:776-782.
8. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol.
2002;39:1890-1900.
9. Costedoat-Chalumeau N, Amoura Z, Villain E, Cohen L, Piette JC. Anti-SSA/Ro antibodies
and the heart: more than complete congenital heart block? A review of electrocardiographic and
myocardial abnormalities and of treatment options. Arthritis Res Ther. 2005;7:69-73.
10. Costedoat-Chalumeau N, Amoura Z, Lupoglazoff JM, Huong DL, Denjoy I, Vauthier D,
18
DOI: 10.1161/CIRCULATIONAHA.114.010027
Sebbouh D, Fain O, Georgin-Lavialle S, Ghillani P, Musset L, Wechsler B, Duhaut P, Piette JC.
Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165 pregnancies,
with special focus on electrocardiographic variations in the children and comparison with a
control group. Arthritis Rheum. 2004;50:3187-3194.
11. Buyon JP, Hiebert R, Copel J, Craft J, Friedman D, Katholi M, Lee LA, Provost TT, Reichlin
M, Rider L, Rupel A, Saleeb S, Weston WL, Skovron ML. Autoimmune-associated congenital
heart block: demographics, mortality, morbidity and recurrence rates obtained from a national
neonatal lupus registry. J Am Coll Cardiol. 1998;31:1658-1666.
12. Llanos C, Friedman DM, Saxena A, Izmirly PM, Tseng CE, Dische R, Abellar RG, Halushka
M, Clancy RM, Buyon JP. Anatomical and pathological findings in hearts from fetuses and
infants with cardiac manifestations of neonatal lupus. Rheumatology (Oxford). 2012;51:10861092.17.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
13. Davey DL, Bratton SL, Bradley DJ, Yetman AT. Relation of maternal anti-Ro/La antibodies
to aortic dilation in patients with congenital complete heart block. Am J Cardiol. 2011;108:561564.
14. Bernatsky S, Joseph L, Pineau CA, Tamblyn R, Feldman DE, Clarke AE. A po
populationopu
pula
laati
tion
on-on
based assessment of systemic lupus erythematosus incidence and prevalence Rheumatology
(Oxford).
2007;46:1814-1818.
(Oxfford)). 2007
0 ;46:1814-1818.
15.
15
5. Joseph
Jo h KS,
KS, Kinniburgh
Kin
inni
nibu
bu
urg
rghh B, Hutcheon
Hut
utch
cheo
eonn JA,
JA, Mehrabadi
Mehhraabad
Me
di A, Basso
Bassso M,
M, Davies
Davi
Da
v es C,
C, Lee
L e L.
Le
Determinants
of
2010.
CMAJ.
Detterminants
te
of increases
in
ncrrea
ease
sees in stillbirth
stil
st
illb
lb
birrth
t rrates
ates ffrom
ro
om 20
2000 tto
o 20
010. CM
CMAJ
AJ. 2013;185:E345–E351.
201
0133;1
3;185:
185::E3
E345
45–E
45
E35
351..
16.
Congenital
Anomalies
(Version
16
6. EUROCAT
EURO
EU
ROCA
CAT
CA
T Subgroups
Subg
Su
bg
grouups
ups of C
onge
on
geni
niitaal An
Anom
omal
om
alliees (V
(Ver
ersi
er
sion
onn 22012;
0 2; iimplemented
01
mple
mp
lem
ment
ment
n ed
d iin
n ED
EDMP
MP
P
2012,
website
prevalence
2012).
2012
12, used
ed ffor
orr w
eb
bsi
site
te pre
revaale
lenc
ncee ta
ttables
bless ffrom
rom
ro
m Ap
April 20
2012
12).
).
17.
Blais
L, B
Bérard
A, K
Kettani
FZ,
Forget
A. Va
Validity
congenital
malformation
17 Bl
Blai
aiss L
érar
ér
ardd A
etta
et
tani
ni F
Z F
orge
or
gett A
Vali
lidi
dity
ty ooff co
cong
ngen
enit
ital
al ma
malf
lfor
orma
mati
tion
on ddiagnostic
iagn
ia
gnos
osti
ticc
codes recorded in Québec's administrative databases. Pharmacoepi Drug Saf. 2013;22:881-889
18. Blais L, Lemière C, Menzies D, Berbiche D. Validity of asthma diagnoses recorded in the
Medical Services database of Quebec. Pharmacoepi Drug Saf. 2006;15:245-252.
19. Wilchesky M, Tamblyn RM, Huang A. Validation of diagnostic codes within medical
services claims. J Clin Epidemiol. 2004;57:131-141.
20. Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in
pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription
claims database in Québec. J Clin Epidemiol. 1995;48:999-1009.
21. Hanley JA, Negassa A, Edwardes MD, Forrester JE. Statistical analysis of correlated data
using generalized estimating equations: an orientation. Am J Epidemiol. 2003;157:364-375.
22. Lateef A, Petri M. Managing lupus patients during pregnancy. Best Pract Res Clin
19
DOI: 10.1161/CIRCULATIONAHA.114.010027
Rheumatol. 2013;27:435-447.
23. Oren D, Nulman I, Makhija M, Ito S, Koren G. Using corticosteroids during pregnancy: Are
topical, inhaled, or systemic agents associated with risk? MOTHERISK August 2004
http://www.motherisk.org/prof/updatesDetail.jsp?content_id=693 (last accessed February 21,
2014)
24. Corrigan N, Brazil DP, McAuliffe F. Fetal cardiac effects of maternal hyperglycemia during
pregnancy. Birth Defects Res A Clin Mol Teratol. 2009;85:523-530
25. Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, Cleves MA, RiehleColarusso TJ, Waller DK, Reece EA. Diabetes mellitus and birth defects. Am J Obstet Gynecol.
2008;199:237.e1-9.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
26. Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, Golightly S, Miller
A. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2
diabetes in England, Wales, and Northern Ireland: population based study. BMJ. 2006;333:177.
Arthritis
27. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy.
preggnan
gnan
ancy
cy
y. Ar
Arth
thri
th
ritis
Rheum. 2006;54:3640-3647.
Vilain
Otis
S,, Forget A, Blais L. Agreement between administrative databases and
28. Vi
V
lain A,, Ot
tis S
medical
medi
me
dica
di
call charts
ca
char
ch
a ts for
ar
for pregnancy-related
pregnancy-related variables among
amoong asthmatic women.
am
w meen.
wo
n. Pharmacoepidemiol
P armacoepidemiol
Ph
Drug
Dr
ug SSaf.
af. 22008;17:345-353.
008;
00
8;17
17
7:3
:345
45
5-3
-353
53..
53
29.
Blaschke
Engl
Med.
29
9. Osterberg
Osterberrg L, B
lascchke T.
T. Adherence
Adh
dher
erren
e cee to medication.
m diccattion
me
tionn. N En
Eng
gl J M
ed. 22005;353:487-497.
005;
00
5;35
3 3:44877-4
35
7-497
497.
Bernatsky
Boivin
Joseph
Pierre
Clarke
Prevalence
30. Be
Bernat
atsk
sky S,
S B
oivvin JF
oi
JF, Jo
Jose
s ph L, St P
ierr
ie
rre Y,
Y Moore
Moo
oore
re A,
A, Rajan
R jaan R, Cla
Ra
ark
rkee A. P
reeva
valeenc
ncee off
influencing
women
with
factors influe
enc
ncin
i g ca
in
ccancer
ncer rrisk
nc
issk in w
o en w
om
i h lupus:
it
l pu
lu
pus:
s:: social
soc
ocia
iall habits,
ia
habi
ha
bits
bi
t , reproductive
ts
r pr
re
prod
oduc
od
ucti
uc
tive
ve iissues,
ssue
ss
ues,
ue
s and
obesity.
Rheumatol.
obes
ob
esit
ityy J Rh
Rheu
euma
mato
toll 22002;29:2551-2554
002;
00
2;29
29:2
:255
5511-25
2554
54
31. Garty BZ, Ludomirsky A, Danon YL, Peter JB, Douglas SD. Placental transfer of
immunoglobulin G subclasses. Clin Diagn Lab Immunol. 1994;1:667-669.
32. Izmirly PM, Buyon JP, Saxena A. Neonatal lupus: advances in understanding pathogenesis
and identifying treatments of cardiac disease. Curr Opin Rheumatol. 2012;24:466-472.
33. Van Praagh R. Section II - Developmental anatomy. Chapter 2 – Embryology. Keane: Nadas'
Pediatric Cardiology, 2006 Saunders, Elsevier p. 13-25.
34. Clark EB: Growth, morphogenesis, and function: the dynamics of cardiovascular
development. In: Moller JM, Neal WA, ed. Fetal, Neonatal, and Infant Heart Disease, New
York: Appleton-Century-Crofts; 1989:1-22.
35. Mekinian A, Lachassinne E, Nicaise-Roland P, Carbillon L, Motta M, Vicaut E, Boinot C,
Avcin T, Letoumelin P, De Carolis S, Rovere-Querini P, Lambert M, Derenne S, Pourrat O,
20
DOI: 10.1161/CIRCULATIONAHA.114.010027
Stirnemann J, Chollet-Martin S, Biasini-Rebaioli C, Rovelli R, Lojacono A, Ambrozic A, Botta
A, Benbara A, Pierre F, Allegri F, Nuzzo M, Hatron PY, Tincani A, Fain O, Aurousseau MH,
Boffa MC. European registry of babies born to mothers with antiphospholipid syndrome. Ann
Rheum Dis. 2013;72:217-222.
36. Zuily S, Huttin O, Mohamed S, Marie PY, Selton-Suty C, Wahl D. Valvular heart disease in
antiphospholipid syndrome. Curr Rheumatol Rep. 2013;15:320.
37. Boffa MC, Lachassinne E. Infant perinatal thrombosis and antiphospholipid antibodies: a
review. Lupus. 2007;16:634-41.
38. Arthur HM, Bamforth SD. TGFȕ signaling and congenital heart disease: Insights from mouse
studies. Birth Defects Res A Clin Mol Teratol. 2011;91:423-434.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
39. Su DL, Lu ZM, Shen MN, Li X, Sun LY. Roles of pro- and anti-inflammatory cytokines in
the pathogenesis of SLE. J Biomed Biotechnol. 2012;2012:347141.
21
DOI: 10.1161/CIRCULATIONAHA.114.010027
Table 1. Characteristics of the SLE offspring and control children (n=9212) in Quebec's
administrative databases, Canada, 1989-2009.
Characteristics
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Maternal characteristics
Mean age, years (sdb)
Mean education, years (sd)
Marital status, n (%)
Couple
Single
Unknown
Comorbidities, n (%)
Hypertension
Asthma
Diabetes
Depression
Paternal characteristics
Mean age, years (sd)
Demographic characteristics
Male gender, n (%)
Ethnic
i ity,
y, n ((%)
%))
Ethnicity,
Cau
auca
c si
sian
an
Caucasian
Oth
ther
Other
Obsstetrical
st
ch
har
arac
accteeri
rist
stic
icss
ic
Obstetrical
characteristics
Mean
gestational
age,
weeks
M
e n gest
ea
tat
ationnal
nal ag
ge, wee
eeekss ((sd)
s )
sd
Mean
weight,
grams
Meaan birth
biirt
rthh we
eig
ight
h , gr
ht
gram
a s (s
am
(sd)
d)
Birth
order,
Bir
irth
th ord
rdeer,, n (%
(%))
1
•2
Obstetrical complications, n (%)
Preterm birth
Small for gestational age
Gestational diabetes
In utero medication information
Public drug coverage, n (%)
Corticosteroids
Antimalarials
Immunosuppressives
Antidepressants
Anticonvulsants
SLE* offspring
(n=719)
Control children
(n=8493)
p-values
30.2 (5.1)
14.0 (3.1)
30.3 (5.0)
13.8 (3.1)
0.56
0.07
576 (80.1)
50 (7.0)
93 (12.9)
6904 (81.3)
523 (6.2)
1066 (12.6)
0.65
47 (6.5)
38 (5.3)
23 (3.2)
11 (1.5)
87 (1.0)
240 (2.8)
143 (1.7)
38 (0.4)
<0.0001
0.0002
0.003
0.0001
33.2 (5.8)
33.3 (5.9)
0.47
0.47
0.
4
47
402 (55.9)
4377 (51.5)
0.02
444
44
44 (61.8)
275
(38.2)
27
75 (3
38.2)
8.2)
6226
62
226
26 (73.3)
2268
22
268
6 (26.7)
(26
266.7
.7)
7)
<0.0001
37.7
37
7.7
7 ((2.9)
2.9)
2.
9)
2976
29
766 ((707)
7077)
70
7)
338.8
8..8 ((1.9)
1.9
. )
.9
33367
367
67 ((566)
566)
56
6)
<0.0001
<
0.000
001
00
<0.0001
<
<0.0
0.000
0011
00
3088 (42.8)
30
(4
42.
2 8)
4111 (57.2)
41
(577 2)
(5
2333
23
33 (27.5)
(27
2 .5
.5))
6160
61
60 (72.5)
(72 5)
<0.0001
157 (22,0)
120 (16.7)
30 (4.2)
614 (7.3)
694 (8.2)
263 (3.1)
<0.0001
<0.0001
0.11
155 (21.6)
34 (21.9)†
25 (16.1)†
11 (7.1)†
11 (7.1)†
1 (0.6)†
1770 (20.8)
12 (0.7)c
1 (0.1)c
0 (0.0)c
52 (2.9)c
7 (0.4)c
0.65
<0.0001
<0.0001
<0.0001
0.005
0.49
*
Systemic lupus erythematosus; †standard deviation; †denominator used for proportion is number of children born to
SLE mothers with public drug coverage during pregnancy; ††denominator used for proportion is number of children
born to control mothers with public drug coverage during pregnancy.
22
DOI: 10.1161/CIRCULATIONAHA.114.010027
Table 2. Frequency of congenital heart defects and subtypes in SLE offspring and control
children (n=9212) in Quebec's administrative databases, Canada, 1989-2000.
Types
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Any congenital heart defects
(CHD), n (%)
Cardiac septal defects, n (%)
Atrial septal defects
Isolated†† ASD
Ventricular septal defects (VSD)
Isolated VSD
Cardiac valve anomalies
Isolated valve anomalies
Other CHD
Other CHD without ASD, VSD,
and valve anomalies†
CHD with •1 extra-cardiac major
congenital anomalies
SLE* offspring
(n=719)
37 (5.1)
Control children
(n=8493)
159 (1.9)
p-values
29 (4.0)
21 (2.9)
11 (1.5)
12 (1.7)
6 (0.8)
7 (1.0)
3 (0.4)
109 (1.3)
68 (0.8)
39 (0.5)
56 (0.7)
38 (0.5)
26 (0.3)
13 (0.2)
<0.0001
<0.0001
0.001
0.002
0.15
0.009
0.12
14 (1.9)
4 (0.6)
5 (0.7)
54 (0.6)
33 (0.4)
15 (0.2)
0.0006
0.53
0.02
0.
02
*
<0.0001
Systemic lupus erythematosus; †Among cases with other CHD, but without ASD, VSD, and val
valve
alvee anomalies,
anoma
mali
liess, th
thee
most frequent diagnosis in SLE offspring cases was pulmonary artery anomaly (2/4), while in control cases, it was
CHD not otherwise specified (12/34); ††Isolated is defined as a specific subtype of CHD occurring without any other
subtype
ubttyp
ypee of C
CHD
HD
23
DOI: 10.1161/CIRCULATIONAHA.114.010027
Table 3. Multivariable analyses of the risk of all types of congenital heart defects and subtypes
in the overall sample of children (n=9212) from Quebec's administrative databases, Canada,
1989-2009
Covariates
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Maternal SLE||
No
Yes
Sex
Male
Female
Education
” High school
• College
Ethnicity
Caucasian
Other
Pregestational
diabetes
No
Yes
Y
es
Gest
Ge
sttat
a ional
Gestational
ddiabetes
iab
bet
e es
No
N
o
Yes
Y
es
Hypertension
Hype
Hy
pert
r ensi
sio
on
No
Yes
Y
es
Asthma
No
Yes
Any CHD*
Odds Ratio
(95% CI†)
ASD‡
Odds Ratio
(95% CI)
VSD§
Odds Ratio
(95% CI)
Valve Anomalies
Odds Ratio
(95% CI)
Reference
2.62 (1.77, 3.88)
Reference
3.32 (1.97, 5.57)
Reference
2.50 (1.31, 4.75)
Reference
2.95 (1.23, 7.07)
Reference
1.06 (0.79, 1.42)
Reference
1.00 (0.66, 1.53)
Reference
1.30 (0.80, 2.11)
Reference
0.71 (0.35, 1.44)
Reference
0.94 (0.68, 1.30)
Reference
0.87 (0.55, 1.38)
Reference
1.16 (0.68, 1.98)
Reference
1.01 (0.47, 2.20)
Reference
1.28 (0.90, 1.81)
Reference
1.35 (0.84, 2.19)
Reference
1.47 (0.85, 2.55)
Reference
Refe
Re
fere
r nc
re
ncee
2.94)
1.30
1.
30 (0.57,
(0.57
0.57
57,, 2.
2.94
94))
Reference
2.05
2 05 (0.99, 4.23)
2.
Reference
Refereence
2.54 (1.03,
(1.03
3, 66.27)
.27)
Reference
Referenc
ce
10.17)
3.56 (1.24,
(1.
1..24
2 , 10
10.1
.17)
Reference
2.14 (0.46, 10.02)
Reference
Refeerenncee
1.17
1.117
1.
17 (0.54,
(0.
0 544, 2.54)
2.54
54))
54
Reference
Reeferennce
nce
1.01 (0.31,
1.01
(0.
0 31
3 , 33.26)
.266)
Reference
Re
efeerencce
33.05
.05
05 (1.28
(1.
1.28
28 , 77.25)
.225)
Reference
R
efeereencee
2.07 (0.48,
2.07
(0.488, 88.96)
.96
6)
Reference
R fe
Re
fere
renc
re
ncce
1 59 (0.70,
(0 70 3.64)
3 64
64))
1.59
Reference
Refe
Re
fere
fe
r nc
re
ncee
22.04
04 (0.76,
(0 76 55.53)
53))
53
Reference
Refe
Re
fere
renc
re
ncee
nc
00.56
56 (0.07,
(0 07 44.24)
24))
24
Reference
Refe
Re
f rence
00.91
91 (0.11,
(0 11 77.66)
66))
66
Reference
Reference
2.76 (1.63, 4.71) 2.00 (0.89, 4.53)
Reference
1.24 (0.38, 4.02)
Reference
4.25 (1.57, 11.53)
*
Congenital heart defects; †confidence interval; ‡atrial septal defects; §ventricular septal defects; ||systemic lupus
erythematosus
24
DOI: 10.1161/CIRCULATIONAHA.114.010027
Table 4. Adjusted effect estimates of the risk of all types of congenital heart defects and
subtypes in the overall sample of children (n=9212) and subsample excluding children with at
least one fetal echocardiography (n=8881), from Quebec's administrative databases, Canada,
1989-2009.
Sample
Any CHD*
Odds Ratio||
(95% CI†)
ASD‡
Odds Ratio||
(95% CI)
VSD§
Odds Ratio||
(95% CI)
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
All children
(n=9212)
Maternal SLE
No
Reference
Reference
Reference
Yes
2.62 (1.77, 3.88) 3.32 (1.97, 5.57) 2.50 (1.31, 4.75)
Excluding children
with •1 fetal
echocardiagraphy
(n=8881)
Maternal SLE
No
Reference
Reference
Reference
Yes
1.95 (1.18, 3.23) 2.41 (1.23, 4.75) 2.06 (0.96, 4.43)
*
Valve Anomalies
Odds Ratio||
(95% CI)
Reference
2.95 (1.23, 7.07)
Reference
R
Re
fere
fe
reenc
ncee
2.32
22.
322 (0.67,
(0.67
67, 88.05)
67
.05
05)
5)
Congenital heart defects; †confidence interval; ‡atrial septal defects; §ventricular septal defects; ||adjusted for
maternal age, calendar year, sex, education, ethnicity, pregestational diabetes, gestational diabetes, hypertension,
and
asthma
nd as
sth
thma
ma
25
DOI: 10.1161/CIRCULATIONAHA.114.010027
Table 5. Multivariable analyses of the risk of all types of congenital heart defects and subtypes
in subsample of children with public drug coverage (n=1925) in Quebec's administrative
databases, Canada, 1989-2009.
Covariates
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Maternal SLE||
No
Yes
Sex
Male
Female
Education
” High school
• College
Ethnicity
Caucasian
Other
Pregestational diabetes
No
Yes
e
Gestational
Gest
Ge
stat
st
atiiona
at
io al di
ddiabetes
ab
bet
etees
es
N
o
No
Y
es
Yes
Corticosteroids
C
Cort
orttic
i ostero
oid
ids
No
N
o
Yes
Y
es
Antimalarials
Antimalarial
alss
No
N
o
Yes
Immunosuppressives
No
Yes
Antidepressants
No
Yes
Hypertension
No
Yes
Asthma
No
Yes
Any CHD*
Odds ratio
(95% CI†)
ASD‡
Odds ratio
(95% CI)
VSD§
Odds ratio
(95% CI)
Reference
1.46 (0.53, 4.04)
Reference
2.05 (0.66, 6.37)
Reference
1.50 (0.28, 8.11)
Reference
0.88 (0.49, 1.57)
Reference
0.77 (0.36, 1.62)
Reference
0.98 (0.37, 2.66)
Reference
0.87 (0.45, 1.68)
Reference
1.07 (0.47, 2.43)
Reference
0.96 (0.33, 2.78)
Reference
0.57 (0.27, 1.18)
Reference
0.66 (0.28, 1.58)
Reference
Re
Refe
fere
fe
renc
n e
nc
0.60
600 (0.19,
(0.
0 199, 1.
11.93)
.93
93))
93
Reference
9.29)
2.99 (0.96, 9.29
9)
Reference
3.72 (0.99, 14.00)
0))
Reference
4.43 (0.85, 23.14)
Reference
Refe
Re
f reenc
fe
ncee
6.55)
22.23
2.
23 (0.76,
23
(0.76, 6.
.55))
Reference
Refere
Re
renc
re
ncee
nc
7.46)
1.68
1.
68 (0.38,
(00.38
0.388, 7.
7.46
46))
Reference
R
Re
fere
fe
reenc
n e
20.12)
55.32
.32 (1.40,
(1.
1 400, 20
20.1
12))
Reference
Re
efeere
renncee
19.34)
55.65
.65
6 (1.65,
(1.65
65,, 19
.34)
34)
Reference
Refe
R
efe
fere
r nc
re
ncee
15.75)
33.26
3.
26 (0.68,
(0.
0 68
6 , 15
15.7
75)
Reference
Ref
Re
fereencce
fere
32.54)
33.73
3.
73 (0.43,
(0.43
43,, 32
32.5
54)
Refe
Re
fere
renc
ncee
Reference
0.29 (0.01, 5.30)
Reference
Re
Refe
fere
renc
ncee
----
Reference
Refe
Re
fere
renc
ncee
0.60 (0.02, 19.96)
Reference
1.77 (0.09, 35.98)
Reference
----
Reference
3.29 (0.08, 132.49)
Reference
1.12 (0.25, 4.92)
Reference
0.98 (0.13, 7.60)
Reference
----
Reference
0.36 (0.04, 3.43)
Reference
0.62 (0.06, 6.02)
Reference
----
Reference
1.79 (0.63, 5.04)
Reference
0.46 (0.06, 3.72)
Reference
1.76 (0.32, 9.60)
*
Congenital heart defects; †confidence interval; ‡atrial septal defects; §ventricular septal defects; ||systemic lupus
erythematosus
26
DOI: 10.1161/CIRCULATIONAHA.114.010027
Table 6. Frequency of congenital heart defects with and without repair procedures among SLE
offspring and control children (n=9212) in Quebec's administrative databases, Canada, 19892009.
Types
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
SLEa offspring
(n=719)
Control children
(n=8493)
p-values
37 (5.1)
4 (0.6)
159 (1.9)
6 (0.1)
<0.0001
0.005
21 (2.9)
2 (0.3)
68 (0.8)
3 (0.0)
<0.0001
0.052
12 (1.7)
1 (0.1)
56 (0.7)
2 (0.0)
0.002
0.22
7 (1.0)
0 (0)
26 (0.3)
0 (0)
0.009
-----
Congenital heart defects (CHD), n (%)
All CHD
CHD with repair procedures
Atrial septal defects (ASD), n (%)
All ASD
ASD with repair procedures
Ventricular septal defects (VSD), n (%)
All VSD
VSD with repair procedures
Cardiac valve anomalies, n (%)
All valve anomalies
Valve anomalies with repair procedures
27
Increased Congenital Heart Defects in Children Born to Women with Systemic Lupus
Erythematosus: Results from the Offspring of Systemic Lupus Erythematosus Mothers Registry
Study
Évelyne Vinet, Christian A. Pineau, Susan Scott, Ann E. Clarke, Robert W. Platt and Sasha Bernatsky
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Circulation. published online October 29, 2014;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/early/2014/10/29/CIRCULATIONAHA.114.010027
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2014/10/29/CIRCULATIONAHA.114.010027.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
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SUPPLEMENTAL MATERIAL
Title:
Increased Congenital Heart Defects in Children Born to
Women with Systemic Lupus Erythematosus: Results
from the Offspring of Systemic Lupus Erythematosus Registry
Study
Authors:
Évelyne Vinet1,2, MD; Christian A. Pineau2, MD; Susan
Scott1, MSc; Ann E. Clarke1,3, MD, MSc; Robert W. Platt4,
PhD; Sasha Bernatsky1,2, MD, PhD.
Table of content
Supplemental methods................................................................................................page 2
Supplemental results...................................................................................................page 3
Table 1S. Diagnostic codes for congenital heart defects............................................page 5
Table 2S. Race/ethnicity definitions...........................................................................page 6
Table 3S. Repair procedure codes..............................................................................page 7
1
Supplemental Methods
For this study, we worked in collaboration with the “Régie de l’Assurance
Maladie du Québec (RAMQ)” which manages both the MED-ECHO and physician
billing databases. The RAMQ employs skilled data analysts, who extracted the data,
according to our pre-specified requirements, to create the exact dataset needed for our
study. Only information judged useful for the conduct of the study was transmitted to the
research team, as data managed by the RAMQ is highly restricted by the "Commission
d'accès à l'information du Québec". Therefore, we only had access to the cohort once it
was created. We verified that the cohort conformed to our selection criteria (i.e.
appropriate SLE case definition, matching with controls, etc). However, we do not have
information on women who were not included in our study and could not produce a flow
diagram illustrating the subject selection from the source population.
Stillbirths were not included in our analyses because a significant proportion of
stillbirths in Quebec result from pregnancy termination, for which no information on the
outcome of interest is recorded. In Quebec, information on stillbirths are recorded based
on the following definition: death prior to the complete expulsion or extraction from its
mother of a product of conception weighing 500 or more grams, regardless of the
gestational age. Since pregnancy terminations are performed up to 24 weeks of gestation
in Quebec, some fetal deaths are labeled as stillbirths even if they result from a pregnancy
termination.
In a matched cohort study, ignoring the matching variables can leave bias if there
are additional confounders, even when controlling for these additional confounders.
2
Therefore, control for the matching variables is needed when dealing with matched
cohort data, although a matched analysis per se is not required.[1]
Models estimated with generalized estimating equations account for the
correlation in outcomes of children born to the same mother (i.e. the probability of a
congenital anomaly is higher when a sibling has been affected), with each mother serving
as the clustering unit.[2]
Multiple imputation was performed assuming an arbitrary missing pattern, using a
multivariable normal approach via the Markov chain Monte Carlo method, and included
the same covariates as the primary multivariable model. Multivariable analysis results
were very similar using either the dataset with missing data or the imputed dataset.
We compared means between SLE offspring and control children with a t-test and
proportions with a chi-square test, unless cells were too sparse, in which case we used a
two-sided Fisher’s exact test.
Results
There were 10 stillbirths among 729 SLE births (1.4%, 95% CI 0.7, 2.6) and 49
stillbirths among 8542 control births (0.6%, 95% CI 0.4, 0.8). For all stillbirths, cause of
death was identified in the mandatory stillbirth report form. In the SLE group, one
stillbirth was due to pregnancy termination, while no stillbirth was attributed to CHD. In
the control group, two stillbirths were due to pregnancy terminations, while one stillbirth
was attributed to CHD. The effect estimate for CHD did not change when we included
stillbirths in the overall analysis (OR 2.80, 95% CI 1.94, 4.04).
3
References
1. Sjölander A, Greenland S. Ignoring the matching variables in cohort studies - when is
it valid and why? Stat Med. 2013 Nov 30;32(27):4696-708.
2. Hanley JA, Negassa A, Edwardes MD, Forrester JE. Statistical analysis of correlated
data using generalized estimating equations: an orientation. Am J Epidemiol.
2003;157(4):364-75.
4
Table 1S. Diagnostic codes for congenital heart defects
Type of congenital anomaly
ICD*-9 codes
ICD-10 codes
Congenital heart defect
745, 746, 7471‐7474
Q20‐Q26 excluding Q24.6, Q25.0
Ventricular septal defect
7454
Q210
Atrial septal defect
7455
Q211
Cardiac valve anomaly
746.0-746.6
Q22, Q23
*International Classification of Diseases (ICD)
5
Table 2S. Race/ethnicity definitions
Race/Ethnicity
Caucasian
Definition
If both maternal and paternal birthplaces are in Canada, United
States, or Europe (excluding Spain) with language at home and maternal
language being English, French, or another language spoken in Europe
(excluding Spanish)
Other
If both maternal and paternal birthplaces are not in Canada, United
States, nor Europe (excluding Spain) and/or
If language at home and maternal language is not English, French, or
another language spoken in Europe (excluding Spanish)
6
Table 3S. Repair procedure codes
Type of congenital anomaly
Repair procedure codes*
Congenital heart defects
47.01-47.97
Cardiac septal defects
47.51-47.55, 47.61-47.64, 47.71-47.74, 47.95
Cardiac valve anomalies
47.01-47.29, 47.96, 47.97
*Reference: Classification canadienne des actes diagnostiques, thérapeutiques, et
chirurgicaux. Institut canadien d'information sur la santé - CCI. 2004.
http://secure.cihi.ca/cihiweb/dispPage.jsp?cw_page=codingclass_cci_f (last accessed
March 4th, 2014)
7
8